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Posts Tagged ‘Pulmonary hypertension’


Author and Reporter: Anamika Sarkar, Ph.D.

Nitric Oxide (NO) is highly regulated in the blood such that it can be released as vasodilator when needed. The importance and pathway of Nitric Oxide has been nicely reviewed by. “Discovery of NO and its effects of vascular biology”. Other articles which are good readings for the importance of NO are  – a) regulation of glycolysis b) NO in cardiovascular disease c) NO and Immune responses Part I and Part II d) NO signaling pathways. The  effects of NO in diseased states have been reviewed by the articles – “Crucial role of Nitric Oxide in Cancer”, “Nitric Oxide and Sepsis, Hemodynamic Collapse, and the Search for Therapeutic Options”.. (Also, please see Source for more articles on NO and its significance).

Computational models are very efficient tools to understand complex reactions like NO towards physiological conditions. Among them wall shear stress is one of the major factors which is reviewed in the article – “Differential Distribution of Nitric Oxide – A 3-D Mathematical Model”.

Moreover, decrease in availability of NO can lead to many complications like pulmonary hypertension. Some of the causes of decrease in NO have been identified as clinical hypertension, right ventricular overload which can lead to cardiac heart failure, low levels of zinc and high levels of cardiac necrosis.

Sickle Cell disease patients, a hereditary disease, are also known to have decreased levels of NO which can become physiologically challenging. In USA alone, there are 90,000 people who are affected by Sickle cell disease.

Sickle cell disease is breakage of red blood cells (RBC) membrane and resulting release of the hemoglobin (Hb) into blood plasma. This process is also known as Hemolysis. Sickle cell disease is caused by single mutation of Hb which changes RBC from round shape to sickle or crescent shapes (Figure 1).

Image

Figure 1 (A) shows normal red blood cells flowing freely through veins. The inset shows a cross section of a normal red blood cell with normal hemoglobin. Figure 1 (B) shows abnormal, sickled red blood cells The inset image shows a cross-section of a sickle cell with long polymerized HbS strands stretching and distorting the cell shape. Image Source: http://en.wikipedia.org/wiki/Sickle-cell_disease

Sickle Cell RBCs has much shorter life span of 10-20 days when compared with normal RBCs 100-120 days lifespan. Shorter life span of Sickle cell disease RBC’s are compensated by bone marrow generation of new RBCs. However, many times new blood generation cannot cope with the small life span of Sickle cell RBCs and causes pathological condition of Anemia.

RBCs generally breakdown and release Hbs in blood plasma after they reach their end of life span. Thus, in case of Sickle cell disease, there is more cell free Hb than normal. Furthermore, it is known that NO has a very high affinity towards Hbs, which is one of the ways free NO is regulated in blood. As a result presence of larger amounts of cell free Hb in Sickle cell disease lead to less availability of NO.

However, the question remained “what is the quantitative relationship between cell free Hb and depletion of NO. Deonikar and Kavdia (J. Appl. Physiol., 2012) addressed this question by developing a 2 dimensional Mathematical Model of a single idealized arteriole, with different layers of blood vessels diffusing nutrients to tissue layers (Figure 2:  Deonikar and Kavdia Figure 1).

Image

cell free Hb in 2 dimensional representations of blood vessels.

The authors used steady state partial differential equation of circular geometry to represent diffusion of NO in blood and in tissues. They used first and second order biochemical reactions to represent the reactions between NO and RBC and NO autooxidation processes. Some of their reaction model parameters were obtained from literature, rest of them were fitted to experimental results from literature. The model and its parameters are explained in the previously published paper by same authors Deonikar and Kavdia, Annals of Biomed., 2010. The authors found that the reaction rate between NO and RBC is 0.2 x 105, M-1 s-1 than 1.4 x 105, M-1 s-1 as reported before by Butler et.al., Biochim. Biophys. Acta, 1998.

Their results show that even small increase in cell free Hb, 0.5uM, can decrease NO concentrations by 3-7 folds approximately (comparing Fig1(b) and 1(d) of Deonikar and Kavdia, 2012, as shown in Figure 2 of this article). Moreover, their mathematical analysis shows that the increase in diffusion resistance of NO from vascular lumen to cell free zone has no effect on NO distribution and concentration with available levels of cell free Hb.

Deonikar and Kavdia’s mathematical model is a simple representation of actual physiological scenario. However, their model results show that for Sickle cell disease patients, decrease in levels of bioavailable NO is an attribute to cell free Hb, which is in abundant for these patients. Their results show that small increase by 0.5 uM in cell free Hb can cause large decrease in NO concentrations.

These interesting insights from the model can help in further understanding in the context of physiological conditions, by replicating experiments in-vivo and then relating them to other known diseases of Sickle cell disease patients like Anemia, Pulmonary Hypertension. Further, drugs can be targeted towards decreasing free cell Hbs to keep balance in availability of NO, which in turn may help in other related disease like Pulmonary Hypertension of Sickle Cell disease patients.

Sources:

Deonikar and Kavdia (2012) :http://www.ncbi.nlm.nih.gov/pubmed/22223452

Previous model explaining mathematical representation and parameters used in the model :Deonikar and Kavdia, Annals of Biomed., 2010.

Previous paper stating reaction rate of Hb and NO: Butler et.al., Biochim. Biophys. Acta, 1998.

Causes of decrease in NO

Clinical Hypertension : http://www.ncbi.nlm.nih.gov/pubmed/11311074

Right ventricular overload : http://www.ncbi.nlm.nih.gov/pubmed/9559613

Low levels of zinc and high levels of cardiac necrosis : http://www.ncbi.nlm.nih.gov/pubmed/11243421

Sickle Cell Source:

http://en.wikipedia.org/wiki/Sickle-cell_disease

http://www.nhlbi.nih.gov/health/health-topics/topics/sca/

NO Source:

Differential Distribution of Nitric Oxide – A 3-D Mathematical Model:

Discovery of NO and its effects of vascular biology

Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Nitric oxide: role in Cardiovascular health and disease

NO signaling pathways

Nitric Oxide and Immune Responses: Part 1

Nitric Oxide and Immune Responses: Part 2

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation

https://pharmaceuticalintelligence.com/2012/10/08/statins-nonlipid-effects-on-vascular-endothelium-through-enos-activation/

Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

Nitric Oxide, Platelets, Endothelium and Hemostasis

Crucial role of Nitric Oxide in Cancer

The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure

Nitric Oxide and Sepsis, Hemodynamic Collapse, and the Search for Therapeutic Options

NO Nutritional remedies for hypertension and atherosclerosis. It’s 12 am: do you know where your electrons are?

Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Endothelial Function and Cardiovascular Disease

Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Endothelial Dysfunction, Diminished Availability of cEPCs,  Increasing  CVD Risk – Macrovascular Disease – Therapeutic Potential of cEPCs

Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

 

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Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Author: Larry H. Bernstein, MD

 

This review identifies the complex interactions and underlying regulatory balances/imbalances between the mechanism of vasorelaxation and vasoconstriction of vascular endothelium by way of nitric oxide (NO), prostacyclin, in response to oxidative stress and intimal injury.

A series of related topics have been covered in this Scientific Web Site: http://pharmaceuticalintelligence.com on the Nitric Oxide series:
Nitric oxide: role in Cardiovascular health and disease
The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure

Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

Intravascular Stimulation of Autonomics: A Letter from Dr. Michael Scherlag

Will these findings impact the Clopidogrel market?

Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs

Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB

Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Nitric Oxide Signalling Pathways

Age-Dependent Depression in Circulating Endothelial Progenitor Cells in Coronary Artery Bypass Grafting Patients

Nitric Oxide: The Nobel Prize in Physiology or Medicine 1998 Robert F. Furchgott, Louis J. Ignarro, Ferid Murad

Nitric Oxide and Platelet Aggregation

Obstructive coronary artery disease diagnosed by RNA levels of 23 genes – CardioDx heart disease test wins Medicare coverage

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents

Nitric Oxide: Chemistry and function

Nitric Oxide: a short historic perspective

Human Embryonic-Derived Cardiac Progenitor Cells for Myocardial Repair

Nitric Oxide production in Systemic sclerosis

Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Endothelial Differentiation and Morphogenesis of Cardiac Precursors

Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Progenitor Cells endogenous augmentation

Nitric Oxide in bone metabolism

Circulating Endothelial Progenitor Cells Milestones in the research on Circulating Endothelial Progenitor Cells as diagnostic markers of cardiovascular risk have been reported in NEJM

Transcription Factor Lyl-1 Critical in Producing Early T-Cell Progenitors

Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

Treatment of Refractory Hypertension via Percutaneous Renal Denervation

Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Study Finds Low Methylation Regions Prone to Structural Mutation

Atherosclerosis, studied extensively, has common features in the aorta, coronary, carotid and peripheral arteries. There is commonality in morphology of atheromatous plaques, the degree of thrombus formation and types of ensuing ischemic events, therefore, plaque disruption, the degree of thrombus formation and types of ensuing ischemic coronary syndromes of patients have been extensively studied. A concept of unstable atherosclerotic plaques that are amenable to rupture is central to acute myocardial infarction, stroke, aortic aneurysm and sequellae, and peripheral artery disease. These unstable atherosclerotic plaques: plaques with an unstable morphology are essential to the onset of unstable coronary artery disease. Plaque formation results from complex cellular interactions in the intima of arteries, which take place between resident cells of the vessel wall (smooth muscle cells and endothelial cells) and cells of the immune system (leukocytes). Local flow disturbances, extracellular matrix composed of lipids and debris are defining characteristics of the ‘atheroma’.
Inflammation and repair are key events in the natural course of atherosclerosis, and inflammatory cells have profound effects on the integrity of the plaques . Smooth muscle cells produce by far most of the extracellular matrix components of a plaque. Transforming growth factor beta (TGF-β) is one of the most potent stimulators of connective tissue production by smooth muscle cells, and large amounts of this growth factor are detected in restenosis lesions after PTCA.
Atherosclerotic plaque rupture – pathologic basis of plaque stability and instability. AC Newby, P Libby, and AC. van der Wal. Cardiovasc Res 1999; 41 (2): 334-344. doi: 10.1016/S0008-6363(98)00276-4. Vascular endothelium acts as a paracrine/endocrine organ by secreting a wide range of biologically active mediators that play a key role in regulating immune responses, vascular tone and coagulation, and act on adjacent smooth muscle cells, monocytes, macrophages, fibroblasts and organ specific cells.

The key culprits include:

VASODILITATION

  • vasodilators (prostacycline (PGI2),
  • nitric oxide (NO),
  • endothelium-derived relaxing factor (EDRF) ) and
  • cardiac specific natriuretic peptides;

The chemical nature of EDRF was not known until Palmer, Ferrige and Moncada demonstrated that nitric oxide accounted for most if not all of the biological activity of EDRF. Both EDRF and NO act through the stimulation of soluble guanylate cyclase and subsequent formation of cyclic GMP (cGMP). Cyclic GMP activates cGMP-dependent protein kinases and leads to dephosphorylation of myosin light chains and muscle relaxation.

Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327:524-6.

Waldman SA, Murad F. Cyclic GMP synthesis and function. Pharma Rev 1987; 39:163-96.

Gryglewski RJ, Botting RM, Vane JR. Mediators produced by the endothelial cell. Hypertension 1988; 12:530-48.

VASOCONSTRICTION

  • vasoconstrictors (endothelin-1 (ET), thromboxane A2, prostaglandin H2 and components of renin-angiotensin system);
  • pro- and anti-thrombotic factors (tissue factor, platelet activating factor (PAF), von Willebrand factor (vWf ) );
  • fibrinolytic activators and inhibitors (tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1));
  • arachidonate metabolites (prostanoids)( Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids, e.g. arachidonic acid (20:4 n 6, AA). Biologically active prostanoids deriving from AA include stable prostaglandins (PGs), e.g. PGE(2), PGF(2alpha), PGD(2), PGJ(2) as well as labile prostanoids, i.e. PG endoperoxides (PGG(2), PGH(2)), thromboxane A(2) (TXA(2)) and prostacyclin (PGI(2)). Stable PGs regulate smooth muscle tone and also modulate inflammatory and immune reactions in this context. PG endoperoxides are intermediates in biosynthesis of all prostanoids. Gryglewski RJ. Prostacyclin among prostanoids. Pharmacol Rep. 2008 Jan-Feb;60(1):3-11.
  • leukocyte adhesion molecules (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, P-selectin);
  • multiple cytokines transforming growth factor, proinflammatory and anti-inflammatory mediators, tumour necrosis factor, chemokines and steroids.
  • HU Rehman. Vascular Endothelium as an Endocrine Organ. Proc R Coll Physicians Edinb 2001; 31:149-154.

Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids (n-6 PUFAs), e.g. arachidonic acid (20:4 n 6, AA). Labile Thromboxane A(2) (TXA(2)) ( half life of 30 s at 37 degrees C), generated by platelets has powerful vasoconstrictor, cytotoxic and thrombogenic properties.

Prostacyclin (PGI(2)) with a half life of 4 min at 37 degrees C  is produced by the vascular wall (predominantly by the endothelium) and is a physiological antagonist of TXA(2), and is a powerful cytoprotective agent that exerts its action through activation of adenylate cyclase. PGI(2) acts in concert with the system consisting of NO synthase (eNOS)/nitric oxide free radical (NO)/guanylate cyclase/cyclic-GMP. Both cyclic nucleotides (c-AMP and c-GMP) act in synergy as two energetic fists which defend the cellular machinery from being destroyed by endogenous or exogenous aggressors.

Recently, a new partner has been recognized in this endogenous defensive squadron, i.e. a system involving heme oxygenase (HO-1) and carbon monoxide (CO). The expanding knowledge on the pharmacological steering of this enzymic triad (PGI(2)-S/eNOS/HO-1) is likely to contribute to the rational therapy of many systemic diseases such as

  • atherosclerosis,
  • diabetes mellitus,
  • arterial hypertension or
  • Alzheimer diseases.

The discovery of prostacyclin broadened our pathophysiological horizon, and by itself opened new therapeutic possibilities.Gryglewski RJ. Prostacyclin among prostanoids. Pharmacol Rep. 2008 Jan-Feb;60(1):3-11.

Circulating and tissue endothelin immunoreactivity correlate with the severity of atherosclerosis. In patients presenting with stable and unstable angina, circulating endothelin concentrations are elevated in the setting of acute myocardial infarction. Plasma endothelin concentrations are also elevated in patients with moderate to severe congestive heart failure and correlate with the severity of the symptoms.

The vasculature of the kidney is about ten times more sensitive than that of other organs to the vasoconstrictor effects of ET-1. Endothelin affects several aspects of renal function, including

  • vasoconstriction,
  • regulation of tubule function,
  • cellular proliferation and
  • matrix production.

Endothelin is also involved in the pathogenesis of glomerulosclerosis.
Komuro I, Kurihara H, Sugiyama T et al. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett 1988; 238:249-52. Miyauchi T, Yanagisawa M, Tomizawa T et al. Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet 1989; 2(8653):53-4.

Physical or chemical damage to the cell membrane results in the release of prostacyclin. Other stimulators of prostacyclin release are

  • bradykinin,
  • thrombin,
  • serotonin,
  • platelet-derived growth factor (PDGF),
  • interleukin-1 and
  • adenine nucleotides.

Prostacyclin acts in a paracrine manner, on the abluminal side causing relaxation of the underlying smooth muscle and in the lumen, preventing platelets clumping onto the endothelium. Vasodilator and anti-platelet actions of prostacyclin are mediated by an increase in the concentrations of cyclic adenosine monophosphate (AMP) in smooth muscle cells and platelets. Aspirin and similar substances prevent prostacyclin formation, but have little effect on normal blood pressure.

This discussion has outlined how the vascular system establishes a tight regulation over the production of these endothelium derived vasoactive factors. Its loss allows local or generalized modifications of the vascular tone. This dysregulation is involved in the pathogenesis of

  • hypertension,
  • atherosclerosis,
  • diabetes mellitus and
  • other vasospastic disorders.

HU Rehman. Vascular Endothelium as an Endocrine Organ. Proc R Coll Physicians Edinb 2001; 31:149-154.

Epicrisis

This discussiion is at the limit of comprehension in one sitting. There is much investigation into the complex issue involving interacting biological regulatory pthaways that intersect among major disease categories, which makes targeting of therapies better, but also limited in the ability to achieve meaningful success. That is a topic for further discussion.

I can say with confidence that the story here is incomplete. The final effective solution will require that we tie together the legs of a three legged stool.

The first leg is genomic, which has not reaped as much benefit as we would like, but the successes generate epectations of better.

The second stool is in the opposing balance of nucleotides involved with vascular tone, such as GMP and the action of prostacyclins.

The third led is off the ledger, but will be developed in detail. This involves the essential role of sulfur, in H2S and in the methylation process, in the interpretation of homocysteine levels in the circulation, in the action of Acetyl CoA, S-adenosyl methionine, and GSH, which requires a knowledge of palnt and protein sources of sulfur amino acids, and variable soil conditions.

There also needs to be an understanding of commonalites between

  • infection,
  • metabolic syndrome,
  • immune-mediated inflammatory disease,
  • HIV wasting, and
  • cancer cachexia as importantly as their separatory features.

There are a few more resources to finish the discussion of NO and prostacyclin. Atherogenesis leads to decreased bioactivity of NO and this, in turn, can precipitate enhanced cell adhesion, proliferation, vasoconstriction and accelerate the generation of atherosclerotic lesions.

It is possible that some of the detrimental effects of atherosclerosis on the NO pathway result from the generation of secondary oxidants such as peroxynitrite, a product of the reaction of NO with superoxide. The pharmacologic strategies including

  • the stimulation of generation of endogenous NO,
  • NO-replacement therapy and
  • decreasing oxidative stress may be useful for ameliorating the clinical course of atherosclerosis.

MW Radomski, E Salas. Nitric oxide— biological mediator, modulator and factor of injury: its role in the pathogenesis of atherosclerosis.Atherosclerosis 1995; 118: S69–S80. (Supplement) http://dx.doi.org/10.1016/0021-9150(95)90075-6,

  • The interactions between endothelium-derived nitric oxide (NO) and prostacyclin as inhibitors of platelet aggregation were examined.
  • Porcine aortic endothelial cells released NO in quantities sufficient to account for the inhibition of platelet aggregation
  • small amounts of prostacyclin and EDRF which synergistically inhibited platelet aggregation.
  • A reciprocal potentiation of both the anti- and the disaggregating activity was also observed between low concentrations of prostacyclin and authentic NO or EDRF released from endothelial cells.
  • It is likely that interactions between prostacyclin and NO released by the endothelium play a role in the homeostatic regulation of platelet-vessel wall interactions.

MW Radomski, RMJ Palmer & S Moncada. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide.  Br. J. Pharmac (1987), 92, 639-646.

The activity of guanylate cyclase is altered to a much larger degree than adenylate cyclase, while cyclic nucleotide phosphodiesterase activity remains unchanged. During the early phases of thrombin- and ADP-induced platelet aggregation a marked activation of the guanylate cyclase occurs whereas aggregation induced by arachidonic acid or epinephrine results in a rapid diminution of this activity.
AJ Barbera. Cyclic nucleotides and platelet aggregation effect of aggregating agents on the activity of cyclic nucleotide-metabolizing enzymes. Biochimica et Biophysica Acta (BBA) – General Subjects 1976; 444(2):579–595.
http://dx.doi.org/10.1016/0304-4165(76)90402-5,

  • We examined the effect of endothelin-1 (ET-1) on basal and isoprenaline-enhanced L-type Ca2P current (ICaL) in guinea-pig ventricular myocytes under nystatin-perforated patch configuration.
  • ET-1 at concentrations of 5 nm had little effect on basal ICa,L, but Ica,L was enhanced by isoprenaline (500 nM) and was significantly attenuated by 5 nm ET-1 by more than 50 %. This effect was reversed upon washout. ICaL enhanced by forskolin was also decreased by ET-1.
  • The inhibitory effect of ET-1 against isoprenaline was completely blocked by the ETA receptor antagonist BQ-123 (1 /LM).
  • Although ET-1 has been shown to activate specific protein kinase C (PKC) isoforms, a significant inhibitory effect of ET-1 was maintained in the presence of the PKC inhibitor bisindolylmaleimide (20 nM). The nitric oxide (NO) donor SIN-1 (10 AM) attenuated but failed to prevent the ET- 1 effect.
  • In summary, our results demonstrate that ET-1 has no effects on basal ica,L. However, it exerts a potent inhibitory effect against isoprenaline-enhanced Ica,L. This effect is mediated through ETA receptors coupled to PTX-sensitive G-proteins and occurs in the presence of PKC inhibition and NO generation.

GP Thomas, SM Sims, M Karmazyn. Differential effects of endothelin- 1 on basal and isoprenaline-enhanced Ca2+ current in guinea-pig ventricular myocytes.  Journal of Physiology 1997;503(1):55-65

(L-arginine methyl ester) L-NAME-sensitive component of endothelium-dependent relaxation was investigated in the preconstricted femoral arteries during isometric conditions as a difference between acetylcholine-induced relaxation before and after acute NG-nitro-L-arginine methyl ester pre-treatment (L-NAME, 10-5 mol/l). Acetylcholine induced vasorelaxation of SHR was significantly greater than that in control WKY. There was a significant positive correlation between BP and L-NAME-sensitive component of relaxation of the femoral artery. There si absence of endothelial dysfunction in the femoral artery of adult borderline and spontaneously hypertensive rats and gradual elevation of L-NAME-sensitive component of vasorelaxation with increasing blood pressure.

A Puzserovap, Z Csizmadiova, I Bernatova. Effect of Blood Pressure on L-NAME-sensitive Component of Vasorelaxation in Adult Rats.  Physiol. Res. 2007:56 (Suppl. 2): S77-S84.

This review concerns the role of nitric oxide (NO) in the pathogenesis of different models of experimental hypertension (NO-deficient, genetic, salt-dependent), which are characterized by a wide range of etiology. Although the contribution of NO may vary between different models of hypertension, a unifying characteristic of these models is the presence of oxidative stress that participates in the maintenance of elevated arterial pressure and seems to be a common denominator underlying endothelial dysfunction in various forms of experimental hypertension. Besides the imbalance between the endothelial production of vasorelaxing and vasoconstricting compounds as well as the relative insufficiency of vasodilator systems to compensate augmented vasoconstrictor systems, there were found numerous structural and functional abnormalities in blood vessels and heart of hypertensive animals.

J Torok. Participation of Nitric Oxide in Different Models of Experimental Hypertension. Physiol. Res. 2008; 57: 813-825.

Cardiac NO–sGC-cGMP signaling blunts cardiac stress responses, including pressure overload–induced hypertrophy. The latter itself depresses signaling through this pathway by reducing NO generation and enhancing cGMP hydrolysis. Pressure overload depresses NO/heme-dependent sGC activation in the heart, consistent with enhanced oxidation. The data reveal a novel additional mechanism for reduced NO-coupled sGC activity related to dynamic shifts in membrane microdomain localization, with Cav3-microdomains protecting sGC from heme-oxidation and facilitating NO responsiveness. Translocation of sGC out of this domain favors sGC oxidation and contributes to depressed NO-stimulated sGC activity.

EJ Tsai, Y Liu, N Koitabashi, D Bedja, et al. Pressure-Overload–Induced Subcellular
Relocalization/Oxidation of Soluble Guanylyl Cyclase in the Heart Modulates Enzyme Stimulation. Circ Res. 2012;110:295-303.

From the studies in several laboratories, we suggest the following mechanisms for the possible regulation of guanylate cyclase activity:

  • factors that could alter the apparent cooperative nature of the enzyme,
  • interactions of metal ions with the substrate or enzyme,
  • factors that could overcome inhibition by ATP,
  • mechanisms that could regulate the interconversion of latent and active forms of the enzyme,
  • possible translocation of particulate and soluble forms of the enzyme, and
  • induction or repression of the enzyme.

H Kimura, F Murada. Two forms of guanylate cyclase in mammalian tissues and possible mechanisms for their regulation. Metabolism 1975; 24(3): 439–445.

 

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Author: Larry Bernstein, MD

 

Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care.  2009;  13(3): 221. Published online 2009 May 29. doi:  10.1186/cc7734. PMCID: PMC2717403.

This article is modified from a review series on Gaseous mediators, edited by Peter Radermacher.  Other articles in the series can be found online athttp://ccforum.com/series/gaseous_mediators

 

Part I.   Basic and downstream effects of inhaled NO

Inhaled nitric oxide (NO), a mediator of vascular tone produces pulmonary vasodilatation with low pulmonary vascular resistance. The route of administration delivers NO selectively improving oxygenation. Developments in our understanding of the cellular and molecular actions of NO may help to explain the results of randomised controlled trials of inhaled NO.

Introduction

Nitric oxide (NO), a determinant of local blood flow is formed by the action of NO synthase (NOS) on L-arginine in the presence of molecular oxygen. Inhaled NO results in preferential pulmonary vasodilatation it lowers pulmonary vascular resistance (PVR), correcting hypoxic pulmonary vasoconstriction (HPV). However, in the therapeutic use of gaseous NO to patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and related conditions, evidence of a benefit is disappointing.

Administration of inhaled nitric oxide to adults

The licensed indication of inhaled NO is restricted to persistent pulmonary hypertension in neonates. Pharma-ceutical NO is costly, and raises concerns over potential adverse effects of NO. Therefore, an advisory board under the auspices of the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists published recommendations in 2005 [1]. The sponsor had no authorship or editorial control over the content of the meetings or any subsequent publication.

The NO is administered as a NO/nitrogen mixture to the tubing of ventilated patients, and the NO and NO2 concen-trations are monitored, with methemoglobin levels measured regularly. Even though rapid withdrawal induces rebound pulmonary hypertension, it is avoided by gradual withdrawal [2]. There is variation in vasodilatory response to administered NO between patients [2] and in the same patient, and there is a leftward shift in the dose-response curve with use. Toxicity and loss of the therapeutic effect is a risk of excessive NO administration [3]. A survey of 54 intensive care units in the UK as well as results of a European survey revealed that the most common usage was in treating ARDS, followed by pulmonary hypertension [4], [5]. The only use of therapeutic inhaled NO usage in US adult patients reported from a single medical site (2000 to 2003) reveals that the most common application was in the treatment of RVF in patients after cardiac surgery and then, in surgical and medical patients for refractory hypoxemia[6].

Inhaled nitric oxide in acute lung injury and acute respiratory distress syndrome

ALI and ARDS are characterised by hypoxemia despite high inspired oxygen (PaO2/FiO[arterial partial pressure of oxygen/fraction of inspired oxygen] ratios of less than 300 mm Hg [40 kPa] and less than 200 mm Hg [27 kPa], respectively) in the context of evidence of pulmonary edema, and the absence of left atrial hypertension suggestive of a cardiogenic mechanism [7]. Pathologically, there is alveolar inflammation and injury leading to increased pulmonary capillary permeability and a serous alveolar fluid with inflammatory infiltrate. This is manifest clinically as hypoxemia, inadequate alveolar perfusion, venous-arterial shunting, atelectasis, and reduced compliance.

Since 1993, when the first investigation on the effects of NO on adult patients with ARDS was published [8], there have been several randomised controlled trials (RCTs) examining the effect in ALI/ARDS  ​(Table 1). The first systematic review and meta-analysis [9] found no beneficial effect on mortality or ventilator-free days. A more recent meta-analysis that considered 12 RCTs with a total of 1,237 patients [10] concluded: [1] no mortality benefit, [2] improved oxygenation at 24 hours (13% improvement in PaO2/FiOratio) at the cost of increased risk of renal dysfunction (relative risk 1.50, 95% confidence interval 1.11 to 2.02). Based on a trend to increased mortality in patients receiving NO, the authors suggested that it not be used in ALI/ARDS.  Why the NO fails to improve patient outcomes requires clarifying the effects of inhaled NO that occur outside the pulmonary vasculature.

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Table 1

Studies of inhaled nitric oxide in adult patients with acute lung injury/acute respiratory distress syndrome

The biological action of inhaled nitric oxide

NO was first identified as an endothelium-derived growth factor (EDGF) and an important determinant of local blood flow [11]. NO reacts very rapidly with free radicals, certain amino acids, and transition metal ions. The action of NOS on the semi-essential amino acid L-arginine in the presence of molecular oxygen and its identity with EDGF was the basis for the Nobel discovery of Furthgott and others [12]. Three isoforms of NO are: neuronal NOS, inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). Calcium-independent iNOS generates higher concentrations of NO [13] than the other isoforms and its role has been implicated in the pathogenesis septic shock.

Exogenous NO is administered by controlled inhalation or through intravenous administration of NO donors. It was thought to have no remote or non-pulmonary effects. The effect NO has on circulating targets is shown. (Figure 1).

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Figure 1

New paradigm of inhaled nitric oxide (NO) action. Figure 1 illustrates the interactions between inhaled NO and the contents of the pulmonary capillaries. Although NO was considered to be inactivated by hemoglobin (Hb), proteins including Hb and albumin contain reduced sulphur (thiol) groups that react reversibly with NO causing it to lose its vasodilating properties. A stable derivate, in the presence of oxyhemoglobin, is formed by a reaction resulting in nitrosylation of a cysteine residue of the β subunit of Hb.  The binding of NO to the heme iron predominates in the deoxygenated state [14]. If circulating erythrocytes store and release NO peripherally in areas of low oxygen tension, this augments peripheral blood flow and oxygen delivery via decreased systemic vascular resistance [15]. Thus, NO can act as an autocrine or paracrine mediator but when stabilised may exert endocrine influences [16]. In addition to de novo synthesis, supposedly inert anions nitrate (NO3) and nitrite (NO2) can be recycled to form NO, and nitrite might mediate extra-pulmonary effects of inhaled NO [17]. In the hypoxic state, NOS cannot produce NO and deoxy-hemoglobin catalyses NO release from nitrite, potentially providing a hypoxia-specific vasodilatory effect. Given that effects of inhaled NO are mediated in part by S-nitrolysation of circulating proteins, therapies aiming at directly increasing S-nitrosothiols have been developed.

Introduce another effect. When inhaled with high concentrations of oxygen, gaseous NO slowly forms the toxic product NO2, but other potential reactions include nitration (addition of NO2+), nitrosation (addition of NO+), or nitrosylation (addition of NO), and reaction with reactive oxygen species such as superoxide to form reactive nitrogen species (RNS) such as peroxynitrite (ONOO). These reactions of NO, potentially cytotoxic NO2 , and covalent nitration of tyrosine in proteins by RNS lead to measures of oxidative stress.

In a small observational study, inhaled ethyl nitrite safely reduced PVR without systemic side effects in persistent pulmonary hypertension of the newborn [18]. In animal models, pulmonary vasodilatation was maximal in hypoxia and had prolonged duration of action after cessation of administration [19].

References

  1. Germann P, Braschi A, Della Rocca G, Dinh-Xuan AT, et al. Inhaled nitric oxide therapy in adults: European expert recommendations.  Intensive Care Med. 2005;31:1029–1041. [PubMed]
  2. Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. 2005;353:2683–2695. [PubMed]
  3. Gerlach H, Keh D, Semmerow A, Busch T, et al. Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Am J Respir Crit Care Med. 2003;167:1008–1015. [PubMed]
  4. Cuthbertson BH, Stott S, Webster NR. Use of inhaled nitric oxide in British intensive therapy units. Br J Anaesth. 1997;78:696–700.[PubMed]
  5. Beloucif S. A European survey of the use of inhaled nitric oxide in the ICU. Working Group on Inhaled NO in the ICU of the European Society of Intensive Care Medicine. Intensive Care Med. 1998;24:864–877.[PubMed]
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  7. Bernard GR, Artigas A, Brigham KL, Carlet J,et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818–824. [PubMed]
  8. Rossaint R, Falke KJ, López F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med.1993;328:399–405. [PubMed]
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  10. Adhikari NK, Burns KE, Friedrich JO, Granton JT, Cook DJ, Meade MO. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis.  BMJ. 2007;334:779.[PMC free article] [PubMed]
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Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care.  2009;  13(3): 221. Published online 2009 May 29. doi:  10.1186/cc7734. PMCID: PMC2717403.

This article is modified from a review series on Gaseous mediators, edited by Peter Radermacher.

Other articles in the series can be found online athttp://ccforum.com/series/gaseous_mediators

Part II. Application of inhaled NO and circulatory effects

Cardiovascular effects

NO activates soluble guanylyl cyclase by binding to its heme group to form cyclic guanosine 3’5′-monophosphate (cGMP)   activating a protein kinase. Consequently, myosin sensitivity to calcium-induced contraction is reduced lowering the intracellular calcium concentration as a result of activating calcium-sensitive potassium channels and inhibiting release of calcium. The smooth muscle cell (SMC) relaxation with decrease in pulmonary vascular resistance (PVR) and decreased RV after load could improve cardiac output. However, left ventricular impairment associated with decrease in PVR allows increased RV output to a greater extent than the left ventricle can accommodate and the increase in left atrial pressure reinforces pulmonary edema.

Inhaled NO augments the normal physiological mechanism of hypoxic pulmonary ventilation (HPV) and improves systemic oxygenation ​(Figure 2). The effects of inhaled NO on systemic oxygenation are limited. Experiments show that intravenously administered vasodilators counteract HPV [3]. However, the non-pulmonary effects of inhaled NO include increased renal and hepatic blood flow and oxygenation [14].

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Figure 2

Hypoxic pulmonary vasoconstriction (HPV).       (a) Normal ventilation-perfusion (VQ) matching. (b) HPV results in VQ matching despite variations in ventilation and gas exchange between lung units. (c) Inhaled nitric oxide (NO) augmenting VQ matching by vasodilating.

Non-cardiovascular effects relevant to lung injury

Neutrophils are important cellular mediators of ALI. Limiting neutrophil production of oxidative species and proteolysis reduces lung injury. In neonates, prolonged administration of NO diminished neutrophil-mediated oxidative stress [19]. Neutrophil deformability and CD18 expression were reduced in animal models [20] accomp-anied by decreases in adhesion and migration [21]. These changes limit damage to the alveolar-capillary membrane and the accumulation of protein-rich fluid within the alveoli. Platelet activation and aggregation, intra-alveolar thrombi, contribute to ALI. Inhaled NO attenuates the procoagulant activity in animal models of ALI [22] and a similar effect is seen in patients with ALI [23], but also in healthy volunteers [23,24]. In patients with ALI, decreased surfactant activity in the alveoli and noncompliance, as we recall is hyaline membrane disease accompanied by impaired pulmonary function [25].  The deleterious effects of the NO damages the alveolar wall with loss of surfactant by reactions with RNS [26]. Finally, prolonged exposure to NO in experimental models impairs cellular respiration [27].

The failure of inhaled NO to improve outcome in ALI/ARDS is therefore potentially due to several factors. First, patients with ALI/ARDS die of multi-organ failure, as the actions of NO are not expected to improve the outcome of multi-organ failure, which is a cytokine driven process leading to circulatory collapse. Indeed, the expected beneficial effect of inhaled NO is abrogated by detrimental downstream systemic effects discussed. Second, ALI/ARDS is a heterogeneous condition with diverse causes. Finally, using inhaled NO without frequent dose titration risks unwanted systemic effects without the expected benefits.

Other clinical uses of inhaled nitric oxide

Pulmonary hypertension and acute right ventricular failure

RVF may develop when there is abnormally elevated PVR and/or impaired RV perfusion.  ​Table 2 lists common causes of acute RVF. The RV responds poorly to inotropic agents but is exquisitely sensitive to after load reduction.

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Table 2

Reducing PVR will have beneficial effects on cardiac output and therefore oxygen delivery. In the context of high RV afterload with low systemic pressures or when there is a limitation of flow within the right coronary artery [28], RV failure triggers a backward failure of venous return, as diagrammatically represented in  ​Figure 3.

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Figure 3

Pathophysiology of right ventricular failure. CO, cardiac output; LV, left ventricle; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; RV, right ventricle.

Inhaled NO is used when RV failure complicates cardiac surgery, as cardiopulmonary bypass per se causes diminished endogenous NO production [29]. There is marked variation in response to inhaled NO between patients [30] and in the same patient over time. After prolonged use, there is a leftward shift in the dose-response curve.  The risk of excessive NO administration is associated with toxicity and loss of the therapeutic effect without regular titration against a therapeutic goal [31].  Further, cardiac transplantation may be complicated by pulmonary hypertension and RVF that are improved with NO [32]. Early ischemia-reperfusion injury after lung transplantation manifests clinically as pulmonary edema and is a cause of significant morbidity and mortality [33,34]. Although NO has been administered in this circumstance [35], it hasn’t prevented ischemia-reperfusion injury in clinical lung transplantation [36]. Inhaled NO has been used successfully in patients with cardiogenic shock and RVF associated with acute myocardial infarction [37,38,46], and in patients with acute RVF following acute pulmonary venous thrombo-emboli [39, 47].  An explanation is needed in view of the downstream effects of systemic vasoconstriction and MOF previously identified. No systematic evaluation of inhaled NO and its effect on clinical outcome has been conducted in these conditions.

Acute chest crises of sickle cell disease

Acute chest crises are the second most common cause of hospital admission in patients with sickle cell disease (SCD) and are responsible for 25% of all related deaths [40]. Acute chest crises are manifest by fever, respiratory symptoms or chest pain, and new pulmonary infiltrate on chest  x-ray. The major contributory factors are related to vaso-occlusion. Hemolysis of sickled erythrocytes releasing Hb into the circulation generates reactive oxygen species and reacts with NO [41]. In SCD, the free Hb depletes NO. In addition arginase 1 is released, depleting the arginine needed for NO production, [42]. While secondary PVH is common in adults with SCD the physiological rationale for the use of inhaled NO needs to be considered, except for the complication just referred to. Thus far, iNO has failed to demonstrate either persistent improvements in physiology or beneficial effects on any accepted measure of outcome in clinical trials (other than its licensed indication in neonates). Therefore, inhaled NO is usually reserved for refractory hypoxemia.

Potential problems in designing and conducting RCTs in the efficacy of inhaled NO are numerous. Blinded trials will be difficult to conduct as the effects of inhaled NO are immediately apparent. Recruitment is limited as there is little time for consent/assent or randomization. Finally, industry funding might cast doubt on the independence of the trial results.

Inhaled NO is an unproved tool in the intensivist’s armamentarium of rescue therapies for refractory hypoxemia even though it has an established role in managing complications of cardiac surgery and in heart/lung transplantation. The current place for inhaled NO in the management of ALI/ARDS, acute sickle chest crisis, acute RV failure, and acute pulmonary embolism is a rescue therapy.

Abbreviations

ALI: acute lung injury; ARDS: acute respiratory distress syndrome; Hb: haemoglobin; HPV: hypoxic pulmonary vasoconstriction; iNO: inhaled nitric oxide; iNOS: inducible nitric oxide synthase; NO: nitric oxide; NO2: nitrogen dioxide; NOS: nitric oxide synthase; PaO2/FiO2: arterial partial pressure of oxygen/fraction of inspired oxygen; PVR: pulmonary vascular resistance; RCT: randomised controlled trial; RNS: reactive nitrogen species; RV: right ventricle; RVF: right ventricular failure; SCD: sickle cell disease; SMC: smooth muscle cell.

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