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Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Posted in Biological Networks, Gene Regulation and Evolution, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Metabolomics, Molecular Genetics & Pharmaceutical, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, PCI, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmacotherapy of Cardiovascular Disease, Stem Cells for Regenerative Medicine, Systemic Inflammatory Response Related Disorders, tagged , , , , , , , , on September 14, 2012| 20 Comments »

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

Posted in Nitric Oxide in Health and Disease, tagged , , , , , , , , , on August 16, 2012| 7 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

On August 16, 2012 I received an e-mail on New@NEJM.org from this e-mail, I selected to post HERE, the

Cardiology Panel — NEJM Dialogue in Medicine, June 22, 2012

http://pharmaceuticalintelligence.com/2012/08/16/cardiology-panel-nejm-dialogue-in-medicine-june-22-2012/

While listening to the 1:35 minutes of the Video of the Cardiology Panel, the Nobel Prize for Nitric Oxide was mentioned. In light of the thrust, this Scientific Web Site has related to Nitric Oxide in Health and in Disease, I decided to cite here the entire Letter from the Nobel Prize Web Site.

October 12, 1998

The Nobel Assembly at Karolinska Institutet has today decided to award
the Nobel Prize in Physiology or Medicine for 1998 jointly to

Robert F. Furchgott, Louis J. Ignarro and Ferid Murad

for their discoveries concerning “nitric oxide as a signalling molecule in the cardiovascular system”.

Summary

Nitric oxide (NO) is a gas that transmits signals in the organism. Signal transmission by a gas that is produced by one cell, penetrates through membranes and regulates the function of another cell represents an entirely new principle for signalling in biological systems. The discoverers of NO as a signal molecule are awarded this year’s Nobel Prize.

Robert F Furchgott, pharmacologist in New York, studied the effect of drugs on blood vessels but often achieved contradictory results. The same drug sometimes caused a contraction and at other occasions a dilatation. Furchgott wondered if the variation could depend on whether the surface cells (the endothelium) inside the blood vessels were intact or damaged. In 1980, he demonstrated in an ingenious experiment that acetylcholine dilated blood vessels only if the endothelium was intact. He concluded that blood vessels are dilated because the endothelial cells produce an unknown signal molecule that makes vascular smooth muscle cells relax. He called this signal molecule EDRF, the endothelium-derived relaxing factor, and his findings led to a quest to identify the factor.

Ferid Murad, MD and pharmacologist now in Houston, analyzed how nitroglycerin and related vasodilating compounds act and discovered in 1977 that they release nitric oxide, which relaxes smooth muscle cells. He was fascinated by the concept that a gas could regulate important cellular functions and speculated that endogenous factors such as hormones might also act through NO. However, there was no experimental evidence to support this idea at the time.

Louis J Ignarro, pharmacologist in Los Angeles, participated in the quest for EDRF’s chemical nature. He performed a brilliant series of analyses and concluded in 1986, together with and independently of Robert Furchgott, that EDRF was identical to NO. The problem was solved and Furchgott’s endothelial factor identified.

When Furchgott and Ignarro presented their conclusions at a conference in July, 1986, it elicited an avalanche of research activities in many different laboratories around the world. This was the first discovery that a gas can act as a signal molecule in the organism.

Background

Nitric oxide protects the heart, stimulates the brain, kills bacteria, etc.
It was a sensation that this simple, common air pollutant, which is formed when nitrogen burns, for instance in automobile exhaust fumes, could exert important functions in the organism. It was particularly surprising since NO is totally different from any other known signal molecule and so unstable that it is converted to nitrate and nitrite within 10 seconds. NO was known to be produced in bacteria but this simple molecule was not expected to be important in higher animals such as mammals.

Further research results rapidly confirmed that NO is a signal molecule of key importance for the cardiovascular system and it was also found to exert a series of other functions. We know today that NO acts as a signal molecule in the nervous system, as a weapon against infections, as a regulator of blood pressure and as a gatekeeper of blood flow to different organs. NO is present in most living creatures and made by many different types of cells.
– When NO is produced by the innermost cell layer of the arteries, the endothelium, it rapidly spreads through the cell membranes to the underlying muscle cells. Their contraction is turned off by NO, resulting in a dilatation of the arteries. In this way, NO controls the blood pressure and its distribution. It also prevents the formation of thrombi.
– When NO is formed in nerve cells, it spreads rapidly in all directions, activating all cells in the vicinity. This can modulate many functions, from behaviour to gastrointestinal motility.
– When NO is produced in white blood cells (such as macrophages), huge quantities are achieved and become toxic to invading bacteria and parasites.

Importance in medicine today and tomorrow
Heart: In atherosclerosis, the endothelium has a reduced capacity to produce NO. However, NO can be furnished by treatment with nitroglycerin. Large efforts in drug discovery are currently aimed at generating more powerful and selective cardiac drugs based on the new knowledge of NO as a signal molecule.

Shock: Bacterial infections can lead to sepsis and circulatory shock. In this situation, NO plays a harmful role. White blood cells react to bacterial products by releasing enormous amounts of NO that dilate the blood vessels. The blood pressure drops and the patient may become unconscious. In this situation, inhibitors of NO synthesis may be useful in intensive care treatment.

Lungs: Intensive care patients can be treated by inhalation of NO gas. This has provided good results and even saved lives. For instance, NO gas has been used to reduce dangerously high blood pressure in the lungs of infants. But the dosage is critical since the gas can be toxic at high concentrations.

Cancer: White blood cells use NO not only to kill infectious agents such as bacteria, fungi and parasites, but also to defend the host against tumours. Scientists are currently testing whether NO can be used to stop the growth of tumours since this gas can induce programmed cell death, apoptosis.

Impotence: NO can initiate erection of the penis by dilating the blood vessels to the erectile bodies. This knowledge has already led to the development of new drugs against impotence.

Diagnostic analyses: Inflammatory diseases can be revealed by analysing the production of NO from e.g. lungs and intestines. This is used for diagnosing asthma, colitis, and other diseases.

NO is important for the olfactory sense and our capacity to recognise different scents. It may even be important for our memory.

Nitroglycerin
Alfred Nobel invented dynamite, a product in which the explosion-prone nitroglycerin is curbed by being absorbed in kieselguhr, a porous soil rich in shells of diatoms. When Nobel was taken ill with heart disease, his doctor prescribed nitroglycerin. Nobel refused to take it, knowing that it caused headache and ruling out that it could eliminate chest pain. In a letter, Nobel wrote: It is ironical that I am now ordered by my physician to eat nitroglycerin. It has been known since last century that the explosive, nitroglycerin, has beneficial effects against chest pain. However, it would take 100 years until it was clarified that nitroglycerin acts by releasing NO gas.

TO CITE THIS PAGE:
MLA style: “Physiology or Medicine for 1998 – Press Release”. Nobelprize.org. 16 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/1998/press.html

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