8/6/14 Clinical Relevance of the Nitric Oxide/Cyclic GMP Pathway

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NO/cGMP-Pathway

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SiteCreated by Dr. Luis Agulló (last update on 28-12-2007)

Clinical Relevance of theNitric Oxide/Cyclic GMP

Pathway

Alteration of nitric oxide (NO) production and/or nitric oxidebioavailability have been shown to occur in the setting of diversedisorders as hypertension, hypercholesterolemia, aging, cigarettesmoking, diabetes, erectile dysfunction, and heart failure.

Given the clinical relevance of deficiencies in nitric oxide production inseveral disorders, important amount of research has been devoted inorder to counteract these abnormalities.

L-Arginine

L-Arginine (substrate for nitric oxide synthesis) has often been tested inexperimental animals and in humans with good results inhypercholesterolemia, hypertension and diabetes. Even oral feeding ofL-arginine, which only doubles plasma levels, appears to havebeneficial effects.

Although in general positive, the reason for the effectiveness of theadministration of this aminoacid is not completely understood. In allthese clinical disorders the main alteration is supposed to occur at theendothelial level. Endothelial cells recover the interior of blood vessels

and regulate nutrient exchange between plasma and tissues. In thesecells, when studied in vitro, nitric oxide production is not altered byincreasing L-arginine concentration. L-Arginine concentration inside the

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increasing L-arginine concentration. L-Arginine concentration inside thecell seems to be high enough to allow maximal activity of nitric oxidesynthase (NOS) and, in addition, these cells are able to resynthesizethis aminoacid from L-citrulline (co-product in the synthesis of nitricoxide).

Suggested mechanisms for this apparent paradox have been forexample that an excess of L-arginine may allow nitric oxide synthesisnot mediated by enzyme activity, that can occur at high concentrationsof this aminoacid, or may compensate for the inhibitory effect of theendogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA).

Natriuretic peptides

Other substances related with this transduction pathway that havebeen administered with good results in patients are natriuretic factors.These compounds are endogenous peptides that activate membraneguanylyl cyclases and in consequence stimulate intracellular formationof cyclic GMP. Both nitric oxide and natriuretic peptides, throughdifferent ways (different enzymes), elicite increases in cyclic GMPsynthesis.

The best known function of these peptides is their diuretic action. Apartfrom this renal action, natriuretic factors have important actions on theCardiovascular System (reduce peripheral vascular resistance andlower blood pressure) and in the Central Nervous System (inhibition ofvasopressin secretion and regulation of salt appetite and waterdrinking).

In accordance with these functions, the efficacy of natriuretic factorshave been tested in disorders like hypertension, renal insufficiency, andcongestive heart failure. Administration of these peptides reducesblood pressure and promotes sodium excretion in patients withessential hypertension. It also lowers blood pressure and improvescentral hemodynamics in patients with chronic heart failure.

Viagra

Recently, an inhibitor of one of the enzymes that degrade cyclic GMP(viagra or sildenafil, inhibitor of the cyclic nucleotide phosphodiesterasetype V) has started to be amply used to treat erectile dysfunction. Thiscompound allows that the same chemical impulses elicit much morecyclic GMP accumulation, since its degradation has been inhibited, andin consequence it improves vasodilation and final erection.

Related Web Sites

Nitric Oxide and Vasodilation [few outlines about NO with someinteresting links; Rutgers, The State University of New Jersey, USA]

8/6/14 Clinical Relevance of the Nitric Oxide/Cyclic GMP Pathway

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interesting links; Rutgers, The State University of New Jersey, USA]

Nitric Oxide and Vascular Health [brief introduction to therapeuticrelevance of NO and related drugs; Health and Age, NovartisFoundation]

Stress-related diseases : a potential role for nitric oxide [Esch T,Stefano GB, Fricchione GL, Benson H]

Parkinson's disease: a potential role for microglia and nitricoxide [Czlonkowska A, Kurkowska-Jastrzebska I, Czlonkowski A,Peter D, Stefano GB]

Sexual Chemistry, Questions and Answers [basic and clearintroduction to erectile dysfunction; BBC]

Erectile Dysfunction [very good introduction to erectile dysfunctiondisease; Milton Lakin MD, The Cleveland Clinic, USA]

Erectile Dysfunction: Serious Research for a Serious Problem [the history of viagra and some hints about the new approaches totreat erectile dysfunction; The Scientist]

The Effects of Viagra on the Action of Nitric Oxide [EmoryUniversity, Georgia, USA]

What is Viagra® and How Does It Work? [introduction to thefunction of viagra; R J Huskey, University of Virginia]

Selected references (open access)

Cardiovascular disease

Kishimoto I, Rossi K, Garbers DL. A genetic model provides evidencethat the receptor for atrial natriuretic peptide (guanylyl cyclase-A)inhibits cardiac ventricular myocyte hypertrophy. Proc Natl Acad SciUSA 27:2703 (2001). [Full Text]

Chen AF, Ren J, Miao CY. Nitric oxide synthase gene therapy forcardiovascular disease. Jpn J Pharmacol 89:327 (2002). Review. [FullText]

Chen AF, Ren J, Miao CY. Nitric oxide synthase gene therapy forcardiovascular disease. Jpn J Pharmacol 89:327 (2002). Review. [FullText]

Wollert KC, Fiedler B, Gambaryan S et al. Gene transfer of cGMP-dependent protein kinase I enhances the antihypertrophic effects ofnitric oxide in cardiomyocytes. Hypertension 39:87 (2002). [Full Text]

Ignarro LJ. Nitric oxide as a unique signaling molecule in the vascularsystem: a historical overview. J Physiol Pharmacol 53:503 (2002).Review. [Full Text]

Channon KM, Guzik TJ.Mechanisms of superoxide production in human

blood vessels: relationship to endothelial dysfunction, clinical andgenetic risk factors. J Physiol Pharmacol 53:515 (2002). Review. [FullText]

Egashira K. Clinical importance of endothelial function inarteriosclerosis and ischemic heart disease. Circ J 66:529 (2002).Review. [Full Text]

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Review. [Full Text]

Holtwick R, van Eickels M, Skryabin BV et al. Pressure-independentcardiac hypertrophy in mice with cardiomyocyte-restricted inactivationof the atrial natriuretic peptide receptor guanylyl cyclase-A. J ClinInvest 111:1399 (2003). [Full Text]

Molkentin JD. A friend within the heart: natriuretic peptide receptorsignaling. J Clin Invest 111:1275 (2003). [Full Text]

Diabetes

Takamura T, Kato I, Kimura N et al. Transgenic mice overexpressingtype 2 nitric-oxide synthase in pancreatic ß-cells develop insulin-dependent diabetes without insulitis. J Biol Chem 273: 2493 (1998).[Full Text]

Spinas GA. The Dual Role of Nitric Oxide in Islet beta-Cells. NewsPhysiol Sci 14:49 (1999). [Full Text]

Igarashi J, Michel T. More sweetness than light? A search for thecauses of diabetic vasculopathy. J Clin Invest 108:1425 (2001). [FullText]

Johannesen J, Pie A, Pociot F et al. Linkage of the human induciblenitric oxide synthase gene to type 1 diabetes. J Clin Endocrinol Metab86:2792 (2001). [Full Text]

Goligorsky MS, Chen J, Brodsky S. Workshop: endothelial celldysfunction leading to diabetic nephropathy: focus on nitric oxide.Hypertension 37:744 (2001). Review. [Full Text]

Calles-Escandon J, Cipolla M. Diabetes and endothelial dysfunction: aclinical perspective. Endocr Rev 22:36 (2001). Review. [Full Text]

Du XL, Edelstein D, Dimmeler S et al. Hyperglycemia inhibitsendothelial nitric oxide synthase activity by posttranslationalmodification at the Akt site. J Clin Invest 108:1341 (2001). [Full Text]

Neurodegeneration

Ischiropoulos H, Beckman JS. Oxidative stress and nitration inneurodegeneration: cause, effect, or association? J Clin Invest 111:163(2003). Review. [Full Text]

Czlonkowska A, Kurkowska-Jastrzebska I, Czlonkowski A et al.Immune processes in the pathogenesis of Parkinson's disease - apotential role for microglia and nitric oxide. Med Sci Monit 8:RA165(2002). Review. [Full Text]

Erectyl Dysfunction

Champion HC, Bivalacqua TJ, Hyman AL et al. Gene transfer ofendothelial nitric oxide synthase to the penis augments erectileresponses in the aged rat. Proc Natl Acad Sci USA 28:11648 (1999).[Full Text]

Hedlund P, Aszodi A, Pfeifer A et al. Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. Proc Natl Acad Sci USA 29:2349

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dependent kinase I-deficient mice. Proc Natl Acad Sci USA 29:2349(2000). [Full Text]

Author: Dr. Luis Agulló (lab[at]lagullo.com).

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