The Role of Nitric Oxide (Formerly Endothelium-Derived Relaxing Factor-EDRF) in Vasodilatation and Vasodilator Therapy (original) (raw)
Related papers
Endothelium-derived relaxing factor and the pulmonary circulation
Lung, 1991
Endothelium-derived relaxing factor (EDRF) is probably identical to nitric oxide (NO) and is released by the vascular endothelium both in the basal unstimulated state and in response to a wide range of physical and chemical stimuli. Since it was first described 10 years ago, evidence is accumulating that it is an important modulator of vascular smooth muscle tone. EDRF acts on the pulmonary vascular bed as on the systemic circulation. EDRF release to pharmacologic stimuli is impaired in pulmonary arteries from patients with chronic hypoxemia. This impairment is associated with severity of respiratory failure and of structural change of vessel walls. Disturbance of EDRF activity may be important in the pathophysiology of pulmonary vascular disease. This brief review describes the current status of experimental studies concerning the possible role of EDRF on the pulmonary circulation in normal conditions and in the pathogenesis of pulmonary hypertension.
European Journal of Pharmacology, 1991
N6-monomethyl-L-arginine (NMA) and N°-nitro-L-arginine (NNA), both of which are inhibitors of nitric oxide (endothelium-derived relaxing factor, EDRF) production from L-arginine, have been shown to be pressor agents in vivo. This study compared the cardiac and vascular responses to intraaortic administration of NMA and NNA in anesthetized dogs. NMA at doses of 3, 10, 30 and 100 mg kg-n i.a. increased systemic vascular resistance and decreased cardiac output; mean arterial pressure increased by 10 mm Hg (at 100 mg kg-~ dose). Heart rate did not change. NNA, administered at doses of 1, 3, 10 and 30 mg kg-i i.a. produced similar cardiovascular actions and was equipotent to NMA. Pretreatment with indomethacin abolished the pressor response to NMA; however, systemic vasoconstriction and cardiac depression still occurred. Increasing mean arterial pressure by phenylephrine infusion to levels much greater than produced by NMA and NNA caused only small reductions in cardiac output. NMA did not reduce coronary blood flow, but instead caused a transient flow increase. Therefore, systemic administration of NMA and NNA result in pronounced systemic vasoconstriction and cardiac depression with only a small pressor response in anesthetized dogs. The cardiac depression did not result from elevated arterial pressure nor was it due to coronary vasoconstriction and reduced myocardial oxygen supply/demand ratio.
American Journal of Surgery, 1995
Nitric oxide (NO), a paracrine-acting gas enzymatically synthesized from L-arginine, is a unique biologic mediator that has been implicated in a myriad of physiologic and pathophysiologic states. It is an important regulator of vascular tone and may be the mediator of the hemodynamic changes involved in sepsis and cirrhosis. In addition, there is increasing evidence that NO is involved in coagulation, immune function, inhibitory innervation of the gastrointestinal tract, protection of gastrointestinal mucosa, and the hepatotoxicity of cirrhosis. It has already been speculated that NO may represent a point of control or intervention in a number of disease states. The purpose of this paper is to provide the surgeon with a broad overview of the scientific and clinical aspects of this important molecule. Am J Surg. 1995;170:292-303.
Influence of endothelial nitric oxide on neurogenic contraction of human pulmonary arteries
European Respiratory Journal, 1995
c co on nt tr ra ac ct ti io on n o of f h hu um ma an n p pu ul lm mo on na ar ry y a ar rt te er ri ie es s ABSTRACT: The present study was designed to investigate the contribution of the endothelium and that of the L-arginine pathway on the contractile responses of isolated human pulmonary arteries to electrical field stimulation (EFS) and noradrenaline.
VASORELAXANT EFFECTS OF ATROPINE: ROLE OF NITRIC OXIDE/ ENDOTHELIUM DERIVED RELAXING FACTOR
This study examined the effects of atropine on isolated rat pulmonary artery rings with or without intact endothelium in the absence and presence of nitric oxide synthase inhibitors, N-omega nitro-L-arginine methyl ester (L-NAME) or N-omega nitro-L-arginine (L-NOARG) that precontracted with phenylephrine (PHE), 5-hydroxytryptamine (5-HT) or KCl. Methods: Segments of the main pulmonary artery (MPA) of male Wistar rats was carefully cut to obtain one ring of approximately three millimeter in diameter was transferred to fresh ice-cold Krebs buffer. Endothelial cells were removed and artery rings were mounted under one gram resting tension. Tension responses were recorded isometrically with Grass FTO3 transducers and were displayed on a Grass model 7 polygraph. The intact endothelium rings precontracted with PHE were confirmed with acetylcholine (ACh), which relaxed artery rings. Results: Atropine (1 nM) blocked the vasorelaxant effect of acethylcholine (1 µM) in pulmonary artery rings precontracted with PHE (100 nM). Also atropine (10 nM-5 µM) produced concentration dependent relaxations in these rings precontracted with PHE or 5-HT, but did not relax rings precontracted with KCl. The vasorelaxant effects of atropine were partially inhibited by the mechanical remove of endothelium or pretreatment rings with L-NAME or L-NOARG, although they were not statistically significant. Conclusion: The results indicate that the ability of atropine to relax pulmonary artery rings may depend on the mechanism of action of the precontracting agonist and suggest that the vasorelaxant effect of atropine is not wholly mediated by the release of NO/EDRF. EDRF L-NAME L-NOARG NO pulmonary artery the release of an endogenous dilator, such as EDRF, or by inhibiting the action of an endogenous vasoconstrictor 9. The demonstration in 1987 of the formation of NO by an enzyme in vascular endothelial cells opened up what can now be considered a new area of biological research 10,11. NO, which accounts for the biological properties of EDRF, is the endogenous stimulator of the soluble guanylate cyclase. In addition, NO is a potent vasodilator that activates guanylate cyclase resulting in the generation of cGMP, which is presumed to be the principal effector of NO-induced vasorelaxation in various tissues. NO is synthesized from the amino acid L-arginine by an enzyme, the NO synthase 12 .
Cardiovascular Research, 2007
Aims b-adrenoceptor (b-AR)-mediated relaxation was characterized in pulmonary arteries from normoxic and hypoxic (as model of pulmonary hypertension) mice. The endothelial NO synthase (eNOS) pathway was especially investigated because of its potential vasculoprotective effects. Methods Pulmonary arteries from control or hypoxic (0.5 atm for 21 days) wild-type or eNOS 2/2 mice were used for pharmacological characterization of b-AR-mediated relaxation in myograph, and for immunohistochemistry using anti-b-AR antibodies. Results In pulmonary arteries from normoxic mice, isoproterenol (b-AR agonist) and procaterol (selective b 2 -AR agonist) elicited relaxation, while cyanopindolol and CL316243 (b 3 -AR agonists) were ineffective. The effect of isoproterenol was antagonized by CGP20712A and ICI118551 (b 1 -or b 2 -AR antagonists, respectively) and also partially inhibited by N v -nitro-L-arginine methylester (L-NAME, a NOS inhibitor), endothelium denudation, or eNOS gene deletion. Relaxation to procaterol was abolished by L-NAME or endothelium removal. In eNOS 2/2 mice, procaterol-induced relaxation was decreased but was insensitive to L-NAME, this residual effect involving other endothelium-dependent relaxant factors as compensatory mechanisms. Immunostaining for b 2 -AR was observed in the endothelial layer, but not the medial layer of pulmonary arteries. Pulmonary arteries from hypoxic mice exhibited decreased endothelial NO-dependent relaxation to acetylcholine. However, in these arteries, relaxation to procaterol was either unaffected (extralobar segments) or even increased (intralobar segments) and was still abolished by L-NAME or endothelium removal. Conclusion b 1 -and b 2 -AR, but not b 3 -AR, mediate relaxation of mice pulmonary arteries. The b 2 -AR component is dependent on eNOS activity and is preserved following chronic hypoxia. These data highlight the role of the b 2 -AR as a pharmacological target to induce/restore endothelial NO-dependent protective effects in pulmonary circulation.
New insights into nitric oxide and coronary circulation
Life Sciences, 1999
Since its discovery over 20 years ago as an intercellular messenger, nitric oxide (NO), has been extensively studied with regard to its involvement in the control of the circulation and, more recently, in the prevention of atherosclerosis. The importance of NO in coronary blood flow control has also been recognized. NO-independent vasodilation causes increased shear stress within the blood vessel which, in turn, stimulates endothelial NO synthase activation, NO release and prolongation of vasodilation. Reactive hyperemia, myogenic vasodilation and vasodilator effects of acetylcholine and bradykinin are all mediated by NO. Ischemic preconditioning, which protects the myocardium from cellular damage and arrhythmias, is itself linked with NO and both the first and second windows of protection may be. due to NO release. Exercise increases NO synthesis via increases in shear stress and pulse pressure and so it is likely that NO is an important blood flow regulatory mechanism in exercise. This phenomenon may account for the beneficial effects of exercise seen in atherosclerotic individuals. Whilst NO plays a protective role in preventing atherosclerosis via superoxide anion scavenging, risk factors such as hypercholesterolemia reduce NO release leading the way for endothelial dysfunction and atherosclerotic lesions. Exercise reverses this process by stimulating NO synthesis and release. Other factors impacting on the activity of NO include estrogens, endothelins, adrenomedullin and adenosine, the last appearing to be a compensatory pathway for coronary control in the presence of NO inhibition. These studies reinforce the pivotal role played by the substance in the control of coronary circulation.