nitroarginine and Constriction--Pathologic

Radial artery (RA) vasospasm remains a potential cause of early graft failure after coronary artery bypass graft surgery, despite pretreatment with alpha-adrenergic or calcium channel blockers. Our aim was to investigate the mechanism of the vasorelaxant effects of Rho-kinase inhibitors (Y-27632 and fasudil) on the human RA. Segments were obtained from 30 patients undergoing coronary artery bypass graft and were divided into 3-4 mm vascular rings. The rings were stimulated with 10(-5) mol/L phenylephrine (PE) by using the isolated tissue bath technique and were relaxed with 10(-6) mol/L acetylcholine. Relaxation responses were recorded for Y-27632 (10(-9)-10(-4) mol/L), fasudil (10(-9)-10(-4) mol/L), and sodium nitroprusside (SNP) (10(-9)-10(-5) mol/L). Y-27632 and fasudil relaxation responses were repeated in either N(G)-nitro-L-arginine (L-NNA), which is a specific endothelial nitric oxide synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which is a guanylate cyclase inhibitor. SNP relaxation responses were repeated in 10(-8) mol/L Y-27632 and 10(-8) mol/L fasudil. Y-27632 and fasudil caused concentration-dependent vasorelaxation in RA rings precontracted with PE, and maximal relaxation (100%) was recorded at the highest concentration used (10(-4) mol/L). The vasorelaxant effects of Y-27632 and fasudil were significantly reduced in the presence of L-NNA and ODQ, and the pD2 values of Y-27632 and fasudil were not changed. The vasorelaxant effects of SNP were significantly increased in the presence of Y-27632 and fasudil, and the pD(2) values of SNP were not changed. These findings indicate that Y-27632 and fasudil caused concentration-dependent vasorelaxation in the RA rings. Because this effect was decreased in a dose-dependent manner by L-NNA and ODQ, the relaxant effects of Y-27632 and fasudil could be due to stimulation by nitric oxide that is being released. Rho-kinase inhibitors may have an important role in preventing vasospasm in arterial grafts used for coronary artery surgery.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Aged; Amides; Constriction, Pathologic; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Nitroarginine; Nitroprusside; Oxadiazoles; Protein Kinase Inhibitors; Pyridines; Quinoxalines; Radial Artery; Receptors, Calcium-Sensing; rho-Associated Kinases; Vasoconstriction; Vasodilation

Endothelins (ET) have opposite vascular effects mediated through different receptors: ET(A) receptors mediating vasoconstriction and ET(B) receptors mediating vasoconstriction as well as vasodilation. The role of ET in acute hypoxic pulmonary vasoconstriction (HPV) was studied after dual ET receptor blockade with bosentan and nitric oxide (NO) synthase inhibition with nitro-L-arginine (L-NA). We started from the hypothesis that ET antagonism may inhibit HPV but, if not, would do so after NO synthase inhibition. HPV was evaluated in anesthetized lambs, with an intact pulmonary circulation, by the increase in the mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao) gradient in response to hypoxia (inspiratory oxygen fraction of 0.1) at different levels of pulmonary flow (multipoint pressure/flow relationships). ET receptor antagonism decreased pulmonary and systemic vascular tone both in hyperoxia and hypoxia. ET antagonism had no effect on HPV. NO synthase inhibition increased pulmonary vascular tone more in hypoxia than in hyperoxia so that HPV was enhanced. After L-NA, bosentan still decreased pulmonary vascular tone in hypoxia but did not affect the magnitude of HPV. The present results suggest that ET and NO are involved in the regulation of basal pulmonary vascular tone. Furthermore, the vasodilator effect of bosentan persisted in the presence of NO synthase inhibition, suggesting a non NO-dependent vasodilator mechanism. The results from these experiments are in agreement with the idea that ET do not play a major role in HPV in the perinatal lamb, even when it is enhanced by NO synthase inhibition.

Topics: Animals; Animals, Newborn; Blood Pressure; Bosentan; Constriction, Pathologic; Dilatation, Pathologic; Endothelin Receptor Antagonists; Endothelins; Hyperoxia; Hypoxia; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pulmonary Artery; Pulmonary Circulation; Sheep, Domestic; Sulfonamides; Vascular Resistance

During gestation endothelium induces decreases in vascular responses to vasopressor agents but endothelium disease is followed by hypertension and enhanced vascular reactivity during preeclampsia. In a rat model of preeclampsia induced by NO synthase inhibition we study here isolated aortic contractions. From day 13 of gestation 2 groups of Wistar female rats were fed control (C) or nitro-arginine enriched diets (0.063%, i.e. 30 mg/kg/d) (treated) (T). On gestational day 20 systolic blood pressure (SBP, mmHg) is measured by tail cuff method and isolated thoracic ring aorta contractions are studied after depolarisation (KCl 60 mM) or norepinephrine (cumulative concentrations 10-9 M-10-5 M). After chronic NOS inhibition, hypertension develops: SBP is 154 +/- 2.17 in T and 116 +/- 3.75 in C, p < 0.01 and significant proteinuria (mg/d) appears: T, 63.4 +/- 21.6 versus C 3.08 +/- 0.48, p < 0.01. NO synthase inhibition in treated rats impairs the depressed contractile response obtained in the presence of endothelium in control rats but addition of L-arginine suppresses the effect of nitroarginine. Taking in account our results and those described in literature it appears that L-arginine treatment could ameliorate some pathologic pregnancies.

Topics: Animals; Aorta, Thoracic; Constriction, Pathologic; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelium, Vascular; Female; In Vitro Techniques; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Norepinephrine; Pre-Eclampsia; Pregnancy; Rats; Rats, Wistar; Vasoconstrictor Agents

After retinal branch vein occlusion (BVO), the arteriole crossing the occluded territories is often constricted. This constriction persists up to several weeks and is correlated with the development of extended territories of nonperfused capillaries. These are results of an investigation supporting the hypothesis that decrease in the production of nitric oxide (NO) accounts for the observed arteriolar constriction.. Preretinal [NO] was measured using an NO microprobe in the anesthetized miniature pigs, before and during the first 4 hours after experimental branch vein occlusion. Modifications of arteriolar diameter were correlated to preretinal [NO] changes. The retinal arteriolar sensitivity to constitutive NO was checked by applying preretinal puff injections of nitro-L-arginine (L-NA) after both systemic hypoxia and branch vein occlusion.. Two hours after branch vein occlusion there was a 73.7 +/- 4% decrease in preretinal [NO] and a simultaneous 25.4 +/- 3.4% decrease in the diameter of the arteriole in the affected territory. Both persisted for at least 4 hours after branch vein occlusion. Applying a puff of L-NA to an arteriole previously dilated by systemic hypoxia induced a vasoconstriction. However, no arteriolar constriction was observed when a puff was applied to an arteriole after branch vein occlusion.. These results show that experimental branch vein occlusion induces in the affected retina an impairment in the release of constitutive NO and an arteriolar constriction, which, in turn, contributes to the development of hypoxia in tissue and neuronal swelling and death in the inner retina.

Topics: Animals; Arterioles; Constriction, Pathologic; Nitric Oxide; Nitroarginine; Retinal Artery; Retinal Vein Occlusion; Swine; Swine, Miniature