Increase In Vasorelaxation Research Articles

Altered alpha adrenergic vasoresponsiveness in a non‐cirrhotic portal hypertension model of E. coli injection

Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamic circulation in cirrhosis. Animal models of cirrhosis and portal vein ligation have helped in our understanding of portal hypertension. The etiopathogenesis of non-cirrhotic portal fibrosis (NCPF), a common cause of portal hypertension, is still poorly understood. The aim of this study was to investigate the pathophysiology of NCPF in a rabbit model. An indwelling cannula was inserted into the gastrosplenic vein of rabbits. Animals were randomly injected with saline (Group I, n = 13) or lipopolysaccharide (Group II, n = 13) from heat killed Escherichia coli at 0, 1, 2, 7, 14 and 28 days. Portal pressure was measured at 3 months and vasoresponsiveness studied in isolated aortic rings in intact and in endothelium-denuded tissues from both groups. In all group II compared with group I animals, the splenic weight (0.89 +/- 0.16 vs 0.62 +/- 0.1 g, P < 0.05) and the portal pressure (14.99 +/- 0.56 vs 7.04 +/- 0.42 mmHg, P < 0.05) were higher at 3 months. The group II animals showed reduced responsiveness to phenylephrine showing maximal contraction of 1.25 +/- 0.08 at 10(-4) mol/L as compared to 2.85 +/- 0.33 g tension in Group I (P < 0.05). Endothelium denudation of aortic rings had no effect on reduced reactivity in Group II animals. Acetylcholine induced an increase in vasorelaxation at lower concentrations in preconstricted aortic rings in Group II compared to Group I animals, but this decreased in higher concentrations. Nifedipine produced comparable vasodilatation in preconstricted rings in both the groups of animals. Repeated injection of lipopolysaccharide into the gastrosplenic vein leads to the development of portal hypertension. This non-cirrhotic model of portal hypertension is characterized by generalized arterial hyporeactivity to vasoconstrictors akin to other models of portal hypertension.

Effect of OS-0689, a novel SERM, on periarterial nerve function in tail arteries of ovariectomized rats

Objective: We have previously shown that OS-0689 attenuates the rise in tail skin temperature of ovariectomized rats, which is believed to be relevant to human symptoms of hot flush. In this study, we elucidate the mechanism underlying the ameliorating effects of OS-0689 on elevated tail skin temperature. Methods: Female Sprague–Dawley rats were ovariectomized and orally treated with OS-0544 (1 mg/kg), OS-0689 (3 mg/kg; (+)-enantiomer of OS-0544) or 17β-estradiol (3 mg/kg; E 2) for 1 week. At 1, 3 or 6 weeks after ovariectomy, the vasoconstrictions and vasorelaxations induced by periarterial nerve stimulation (PNS), l-noradrenaline (NA), and rat calcitonin gene-related peptide (CGRP) in isolated tail arteries were compared between OVX and sham-operated rats. Results: Three weeks after ovariectomy, vasoconstrictions in response to PNS and NA in the arteries of OVX rats were markedly less than those in the arteries of sham-operated rats. However, at 1 and 6 weeks after ovariectomy the stimuli-induced vasoconstrictions in the arteries of OVX rats were greater than those of sham-operated rats. Moreover, NA reactivity was not attenuated in the mesenteric arteries at 3 weeks after ovariectomy. OS-0544, OS-0689 and E 2 prevented the decrease in vasoconstrictions in the tail arteries. Vasorelaxations in response to PNS and rat CGRP were significantly greater in the arteries of OVX rats than in those of the sham-operated rats. OS-0689 inhibited the increase in vasorelaxation induced by both stimuli, whereas E 2 had no effects. Conclusions: Ovariectomy not only decreases adrenergic function but also enhances CGRPergic function in rats’ tail arteries. OS-0689 improves both impairments and thereby improves on rat hot flush.

Up-regulation of nNOS and associated increase in vasorelaxation in superior mesenteric arteries in portal hypertension

Splanchnic arterial vasodilatation is the pathophysiological hallmark in the development of the hyperdynamic circulation in portal hypertension. This has been attributed largely to vascular NO overproduction. Three NO-synthase-(NOS)-isoforms have been identified of which e(ndothelial)-NOS has been found up-regulated and I(nducible)-NOS not expressed in the splanchnic circulation in portal hypertension. N(euronal)-NOS so far has not been investigated and hence, the current study evaluates in a model of portal vein-ligated rats (PVL) nNOS-expression and nNOS-mediated vasorelaxation. Methods: Mesenteric vasculature of PVL and sham rats was stained for nNOS immunohistochemically and analyzed for nNOS-protein level by western blots. In-vitro perfused de-endothelialized mesenteric arterial vasculature were preconstricted with norepinephrine (EC80) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2–12 Hz, 45V) before and after incubation with the NO-inhibitor L-NAME (10-4 M). Results: nNOS was localized to the adventitia of the mesenteric arterial tree showing more intense staining in PVL as compared to sham rats. Correspondingly, nNOS protein expression was markedly up-regulated in mesenteric arteries in PVL rats. PNS induced a frequency-dependent vasorelaxation which was more pronounced in PVL rats (Fig.1A). This difference in nerval-mediated vasorelaxation was abolished by incubation with L-NAME (Fig.1B). The effect of NO-inhibition on vasorelaxation, representing nNOS-mediated vasorelaxation, was significantly greater in PVL rats than in sham animals (Fig.1C). Conclusion: Perivascular nNOS protein expression is enhanced in mesenteric arteries in portal hypertension mediating an increased nerval NO-mediated vasorelaxation. This nNOS-derived NO overproduction may play an important role in the pathogenesis of arterial vasodilation and hyperdynamic circulatory syndrome in portal hypertension.

Vascular β -Adrenergic Receptor Adenylyl Cyclase System in Maturation and Aging

M. A. Gaballa, A. D. Eckhart, W. J. Koch and S. Goldman. Vascular β -Adrenergic Receptor Adenylyl Cyclase System in Maturation and Aging. Journal of Molecular and Cellular Cardiology (2000) 32, 1745–1755. The objective of this study was to determine how maturation and aging affects beta (β)-adrenergic receptor (AR) control of arterial vasorelaxation. Left ventricular (LV) hemodynamics and arterial vasorelaxation in thoracic artery segments were studied in Brown Norway, Fisher 344 cross rats at 6 weeks, 6 months, and 23 months of age. We defined changes in maturation as occurring between 6 weeks and 6 months of age and changes in aging as occurring between 6 months and 23 months of age. With maturation, isoproterenol resulted in a downward shift in heart rate and an upward shift in both LV dP/dt and peripheral vascular resistance responses. Similar changes were noted with aging except for the downward shift in LV dP/dt isoproterenol response. There was a dose-dependent increase in arterial vasorelaxation in response to isoproterenol in all age groups, but the 6-week-old animals had a 5-fold (P<0.01) increase in vasorelaxation compared to other age groups. The isoproterenol-induced arterial vasorelaxation response was not altered by removal of the endothelium. The vasodilatory responses to nitroglycerin, acetylcholine, and adenosine were diminished (P<0.05) with aging. The vasorelaxation responses to forskolin and IBMX were unchanged with maturation and diminished with aging. Incubation of arterial rings in cholera toxin resulted in a reduction in relaxation only in arteries from 6-week-old rats. Maturation resulted in no change in β -AR density [20.2±0.7 v 18.5±0.5 fmol/mg protein, P=n.s., 6 weeks (n=2, 18 aortas were combined v 6-month-old rats)]. With maturation, there was no change in Gαi level. However, β ARK1 levels were increased (55.4±2.1 v 40.8±0.4, arbitrary densitometry units) and G αslevels were decreased (29.5±0.8 v 49.9±1.9, arbitrary densitometry units). Aging resulted in no change in β -AR density (15.3±1.7 v 18.5±0.5 fmol/mg membrane protein), but decreases in basal, isoproterenol-, naF-, and forskolin-stimulated AC activities. Compared to 6 week data, 23-month-old rats exhibited no change in either G αior β ARK1, however, G αswas decreased. In summary, β -AR-stimulated arterial vasorelaxation is depressed during maturation and aging. Since there is no change in β -AR density but a decrease in Gαs and in basal/stimulated AC activities, the defect in β -AR signaling during maturation and aging is probably a post receptor defect, i.e. possibly in the receptor-G protein coupling.