Smooth muscle cell responsiveness to nitrovasodilators in hypertensive and normotensive rats.

Abstract

Endothelium-derived relaxing factor and exogenous nitrovasodilators are thought to produce smooth muscle relaxation by activation of soluble guanylate cyclase. To investigate whether diminished cyclic GMP (cGMP) accumulation underlies the differences in vascular reactivity to nitrovasodilators between Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), we determined cGMP formation in aortic smooth muscle cells from the two strains. Both cultured cells and aortic rings from 12-to 14-week-old SHR accumulated greater amounts of cGMP on stimulation with exogenous nitrovasodilators (ie, sodium nitroprusside) than those from WKY rats, whereas there was no difference observed in cells from prehypertensive animals (5-to 6-week old) between the two strains. Responsiveness of smooth muscle cells to endothelium-derived relaxing factor was investigated in cocultures of bovine aortic endothelial cells (BAE) and smooth muscle cells from SHR and WKY rats. cGMP accumulation elicited by endothelium-N itrovasodilators are thought to produce vascular smooth muscle relaxation through activation of the soluble isoform of guanylate cyclase, increasing cellular cyclic GMP (cGMP).14 Although the mechanism of action of cGMP is not fully understood, it has been shown that cGMP lowers intracellular Ca 2+ levels and alters the phosphorylation pattern of cellular proteins involved in contraction. -6 It has been suggested that some of the actions of cGMP are mediated by activation of cGMP-dependent protein kinase. 7 Vascular endothelium has been shown to release, both under basal conditions and after agonist stimulation (ie, bradykinin, acetylcholine, calcium ionophore A23187), an endogenous nitrovasodilator, known as endothelium-derived relaxing factor (EDRF), which is nitric oxide 89 or a nitric oxide-containing molecule, synthesized from L-arginine.10 EDRF release produces vascular relaxation through elevation of cGMP levels in the smooth muscle."" 13 Basal release of EDRF in vivo regulates vascular tone because L-arginine analogues, which inhibit nitric oxide synthase, elevate blood pressure. In several models of hypertension, both endotheliumdependent and -independent responses are altered. 19Increased total peripheral resistance has been hypothesized to be partly due to decreased EDRF action and/or increased release of endothelium-derived constricting factors, which in the spontaneously hypertensive rat (SHR), the most commonly used model of genetic hypertension, are mediated by a cyclooxygenase pathway product.20 Studies on both endothelium-dependent and -independent relaxations in SHR have yielded conflicting results. Whereas many investigators report decreased relaxation to sodium nitroprusside (SNP) or glyceryl trinitrate (GTN) in the aortas and carotid arteries of SHR, 21 -22 others have shown unchanged or even enhanced relaxation in response to nitrovasodilators in the aorta and mesenteric resistance arteries from SHR or stroke-prone SHR compared with Wistar-Kyoto (WKY) rats. 2325 The use of different age...

Effect of antioxidant treatments on nitrate tolerance development in normotensive and hypertensive rats

“…The increase in expression of the soluble guanylate cyclase, the target enzyme of NO, reported by Papapetropoulos et al [20], in vascular smooth muscle cells of SHR as compared to WKY, supports our data in coronary resistance vessels. This ®nding may represent a compensatory response against the increased coronary vascular resistance that is present in 16-week-old SHR.…”

Decreased Flow-Induced Dilation and Increased Production of cGMP in Spontaneously Hypertensive Rats

“…These results are in agreement with previous studies of the mesenteric vascular bed 38 and of cultured smooth muscle cells and aortic rings. 39 Thus, decreased ACh-induced dilation in hypertension may reflect an alteration in affinity for muscarinic receptors. 40 In conclusion, in genetically hypertensive rats, the mesenteric arterial network exhibited an overactivated endothelium-dependent L-arginine/NO/cGMP pathway associated with decreased flow-induced dilation.…”

Vanadate Is a Potent Activator of Endothelial Nitric-Oxide Synthase: Evidence for the Role of the Serine/Threonine Kinase Akt and the 90-kDa Heat Shock Protein

“…Cultures had typical cobblestone morphology and stained uniformly for von Willebrand factor, as assessed by indirect immunofluorescence. Smooth muscle cells were isolated from rat aortae (Papapetropoulos et al, 1994) and were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum, antibiotics, and L-glutamine.…”