Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is thought to be the endothelium-dependent relaxing factor (EDRF) which mediates vascular relaxation in response to acetylcholine, bradykinin and substance P in many vascular beds. NO has been implicated in the regulation of blood pressure and regional blood flow, and also affects vascular smooth-muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes and hypertension. Pharmacological blockade of NO production with arginine analogues such as L-nitroarginine (L-NA) or L-N-arginine methyl ester affects multiple isoforms of nitric oxide synthase (NOS), and so cannot distinguish their physiological roles. To study the role of endothelial NOS (eNOS) in vascular function, we disrupted the gene encoding eNOS in mice. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, is absent, and the eNOS mutant mice are hypertensive. Thus eNOS mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure.
NO, synthesized in endothelial cells by endothelial NO synthase (NOS 3), is believed to be an important endogenous pulmonary vasodilator substance that contributes to the normal low pulmonary vascular resistance. To selectively investigate the role of NOS 3 in the pulmonary circulation, mice with targeted disruption of the NOS 3 gene were studied. Pulmonary hemodynamics were studied by measuring pulmonary artery pressure, left ventricular end-diastolic pressure, and lower thoracic aortic flow by using a novel open-chest technique. Transient partial occlusion of the inferior vena cava was used to assess the pulmonary artery pressure-flow relationship. Tension developed by isolated pulmonary artery segments after acetylcholine stimulation was measured in vitro. The histological appearance of NOS 3-deficient and wild-type murine lungs was compared. NOS 3-deficient mice (n = 27), when compared with wild-type mice (n = 32), had pulmonary hypertension (pulmonary artery pressure, 19.0 +/- 0.8 versus 16.4 +/- 0.6 mm Hg [mean +/- SE]; P < .05) that was due to an increased total pulmonary resistance (62 +/- 6 versus 33 +/- 2 mm Hg.min.g.mL-1; P < .001). In vitro, acetylcholine induced vasodilation in the main pulmonary arteries of wild-type but not NOS 3-deficient mice. The morphology of the lungs of NOS 3-deficient mice did not differ from that of wild-type mice. We conclude that NOS 3 is a key enzyme responsible for providing basal pulmonary NO release. Congenital NOS 3 deficiency produces mild pulmonary hypertension in mice.
Most small arteries are partially constricted in vivo. After excluding neurogenic, metabolic, and circulating as well as local hormonal influences, a sizeable component of tone persists which is commonly called basal tone. In the absence of such tone, cardiac output would be insufficient to maintain the circulation. This review focuses on the contribution of stretch, induced by changes in transmural pressure, and flow acting through shear forces exerted at the blood vessel wall interface, to basal tone. Evidence concerning the cellular processes that may be activated by these physical forces--the mechanotransducing systems--are discussed. The involvement of the endothelium and the role of change in membrane potential are evaluated and lead to the conclusion that pressure and flow effects do not depend exclusively on the release of endothelial factors nor the activation of voltage-gated Ca2+ channels. Stretch/pressure-induced changes in tone show distinctive pharmacological profiles. They are dependent on extracellular calcium and yet in many instances are only weakly affected by organic Ca(2+)-entry inhibitors. Flow-dependent vascular effects, both constrictor and dilator, are both exquisitely sensitive to changes in extracellular Na+ and appear to be related to its transmembrane gradient. Stretch/pressure cause activation of protein kinase C, an intracellular modulator of Ca(2+)-dependent contractile processes. The existence of separate and distinctive cellular sensing and responding systems to pressure and flow raise the possibility that the smooth muscle tone of the vascular system can be influenced independently by the pressure and rate of flow of the blood.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.