Endothelial cells in most vascular beds release a factor that hyperpolarizes the underlying smooth muscle, produces vasodilatation, and plays a fundamental role in the regulation of local blood flow and systemic blood pressure. The identity of this endotheliumderived hyperpolarizing factor (EDHF), which is neither NO nor prostacyclin, remains obscure. Herein, we demonstrate that in mesenteric resistance arteries, release of C-type natriuretic peptide (
Abstract-Myogenic constriction describes the innate ability of resistance arteries to constrict in response to elevations in intraluminal pressure and is a fundamental determinant of peripheral resistance and, hence, organ perfusion and systemic blood pressure. However, the receptor/cell-type that senses changes in pressure on the blood vessel wall and the pathway that couples this to constriction of vascular smooth muscle remain unclear. In this study, we show that elevation of intraluminal transmural pressure of mesenteric small arteries in vitro results in a myogenic response that is profoundly suppressed following ablation of sensory C-fiber activity (using in vitro capsaicin desensitization resulted in 72.8Ϯ10.3% inhibition, nϭ8; PϽ0.05). Key Words: mechanotransduction Ⅲ nonselective cation channels Ⅲ cardiovascular physiology I n 1902, Bayliss made the seminal observation that resistance arteries possess an innate ability to constrict in response to elevations in intraluminal pressure. 1 He described this phenomenon as the myogenic response. Today, we understand that myogenic constriction is a major determinant of peripheral resistance and organ perfusion. 2,3 As such, it plays an important role in the maintenance of an appropriate level of perfusion to vascular beds, independent of systemic pressure, providing a mechanism whereby tissues are protected from variations in blood pressure. 2,3 Myogenic responses predominate in small resistance arteries (Ͻ500 m) 4 and are considered to be attributable to an increase in smooth muscle intracellular free calcium concentration ([Ca 2ϩ ] i ) after depolarization of these cells. 5 Many studies have attempted to elucidate the signaling mechanisms involved in the myogenic response and several possibilities have been proposed including activation of ion channels, ion exchangers/transporters, and enzyme systems/ second messengers. 2 In particular, there is compelling evidence supporting a role for stretch activated ion channels and the arachidonate metabolite 20-hydroxyeicosatetraenoic acid (20-HETE). 2 However, the receptor/cell-type that senses changes in pressure on the blood vessel wall and the pathway that couples this to constriction of vascular smooth muscle remain unclear.Until recently the myogenic response was thought to be derived entirely from a direct effect of intraluminal pressure on the smooth muscle. 6 It is now clear that the endothelium,
Endothelial dysfunction is a characteristic of, and may be pathogenic in, inflammatory cardiovascular diseases, including sepsis. The mechanism underlying inflammation-induced endothelial dysfunction may be related to the expression and activity of inducible nitric oxide synthase (iNOS). This possibility was investigated in isolated resistance (mesenteric) and conduit (aorta) arteries taken from lipopolysaccharide (LPS)-treated (12.5 mg/kg i.v.) or saline-treated iNOS knockout (KO) and wild-type (WT) mice. LPS pretreatment (for 15 h, but not 4 h) profoundly suppressed responses to acetylcholine (ACh) and significantly reduced sensitivity to the NO donor spermine-NONOate (SPER-NO) in aorta and mesenteric arteries of WT mice. This effect was temporally associated with iNOS protein expression in both conduit and resistance arteries and with a 10-fold increase in plasma NOx levels. In contrast, no elevation of plasma NOx was observed in LPS-treated iNOS KO animals, and arteries dissected from these animals did not express iNOS or display hyporeactivity to ACh or SPER-NO. The mechanism underlying this phenomenon may be suppression of eNOS expression, as observed in arteries of WT animals, that was absent in arteries of iNOS KO animals. These results clearly demonstrate that iNOS induction plays an integral role in mediation of the endothelial dysfunction associated with sepsis in both resistance and conduit arteries.
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