Chronic Endothelin-1 Improves Nitric Oxide–Dependent Flow-Induced Dilation in Resistance Arteries From Normotensive and Hypertensive Rats

Abstract

Abstract-Endothelin-1 (ET-1) is released on stimulation by shear stress of the vascular wall. In several pathological situations, an involvement of ET-1 is suspected. Nevertheless, the effect of a chronic increase in circulating ET-1 on vascular tone in resistance arteries is not yet fully understood. We investigated the response to tensile stress (pressure-induced myogenic tone) and shear stress (flow-induced dilation, FD) of rat mesenteric resistance arteries cannulated in an arteriograph. Intraluminal diameter was measured continuously. Rats (normotensive Wistar-Kyoto rats [WKYs] and spontaneously hypertensive rats [SHRs]) were treated for 2 weeks with ET-1 (5 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 SC; nϭ8 to 16 per group). Systolic arterial blood pressure increased significantly in ET-1-treated rats (171Ϯ7 versus 196Ϯ6 mm Hg in WKYs and 216Ϯ8 versus 245Ϯ6 mm Hg in SHRs, PϽ0.05). Passive arterial diameter in isolated resistance arteries ranged from 78Ϯ9 to 169Ϯ4 m in WKYs and from 62Ϯ6 to 149Ϯ7 m in SHRs (pressure from 10 to 150 mm Hg). Myogenic tone was not significantly affected by chronic ET-1. Flow (9 to 150 L/min) significantly increased the arterial diameter by 2Ϯ0.5 to 22Ϯ2 m in WKYs and by 1.3Ϯ0.7 to 8.3Ϯ0.8 m in SHRs (PϽ0.001 versus WKYs). The NO synthesis blocker N G -nitro-L-arginine methyl ester (L-NAME; 100 mol/L) attenuated FD in WKYs (eg, 22Ϯ2 versus 15Ϯ3 m after L-NAME, flowϭ150 L/min) and, to a lesser extent, in SHRs (PϽ0.001 versus WKYs). The cyclooxygenase inhibitor indomethacin (3 mol/L) attenuated the remaining FD in WKYs (eg, 15Ϯ3 versus 8Ϯ3 m, flowϭ150 L/min) and in SHRs (eg, 7.5Ϯ0.5 versus 5.0Ϯ0.6 m). Chronic ET-1 significantly increased FD in SHRs but not in WKYs. In both strains, NO-dependent FD was significantly increased by chronic ET-1. Furthermore, indomethacin-sensitive FD was increased by chronic ET-1 in SHRs only. Thus, chronic ET-1 increased NO-dependent FD in resistance mesenteric arteries from both WKYs and SHRs and increased indomethacin-sensitive Key Words: myogenic tone Ⅲ shear stress Ⅲ resistance arteries Ⅲ endothelin Ⅲ hypertension P ressure-induced tone (myogenic tone) is a characteristic of small resistance arteries and of some veins. [1][2][3][4][5] It is opposed by flow-induced dilation in vitro as well as in vivo. 1,2,6 -8 These 2 mechanical stimuli determine a basal vascular tone in resistance arteries and allow a rapid adaptation to changes in flow and pressure. 1,8 Whereas myogenic tone is mainly independent of endothelial factors, 1,5 flow produces shear stress and triggers an endothelium-dependent dilation. 1,7,8 Flow-induced dilation depends in part on the production of NO 8 -11 and cyclooxygenase (COX) products 10 -13 by endothelial cells.Endothelial cells stimulated by hormonal 14 or mechanical 15-17 factors can produce endothelin-1 (ET-1). Mechanical factors such as pressure or wall stretch increase ET-1 gene expression and ET-1 production. 16,17 Flow, or shear stress, exerts a flow rate-dependent effect on the production of ET-1. A low flow rate or a short-term increas...

Vascular Dilation Responses of Rat Small Mesenteric Arteries at High Intravascular Pressure in Spontaneously Hypertensive Rats

“…28,29 It has been confirmed by a number of studies that SMA from SHR have a smaller lumen, as well as an increased media to lumen ratio and cross-sectional area of media. 12,13,16 In agreement with previous studies, 30,31 our results indicate that the passive diameter of SHR arteries is significantly reduced and the initial tone significantly increased at all pressures measured (ie, 50, 80 and 120 mmHg).…”

Flow (Shear Stress)–Induced Endothelium-Dependent Dilation Is Altered in Mice Lacking the Gene Encoding for Dystrophin

“…20 Then right carotid and mesenteric arteries were isolated and cannulated at both ends in a video-monitored perfusion system 34 (LSI) as previously described. 20,[35][36][37] Briefly, arteries were bathed in a physiological salt solution (pH 7.4, PO 2 160 mm Hg, PCO 2 37 mm Hg). Pressure was controlled by a servoperfusion system, and flow was generated by a peristaltic pump.…”

“…At the end of each experiment, arteries were perfused and superfused with a calcium-free physiological salt solution containing EGTA 2 mmol/L and sodium nitroprusside 10 mol/L, and pressure steps were repeated to determine the passive diameter of the arteries. 20,[35][36][37] Contractions to phenylephrine (1 nmol/L to 10 mol/L), KCl (80 mmol/L), and calcium (0.1 to 1 mmol/L in a calcium-free medium ϩ 80 mmol/L KCl) were tested separately. Dilations to acetylcholine and sodium nitroprusside were tested after preconstriction of the arteries with phenylephrine (50% of the maximal contraction).…”

Smooth Muscle Dysfunction in Resistance Arteries of the Staggerer Mouse, a Mutant of the Nuclear Receptor RORα

“…8,10 Briefly, arteries were bathed in a physiological salt solution (PSS) (pH 7.4; PO 2 160 mm Hg, PCO 2 37 mm Hg). Pressure was controlled by a servo-perfusion system and flow was generated by a peristaltic pump.…”

“…At the end of each experiment, arteries were perfused and superfused with a Ca 2ϩ -free PSS containing EGTA (2 mmol/L) and sodium nitroprusside (SNP) (10 mol/L), and pressure steps were repeated to determine the passive diameter of the artery. 8,10 …”