Effects of endothelin receptor antagonists and nitric oxide on myogenic tone and alpha-adrenergic-dependent contractions of rabbit resistance arteries

Regulation of vascular contractions by endothelium-derived endothelin-1 (ET -1) and nitric oxide (NO) may vary depending on the stimulus. Objectives: T o investigate if ET-1 receptor stimulation and NO contributed to a similar extent to the regulation of pressure- and a-adrenergic receptor (AR) agonis t-induced smooth muscle contraction. Methods: Rabbit mesenteric arteries (1 50-200 mu m) were isolated, cannulated and pressurized. Changes in diameter were recorded as a function of the perfusion pressure (PP) or a-AR agonist addition at a PP of 60 mmHg, All experiments were performed in the presenc e of indomethacin (10 mu mol 1-'). Results: At a PP of 60 mmHg, myogenic to ne (MT) developed to represent 17+/-1% of the minimal diameter. The magnitu de of the MT was increased by 140% (P<0.05) by the inhibition of NO product ion with N-omega-nitro-L-arginine (L-NOARG). Bosentan, an ETA/B receptor an tagonist, and BQ 123, a selective ETA receptor antagonist, decreased (P<0.0 5) MT either alone or in combination with L-NOARG by approximate to 30%. Ph enylephrine (Phe), an alpha(1)-AR agonist, induced contraction; the sensiti vity to Phe (pD(2), 6.2+/-0.2) was unaffected by bosentan or BQ 123 alone b ut increased (P<0.05) by L-NOARG (pD(2), 7.3+/-0.5). Further addition of bo sentan or BQ 123 restored the sensitivity to Phe to its control value. Oxym etazoline (OXY), an alpha(1)-AR agonist, induced contraction; the sensitivi ty to OXY (pD=(2), 7.7+/-0.2) was unaffected by L-NOARG, bosentan or BQ 123 , Conclusion: Our results indicate that pressure-induced tone is independen tly regulated by endothelium-derived NO and ET-1. In contrast, alpha(1)-AR stimulation-induced tone is sensitive to ET-1 in the absence of NO, whereas occupation of alpha(2)-AR mediates a contraction unregulated by the endoth elium. (C) 1999 Elsevier Science B.V. All rights reserved.