1-ethyl-2-benzimidazolinone stimulates endothelial K-Ca channels and nitric oxide formation in rat mesenteric vessels

Hyperpolarization of most blood vessels occurs by the opening of K-Ca chann els. 1-Ethyl-2-benzimidazolinone (1-EBIO) is a direct activator of K-Ca cha nnels in epithelial cells and is potentially valuable for studying cellular hyperpolarization. This study reports the effects of 1-EBIO on isolated ra t mesenteric beds perfused with normal (4.7 mM), or high (20 or 80 mM) K+ p hysiological salt solution (PSS) and constricted with an alpha(1)-adrenocep tor agonist, cirazoline (0.3-1 mu M). Arterial perfusion pressures were dec reased by 1-EBIO (0.1-30 nmol) in a dose- and endothelium-dependent manner. Infusion of penitrem A (100 nM), a maxi-K+ channel blocker, or apamin (0.5 mu M), a small-conductance (SKCa) K+ channel blocker, produced significant increases in cirazoline-mediated tone (mm Hg): 103.3 +/- 8.7 (control) vs. 156.3 +/- 14.3 (penitrem A); or 93.0 +/- 15.8 (control) vs. 114.0 +/- 15.4 (apamin). 1-EBIO relaxations were attenuated by penitrem A, while apamin, dendrotoxin (50 nM; a K-V channel antagonist), or ouabain (100 mu M; a sodi um pump blocker) failed to alter the responses. 1-EBIO-mediated relaxations decreased significantly with increasing extracellular [K+]: relaxations to 30 nmol were 89.3% +/- 3.2% (4.7 mM Kc, normal PSS) vs. 59.5% +/- 3.4% and 19.0%,3.9% for 20 and 80 mM K+ PSS, respectively. N omega-nitro-L-arginine -methyl ester (L-NAME; 100 mu M), and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin -1-one (ODQ; 10 mu M), selective inhibitors of nitric oxide synthase, and n itric oxide-sensitive guanylate cyclase, respectively, abolished 1-EBIO rel axations in vessels pet-fused with 20 or 80 mM KC PSS. We conclude that: (1 ) maxi-K+ and SKCa channels are present in rat mesenteric arterial vessels and actively contribute to vascular tone, (2) vasodilator action of 1-EBIO involves the opening of endothelial maxi-K+ channels and nitric oxide synth esis. (C) 1999 Elsevier Science B.V. All rights reserved.