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Activation of endothelial cell IK(Ca) with 1-ethyl-2-benzimidazolinone evokes smooth muscle hyperpolarization in rat isolated mesenteric artery.

ABSTRACT: 1. In rat small mesenteric arteries contracted with phenylephrine, 1-ethyl-2-benzimidazolinone (1-EBIO; 3-300 microM) evoked concentration-dependent relaxation that, above 100 microM, was associated with smooth muscle hyperpolarization. 2. 1-EBIO-evoked hyperpolarization (maximum 22.1+/-3.6 mV with 300 microM, n=4) was endothelium-dependent and inhibited by charybdotoxin (ChTX 100 nM; n=4) but not iberiotoxin (IbTX 100 nM; n=4). 3. In endothelium-intact arteries, smooth muscle relaxation to 1-EBIO was not altered by either of the potassium channel blockers ChTX (100 nM; n=7), or IbTX (100 nM; n=4), or raised extracellular K(+) (25 mM). Removal of the endothelium shifted the relaxation curve to the right but did not reduce the maximum relaxation. 4. In freshly isolated mesenteric endothelial cells, 1-EBIO (600 microM) evoked a ChTX-sensitive outward K-current. In contrast, 1-EBIO had no effect on smooth muscle cell conductance whereas NS 1619 (33 microM) stimulated an outward current while having no effect on the endothelial cells. 5. These data show that with concentrations greater than 100 microM, 1-EBIO selectively activates outward current in endothelial cells, which presumably underlies the smooth muscle hyperpolarization and a component of the relaxation. Sensitivity to block with charybdotoxin but not iberiotoxin indicates this current is due to activation of IK(Ca). However, 1-EBIO can also relax the smooth muscle by an undefined mechanism, independent of any change in membrane potential.

SUBMITTER: Walker SD

PROVIDER: S-EPMC1573096 | biostudies-other | 2001 Dec

REPOSITORIES: biostudies-other

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Project description:(1) Vasorelaxation and hyperpolarization of endothelial cells by adenosine 5'-[beta-thio]diphosphate (ADPbetaS) and adenosine 5'-[gamma-thio]triphosphate (ATPgammaS) were studied in rat-isolated mesenteric artery. Effects from stimulation of P2X receptors were avoided by desensitization with alpha,beta-methylene adenosine triphosphate. (2) ADPbetaS caused concentration- and endothelium-dependent relaxations of methoxamine-precontracted small (third generation) and main mesenteric artery. These were inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME) or a combination of apamin plus charybdotoxin (inhibitors of Ca(2+)-activated K(+) channels); L-NAME, apamin and charybdotoxin applied together abolished the response. (3) ATPgammaS induced limited relaxation (35% of methoxamine-induced tone at 10 micro M) of small mesenteric artery, which was sensitive to L-NAME or endothelium denudation. However, it almost completely relaxed the main mesenteric artery over an extended concentration range (>6 orders of magnitude) in an endothelium-dependent manner. This relaxation was inhibited by either L-NAME or a combination of apamin with charybdotoxin, and abolished by a combination of all the three inhibitors. (4) The P2Y(1) receptor antagonist MRS 2179 (2'-deoxy-N(6)-methyladenosine 3',5'-bisphosphate; 0.3-3 micro M) caused parallel rightward shifts of the concentration/relaxation curve to ADPbetaS (pA(2)=7.1). However, MRS 2179 did not inhibit, but potentiated, relaxant responses to ATPgammaS. MRS 2179 did not affect the contractile responses ATPgammaS in small mesenteric artery; ATPgammaS did not contract the main mesenteric artery. (5) ADPbetaS hyperpolarized the endothelium of the main mesenteric artery in a concentration-dependent manner. This was unaffected by L-NAME but antagonized by MRS 2179. ATPgammaS also hyperpolarized the mesenteric artery endothelium in a concentration-dependent manner but, when ATPgammaS was applied at 10 micro M, its effect was potentiated by MRS 2179 (3 micro M). (6) It is concluded that both relaxation and hyperpolarization to ADPbetaS are mediated by P2Y(1) receptors and that the endothelial hyperpolarization is related to the L-NAME-resistant relaxation. Relaxation to the P2Y(2) agonist ATPgammaS shows regional variation along the mesenteric vasculature. The mechanisms for potentiation of relaxation and hyperpolarization by ATPgammaS are unknown, but may indicate interactions between P2Y receptor subtypes.

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Activation of endothelial cell IK(Ca) with 1-ethyl-2-benzimidazolinone evokes smooth muscle hyperpolarization in rat isolated mesenteric artery.

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