Impaired beta-adrenergic hyperpolarization in arteries from prehypertensive spontaneously hypertensive rats.
Stimulation of beta-adrenoceptors leads to vascular smooth muscle hyperpolarization, presumably through the beta-adrenoceptors/Gs protein/adenylate cyclase/ATP-sensitive K(+)-channels (KATP) signaling cascade, which may play an important role in the sympathetic control of membrane potential. beta-Adrenoceptor-mediated hyperpolarization has been shown to be impaired in the established stage of experimental hypertension. The present study tested the hypothesis that beta-adrenergic hyperpolarization may be defective before the development of hypertension in some forms of genetic hypertension. We evaluated beta-adrenoceptor-mediated hyperpolarization using microelectrodes in mesenteric resistance arteries from 5-week-old, prehypertensive, spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). Isoproterenol-induced hyperpolarization was significantly smaller in SHR than in WKY (10(-7) mol/L: -4.6+/-0.6 versus -7.8+/-0.8 mV, P<0.01; 10(-6) mol/L -7.8+/-0.5 versus -9.8+/-0.6 mV, P<0.05; n=9). Furthermore, hyperpolarization to cholera toxin, a direct activator of Gs protein, was also impaired in SHR. On the other hand, hyperpolarization to forskolin, an adenylate cyclase activator, and to levcromakalim, a KATP opener, was comparable between groups. These findings suggest that beta-adrenoceptor-mediated hyperpolarization is defective in SHR before the development of hypertension, presumably because of an abnormality at the Gs protein site. Considering the importance of membrane potential in the control of vascular tone, altered beta-adrenergic control of membrane potential might play a role in the development of hypertension in SHR.
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
K
K
Goto
K
K
Fujii
I
I
Abe
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials; D008638:Mesenteric Arteries / Q000378:metabolism; D008839:Microelectrodes; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014655:Vascular Resistance
D000959:Antihypertensive Agents; D011943:Receptors, Adrenergic, beta; D019806:Cromakalim; D005576:Colforsin; D002772:Cholera Toxin; D007545:Isoproterenol