Impaired isoproterenol-induced hyperpolarization in isolated mesenteric arteries of aged rats.
Stimulation of vascular beta-adrenoceptors leads to membrane hyperpolarization, presumably via the beta-adrenoceptor/G(s) protein/adenylate cyclase signaling cascade; the ionic mechanisms of this phenomenon remain unclear. beta-Adrenoceptor-mediated vascular relaxation is impaired with aging; however, little is known concerning whether beta-adrenoceptor-mediated hyperpolarization is altered with aging. We sought to determine the ionic mechanisms of isoproterenol-induced hyperpolarization in the rat mesenteric resistance artery, as well as the age-related changes in isoproterenol-induced hyperpolarization and their underlying mechanisms. Isoproterenol-induced hyperpolarization was inhibited by high-K(+) solution and glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive K(+) channels (K(ATP)), but not by apamin, iberiotoxin, or charybdotoxin, inhibitors of Ca(2+)-activated K(+) channels. Isoproterenol-induced hyperpolarization was markedly less in aged rats (>/=24 months) than in adults rats (12 to 20 weeks) (3x10(-6) mol/L; -3.1 versus -9.9 mV; P<0.001; n=8 to 9). Cholera toxin (10(-9) g/mL), an activator of G(s), evoked hyperpolarization only in adult rats. Hyperpolarization to forskolin, a direct activator of adenylate cyclase, was also reduced to some extent in aged rats (10(-5) mol/L; -8.8 versus -13 mV; P<0.05; n=6), whereas hyperpolarization to levcromakalim, a K(ATP) opener, was comparable in both groups. These findings suggest that isoproterenol elicits hyperpolarization via an opening of K(ATP) in the rat resistance artery and that isoproterenol-induced hyperpolarization is attenuated in aged rats mainly because of a defective coupling of beta-adrenoceptors to adenylate cyclase and partly because of a defect at the level of adenylate cyclase, but not because of an alteration of K(ATP) per se.
Fujii
K
K
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan. fujii@intmed2.med.kyushu-u.ac.jp
Onaka
U
U
Goto
K
K
Abe
I
I
Fujishima
M
M
D000262:Adenylyl Cyclases / Q000378:metabolism / Q000502:physiology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000367:Age Factors; D000375:Aging; D000818:Animals; D002078:Butoxamine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008790:Metoprolol / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D015221:Potassium Channels; D011943:Receptors, Adrenergic, beta; D014665:Vasodilator Agents; D019806:Cromakalim; D002078:Butoxamine; D005576:Colforsin; D000262:Adenylyl Cyclases; D008790:Metoprolol; D007545:Isoproterenol