Fujii K, Onaka U, Goto K, Abe I, Fujishima M
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Hypertension. 1999 Aug;34(2):222-8. doi: 10.1161/01.hyp.34.2.222.
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.
血管β-肾上腺素能受体的刺激可能通过β-肾上腺素能受体/G(s)蛋白/腺苷酸环化酶信号级联反应导致膜超极化；这一现象的离子机制仍不清楚。β-肾上腺素能受体介导的血管舒张功能会随着衰老而受损；然而，关于β-肾上腺素能受体介导的超极化是否会随衰老而改变，人们知之甚少。我们试图确定异丙肾上腺素诱导大鼠肠系膜阻力动脉超极化的离子机制，以及异丙肾上腺素诱导的超极化的年龄相关变化及其潜在机制。高钾溶液和格列本脲（10(-6) mol/L）可抑制异丙肾上腺素诱导的超极化，格列本脲是一种ATP敏感性钾通道（K(ATP)）抑制剂，但阿帕明、iberiotoxin或大蝎毒素（均为钙激活钾通道抑制剂）则无此作用。与成年大鼠（12至20周）相比，老年大鼠（≥24个月）中异丙肾上腺素诱导的超极化明显减弱（3×10(-6) mol/L；-3.1 mV对-9.9 mV；P<0.001；n = 8至9）。霍乱毒素（10(-9) g/mL）是G(s)的激活剂，仅在成年大鼠中引起超极化。在老年大鼠中，对腺苷酸环化酶直接激活剂福斯可林的超极化也有一定程度的降低（10(-5) mol/L；-8.8 mV对-13 mV；P<0.05；n = 6），而对K(ATP)开放剂左旋克罗卡林的超极化在两组中相当。这些发现表明，异丙肾上腺素通过开放大鼠阻力动脉中的K(ATP)引发超极化，并且老年大鼠中异丙肾上腺素诱导的超极化减弱主要是由于β-肾上腺素能受体与腺苷酸环化酶的偶联缺陷，部分原因是腺苷酸环化酶水平的缺陷，但不是因为K(ATP)本身的改变。
