Impaired β-Adrenoceptor-Mediated Hyperpolarization in Resistance Arteries from Prehypertensive Shr
Stimulation of vascularβ-adrenoceptors leads to smooth muscle hyperpolarization, presumably through theβ-adrenoceptors/Gs protein/adenylate cyclase/ATP-sensitive K+-channels (KATP) signaling cascade, which has been shown to play an important role in the sympathetic control of membrane potential. Impairedβ-adrenoceptor-mediated hyperpolarization has been reported in established stage of hypertension in rat models. However, it is not known whether such an abnormality exists in prehypertensive stage. To clarify this point, we comparedβ-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). Systolic blood pressure did not differ between these rats (137.5±4.3 vs. 138.1±2.3mmHg; P=ns, n=10). Isoproterenol-induced hyperpolarization was significantly less in prehypertensive SHR than in WKY (10-7mol/L; -4.6±0.6 vs. -7.8±0.8mV; P<0.01, 10-6mol/L; -7.8±0.5 vs. -9.8±0.6mV; P<0.05; n=9 in each). Furthermore, hyperpolarization to cholera toxin, a direct activator of Gs protein, was also impaired in SHR (10-6mol/L; -2.1±0.9 vs. -4.5±0.6mV; P<0.05; n=6 in each). On the other hand, hyperpolarization to forskolin, a direct activator of adenylate cyclase, and that to levcromakalim, a KATP opener, were comparable in both groups. These findings suggest thatβ-adrenoceptor-mediated hyperpolarization is defective already in prehypertensive SHR, presumably due to an abnormality at the level of Gs protein. In view of the importance of membrane potential in the control of vascular tone, such a defect may play a pathogenic role in genetic hypertension through an increase in vascular resistance.