Impaired β-Adrenergic Hyperpolarization in Arteries From Prehypertensive Spontaneously Hypertensive Rats

Abstract

Abstract-Stimulation of ␤-adrenoceptors leads to vascular smooth muscle hyperpolarization, presumably through the ␤-adrenoceptors/Gs protein/adenylate cyclase/ATP-sensitive K ϩ -channels (KATP) signaling cascade, which may play an important role in the sympathetic control of membrane potential. ␤-Adrenoceptor-mediated hyperpolarization has been shown to be impaired in the established stage of experimental hypertension. The present study tested the hypothesis that ␤-adrenergic hyperpolarization may be defective before the development of hypertension in some forms of genetic hypertension. We evaluated ␤-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 Ϫ7 mol/L: Ϫ4.6Ϯ0.6 versus Ϫ7.8Ϯ0.8 mV, PϽ0.01; 10 Ϫ6 mol/L: Ϫ7.8Ϯ0.5 versus Ϫ9.8Ϯ0.6 mV, PϽ0.05; nϭ9). 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 ␤-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 ␤-adrenergic control of membrane potential might play a role in the development of hypertension in SHR. Key Words: receptors, adrenergic Ⅲ membrane potentials Ⅲ hyperpolarization Ⅲ hypertension, genetic Ⅲ rats, spontaneously hypertensive S timulation of vascular ␤-adrenoceptors leads to smooth muscle hyperpolarization and relaxation, presumably through the ␤-adrenoceptors/Gs protein/adenylate cyclase/ cAMP signaling cascade. 1,2 We recently demonstrated that isoproterenol-induced hyperpolarization is mediated by the opening of ATP-sensitive K ϩ channels (KATP) in rat mesenteric resistance arteries, 2 which parallels the case of the canine saphenous veins, 3 and that this ␤-adrenergic hyperpolarization plays an important role in the sympathetic control of membrane potential by opposing ␣-adrenoceptor-mediated depolarization. 4 In view of the importance of membrane potential as a determinant of smooth muscle tone, 5 ␤-adrenoceptor-mediated hyperpolarization may play an important role in the control of vascular tone.␤-Adrenoceptor-mediated relaxation is impaired in arteries from hypertensive rats, 6 -11 and in some models, such an abnormality has been shown to precede the development of hypertension. 6,7 On the other hand, information is limited regarding ␤-adrenoceptor-mediated hyperpolarization in hypertension. To the best of our knowledge, the only previous report on this topic, made by Stekiel et al, 1 demonstrated that in situ hyperpolarization to isoproterenol is impaired in arterioles f...

Reduced KCNQ4-Encoded Voltage-Dependent Potassium Channel Activity Underlies Impaired β-Adrenoceptor–Mediated Relaxation of Renal Arteries in Hypertension

“…[6][7][8][9][10][11] To date there is no information on the role of Kv7 channels in the physiological response to endogenous vasorelaxants, such as ␤-adrenoceptor stimulants. Figure 3A shows that the ␤-adrenoceptor agonist isoproterenol (0.001-3.000 mol/L) caused concentration-dependent relaxation in renal arteries from NT animals, which was attenuated by 10 mol/L of linopirdine (maximum effect: linopirdine 39.3Ϯ15.5, vehicle 103.6Ϯ4.2; nϭ5; Pϭ0.0079).…”

“…5 Moreover, it is widely recognized that altered sympathetic effects on the renal artery are strongly implicated in the initiation and perpetuation of the hypertensive state with dysfunction of the ␤-adrenoceptor pathway a dominant feature. [6][7][8][9][10][11] However, little is known about the molecular mechanisms that contribute to renal artery vasospasm and decreased ␤-adrenoceptor-mediated dilation. Potassium (K ϩ ) channels regulate resting membrane potential in smooth muscle cells (SMCs) and are, thus, key determinants of smooth muscle contractility.…”

Vascular Smooth Muscle Overexpression of G Protein–Coupled Receptor Kinase 5 Elevates Blood Pressure, Which Segregates With Sex and Is Dependent on G i -Mediated Signaling

“…For example, impairment in ␤-adrenergic receptor (AR)-G s heterotrimeric signaling has been documented in patients with hypertension, and studies from animal models provide further support for the critical role of ␤ARs in hypertension. [1][2][3][4][5] Other GPCRs, such as angiotensin II (Ang II) receptors, are also essential to BP regulation. 6 Ang II receptors couple to both G q and G i , and activation of both these heterotrimeric G proteins mediates vasoconstriction.…”

Prehypertension: Underlying pathology and therapeutic options

“…Prior to this observation, Fujimoto et al [120] demonstrated that β-adrenoceptor-mediated relaxation of arteries, in the same species, was diminished before and during development of HTN. The diminished relaxation may be because of defective hyperpolarization induced by these receptors [121] . In the same rat species, both the M3 cholinoceptors-and P2y-mediated relaxation was not altered [122] ruling out involvement of any other component of the autonomic nervous system apart from the sympathetic.…”