Chronic activation of central α 2-adrenoceptors prevents hypertension in DOCA-salt rats

Abstract

The effects of chronic intracerebroventricular (i.c.v.) injections of the α 2-adrenoceptor agonist, xylazine, on blood pressure were examined in DOCA-salt rats. Acute studies also examined the renal sympathetic nerve activity (RSNA) and renal excretory responses produced by i.c.v. xylazine in rats with established DOCA-salt hypertension. Rats implanted with a chronic i.c.v. cannula for drug injection were used. In chronic studies, four groups were investigated: control rats treated with s.c. soybean oil and i.c.v. saline; DOCA-salt rats (s.c. deoxycorticosterone acetate) receiving i.c.v. saline, xylazine or the α 2-adrenoceptor antagonist, yohimbine. During vehicle or DOCA-salt treatment, xylazine (0.2 ng/μg) or yohimbine (10 μg/kg) was injected i.c.v. daily (three times). In DOCA-salt rats receiving i.c.v. saline, resting mean arterial pressure (MAP) was elevated on days 15 and 30 (135±5 and 160±6 mmHg, respectively). Chronic i.c.v. xylazine significantly attenuated the rise in MAP produced by DOCA-salt (day 15, 118±5 mmHg; day 30, 121±4 mmHg). Alternatively, chronic i.c.v. yohimbine shortened the onset (day 15, 152±7 mmHg) and augmented the hypertension in DOCA-salt rats (0 survival by day 30). In acute studies, i.c.v. xylazine elicited a profound natriuresis and diuresis as well as a reduction in RSNA without altering MAP. This study demonstrates that the ongoing (tonic) activity of central α 2-adrenoceptor mechanisms are critically involved in regulating blood pressure in the DOCA-salt treated rat. In this manner, an enhanced activity of central α 2-adrenoceptor systems acts to protect against a rise in blood pressure. In contrast, the attenuation of central α 2-adrenoceptor stimulation evokes hypertension. The central action of xylazine to prevent hypertension may be associated with the inhibition of sympathetic outflow to the kidneys and evokes an enhanced natriuresis. By inhibiting the avid sodium retention elicited by DOCA-salt treatment, the central activation of α 2-adrenoceptors delays the onset and the severity of hypertension in this pathological model.