Sympathoinhibitory and depressor responses to long-term infusion of nifedipine in spontaneously hypertensive rats on high-salt diet.

Abstract

Short-term (by hour) intracerebroventricular (i.c.v.) or i.v. infusion of nifedipine at low rates evokes parallel decreases in renal sympathetic nerve activity (RSNA) and blood pressure (BP) in spontaneously hypertensive rats (SHR). In the present study, effects of long-term administration of nifedipine on BP and control of sympathetic tone were examined in SHR on a high-salt (8%) diet. From 6 to 8 weeks of age, for 2 weeks concomitant with taking a high-salt diet, rats were also treated with subcutaneous infusion of nifedipine at 10, 50, or 100 microg/kg/h or vehicle solvent as control using osmotic minipumps. At the end of the 2-week treatment period, mean arterial pressure (MAP), heart rate (HR), and RSNA at rest and in response to air-jet stress, i.c.v. injection of the alpha-adrenoceptor agonist guanabenz (25 microg), and i.v. injection of the ganglionic blocker hexamethonium were recorded in conscious rats. In rats on nifedipine 50 or 100 microg/kg/h, resting MAP was significantly lower (136+/-4 or 130+/-4 vs. 145+/-2 mm Hg in control rats, p < 0.05 for both), the sympathoinhibitory and depressor responses to i.c.v. guanabenz were significantly decreased, and the absolute decreases in MAP in response to i.v. injection of hexamethonium were significantly smaller. Sympathoexcitatory and pressor responses to air-jet stress, however, were not affected by nifedipine. Infusion of nifedipine at the three rates for 2 weeks caused concentrations of plasma nifedipine in a dose-related manner. Nifedipine was not detected in tissues of rats treated with 10 microg/kg/h nifedipine but was present in brain and other tissues of rats treated with nifedipine at the two higher rates. Thus in SHR on high-salt intake long-term treatment with nifedipine at 50 or 100 microg/kg/h decreased resting BP and the sympathetic component in BP control. In addition to possible peripheral effects, long-term administration of nifedipine may also act centrally to decrease sympathetic activity and BP, likely by increasing activity in central pathways involving sympathoinhibition, but not in pathways involving sympathoexcitation as evaluated by air-stress.