Chronic central nervous system MC3/4R blockade attenuates hypertension induced by nitric oxide synthase inhibition but not by angiotensin II infusion

Abstract

We examined whether central melanocortin 3 and 4 receptor (MC3/4R) blockade attenuates the blood pressure (BP) responses to chronic L-NAME or angiotensin II (Ang II) infusion in Sprague-Dawley rats implanted with telemetry transmitters, venous catheters, and intracerebroventricular cannula into the lateral ventricle. After 5 days of control measurements, L-NAME (10 μg/kg/min IV, groups 1 and 2) or Ang II (10 ng/kg/min IV, groups 3 and 4) were infused for 24 days, and starting on day 7 of L-NAME or Ang II infusion, the MC3/4R antagonist SHU-9119 (24 nmol/d, n=6/group; groups 1 and 3) or vehicle (saline 0.5 μL/h, n=6/group; groups 2 and 4) was infused intracerebroventricularly for 10 days. A control normotensive group also received SHU-9119 for 10 days (n=5). L-NAME and Ang II increased BP by 40±3 and 56±5 mm Hg, respectively, although heart rate was slightly reduced. MC3/4R blockade doubled food intake and reduced heart rate (≈40 to ≈50 bpm) in all groups. MC3/4R blockade caused only a small reduction in BP in normotensive group (4 mm Hg) and no change in rats receiving Ang II, although markedly reducing BP by 21±4 mm Hg in L-NAME-treated rats. After SHU-9119 infusion was stopped, food intake, heart rate, and BP gradually returned to values observed before SHU-9119 infusion was started. Ganglionic blockade at the end of L-NAME or Ang II infusion caused similar BP reduction in both groups. These results suggest that the brain MC3/4R contributes, at least in part, to the hypertension induced by chronic L-NAME infusion but not by Ang II.

Keywords: CNS; blood pressure; food intake; heart rate.

Figure 1

(A) Food intake, (B) mean arterial pressure, and (C) heart rate responses to L-NAME, the MC3/4R antagonist (SHU-9119), or both in Sprague-Dawley rats. * p<0.05 vs. control values within same group. # p<0.05 vs. L-NAME + Vehicle group.

Figure 2

(A) Food intake, (B) mean arterial pressure, and (C) heart rate responses to angiotensin II (Ang II), the MC3/4R antagonist (SHU-9119), or both in Sprague-Dawley rats. * p<0.05 vs. control values within same group. # p<0.05 vs. Ang II + Vehicle group. ‡ P<0.05 vs. Vehicle + SHU-9119 group.

Figure 3

Change in mean arterial pressure in response to acute ganglionic blockade with hexamethonium in L-NAME- and angiotensin II (Ang II)-treated groups. Hexamethonium was injected on the last day of the 3^rd week of L-NAME or Ang II treatment.