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 BP responses to chronic L-NAME or angiotensin II (Ang-II) infusion in Sprague Dawley rats implanted with telemetry transmitters, venous catheters and intracerebroventricular (ICV) cannula into the lateral ventricle. After 5 days of control measurements, L-NAME (10 μg/kg/day, i.v. – groups 1 and 2) or Ang II (10 ng/kg/min, i.v. – 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/day, n=6/group – groups 1 and 3) or vehicle (saline 0.5 μl/hr, n=6/group – groups 2 and 4) was infused ICV 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 mmHg, respectively; while heart rate (HR) was slightly reduced. MC3/4R blockade doubled food intake and reduced HR (~40 to ~50 bpm) in all groups. MC3/4R blockade caused only a small reduction in BP in normotensive group (4 mmHg) and no change in rats receiving Ang II, while markedly reducing BP by 21±4 mmHg in L-NAME treated rats. After SHU-9119 infusion was stopped, food intake, HR and BP gradually returned to values observed before SHU-9119 infusion was started. Ganglionic blockade performed 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.

Obesity-Induced Hypertension

“…MC4R antagonism also reduced BP in obese Zucker rats with defective LepR signaling 127 and attenuated BP effects of other peptides besides leptin, including nesfatin-1 and neuronostatin 128,129 . Also, MC4R blockade attenuated hypertension associated with inhibition of NO synthesis but did not lower BP in AngII hypertension which is associated with decreased RSNA 130 . Studies in humans also show that increased MSNA during hypoxic stress is attenuated in MC4R deficient subjects 131 .…”

Role of hindbrain melanocortin-4 receptor activity in controlling cardiovascular and metabolic functions in spontaneously hypertensive rats

“…Also our previous studies support an important participation of brain MC3/4R in regulating BP in other nonobese models of hypertension. For instance, chronic infusion of MC3/4R antagonist into the lateral ventricles caused marked BP reductions after blockade of nitric oxide synthesis in L-NAME-treated rats, suggesting that endogenous brain MC3/4R activation may play an important role in regulating BP in this model of hypertension [7]. …”

“…For instance, we found that chronic infusion of MC3/4R antagonist into the lateral ventricles of lean spontaneous hypertensive rats (SHRs), a model of hypertension associated with high sympathetic tone, markedly reduced their BP to the same degree as accomplished by adrenergic receptor blockade [6]. In addition, chronic MC3/4R antagonism markedly reduced the hypertension induced by chronic nitric oxide synthase inhibition using N G -nitro-L-argenine methyl ester (L-NAME) in lean Sprague–Dawley rats [7]. Therefore, the CNS melanocortin system appears to play a more fundamental role in regulating SNS activity and BP than previously appreciated.…”

Role of the brain melanocortins in blood pressure regulation

“…In lean normotensive animals, chronic MC4R antagonism caused sustained bradycardia and reduced BP in spite of hyperphagia and rapid weight gain which normally would evoke tachycardia and elevated BP [56]. Blockade of endogenous MC4R activity also reduced BP in several non-obese experimental models of hypertension, especially those associated with increased SNS activity [42, 57] (Figure 2). For instance, the BP-lowering effects of MC4R antagonism are especially pronounced in spontaneously hypertensive rats (SHR), a genetic model of hypertension that has increased SNS activity [42].…”

“…However, MC4R blockade failed to lower BP in angiotensin-II-induced hypertension, an experimental model with baroreflex mediated reductions in SNS activity [57]. These findings highlight the key role of the brain melanocortin system in maintenance of SNS activity and BP in normotensive subjects as well as in non-obese forms of hypertension that have increased sympathetic activity [41, 42, 57, 58]. …”