Role of melanocortin 4 receptor in hypertension induced by chronic intermittent hypoxia

Aim We previously demonstrated that central nervous system (CNS) melanocortin 4 receptors (MC4R) play a key role in regulating blood pressure (BP) in some conditions associated with increased SNS activity, including obesity. In this study, we examined whether activation of CNS MC4R contributes to chronic intermittent hypoxia (CIH)-induced hypertension and ventilatory responses to hypercapnia. Methods Rats were instrumented with an intracerebroventricular (ICV) cannula in the lateral cerebral ventricle for continuous infusion of MC4R antagonist (SHU-9119) and telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR). Untreated and SHU-9119-treated rats as well as obese and lean MC4R-deficient rats were exposed to CIH for 7-18 consecutive days. Results Chronic intermittent hypoxia reduced cumulative food intake by 18 +/- 5 g while MAP and HR increased by 10 +/- 3 mm Hg and 9 +/- 5 bpm in untreated rats. SHU-9119 increased food intake (from 15 +/- 1 to 46 +/- 3 g) and prevented CIH-induced reduction in food intake. CIH-induced hypertension was not attenuated by MC4R antagonism (average increase of 10 +/- 1 vs 9 +/- 1 mm Hg for untreated and SHU-9119 treated rats). In obese MC4R-deficient rats, CIH for 7 days raised BP by 11 +/- 4 mm Hg. However, when MC4R-deficient rats were food restricted to prevent obesity, CIH-induced hypertension was attenuated by 32%. We also found that MC4R deficiency was associated with impaired ventilatory responses to hypercapnia independently of obesity. Conclusion These results show that obesity and the CNS melanocortin system interact in complex ways to elevate BP during CIH and that MC4R may be important in the ventilatory responses to hypercapnia.