Cardiovascular responses to melanocortin 4-receptor stimulation in conscious unrestrained normotensive rats

In the present studies, we used a non-selective melanocortin MC3/4 receptor agonist (HP228) and a novel selective melanocortin MC4 receptor (MC4-R) agonist (MK-cpd1) to study the cardiovascular, temperature, locomotor and feeding responses to melanocortin receptor stimulation in comparison to sibutramine in rats instrumented with a telemetry transmitter. Moreover, norepinephrine turnover rates in heart and brown adipose tissue were determined. HP228 (1, 3 and 10 mg/kg, i.p.) reduced 24 h food intake dose-dependently and increased heart rate and mean arterial pressure (maximal differences: +60 ± 8 beats/min and +8 ± 1 mmHg, means ± S.E.M., p < 0.001 and p < 0.01, respectively). After 10 mg/kg HP228 showed a three-fold increase in norepinephrine turnover in the heart. The selective MC4-R agonist MK-cpd1 tended to decrease 24 h food intake only at the highest dose tested (10 mg/kg, i.p., p = 0.06) and increased both heart rate (+17 ± 4 and +22 ± 5 beats/min at 3 and 10 mg/kg, p < 0.01) and mean arterial pressure (+4 ± 1 mmHg at 10 mg/kg, p < 0.05). Sibutramine reduced food intake at all doses tested (1, 3 and 10 mg/kg, i.p.). It did not change mean arterial pressure significantly, and increased heart rate only at the highest dose tested (+36 ± 6 beats/min, p < 0.05). If also observed in humans, the pharmacological profile of MC4-R agonists would not offer a significant therapeutic advantage over currently used appetite suppressants such as sibutramine.