Abstract
Progression of myocardial infarction (MI) to heart failure may be exacerbated by excessive activation of the sympathetic nervous system (SNS). We previously showed that the central nervous system (CNS) melanocortin system plays a key role in regulating SNS activity and blood pressure (BP) in several different conditions, including hypertension and obesity. Therefore, we tested whether melanocortin-4 receptor (MC4R) blockade protects against cardiac dysfunction associated with MI in rats. Male Sprague-Dawley rats at 12 weeks of age were implanted with BP telemetry transmitters and an intracerebroventricular (ICV) cannula was inserted into the lateral ventricle. After 10 days of recovery, food intake, mean arterial pressure (MAP) and heart rate (HR) were measured 24-hrs/day by telemetry and cardiac function was assessed by echocardiography (VEVO 2100 @ ). After stable baseline measurements for 4 days, the left coronary artery was permanently ligated and vehicle (n=5) or the MC4R antagonist (SHU-9119, 1 nmol/h, n=7) was infused ICV via osmotic minipump for 28 consecutive days. Chronic MC4R antagonism significantly increased food intake and body weight (25±1 to 37±4 g/day and 365±4 to 497±10 g) compared to vehicle treatment (24±1 to 20±1 g/day and 372±6 to 417±5 g). Chronic SHU-9119 infusion did not alter MAP (108±1 to 105±2 mmHg) whereas MAP was significantly reduced in vehicle-treated rats with MI (104±1 to 97±2 mmHg). However, HR decreased more in SHU-9119-treated rats (~-70 bpm) than in vehicle group (~-42 bpm). Compared to vehicle, SHU-9119 infusion for 4 weeks did not prevent cardiac dysfunction caused by MI as evidenced by low cardiac radial strain (40±1 to 18±3 vs. 44±2 to 23±5 %), cardiac output (106±7 to 68±4 vs. 114±5 to 86±8 ml/min) and ejection fraction (71±2 to 33±2 vs. 71±2 to 38±4 %). These results suggest that chronic central MC4R inhibition does not attenuate the progression to heart failure after MI in rats. (NHLBI-PO1HL51971, NIGMS- P20GM104357)
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