DIRECT CARDIAC AND VASCULAR ACTIONS OF ADRENOMEDULLIN IN CONSCIOUS SHEEP

1 Adrenomedullin (ADM) is a recently characterized circulating hormone which affects haemodynamic, renal and pituitary function in mammals. We have shown previously that in sheep, ADM produces vasodilatation to gether with increases in cardiac output and contractility. However, wh ether these effects are direct or mediated by autonomic reflexes is un clear. The present study examined the cardiovascular actions of an int ravenous infusion of ADM in conscious, chronically instrumented sheep with either sympathetic, parasympathetic or autonomic ganglion blockad e, to determine the role of the autonomic nervous system in mediating these cardiovascular changes. 2 Human ADM (1-52) was infused for 60 mi n at 2 mu g kg(-1) h(-1) following: (1) saline control, (2) combined a lpha/beta-adrenoceptor (sympathetic) blockade (proporanolol 0.4 mg kg( -1) h(-1)+phentolamine 0.15 mg kg(-1) h(-1) for 20 h), (3) muscarinic (parasympathetic) blockade (methscopolamine 0.05 mg kg(-1) h(-1) for 2 0 h) or (4) ganglion blockade (hexamethonium 3 mg kg(-1) h(-1) for 4 h ). Measurements were made of mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral conduc tance (TPC), maximal aortic flow (Fmax) and maximal rate of change of aortic flow (dF/dt). 3 ADM reduced MAP by 3+/-1 mmHg, and increased CO (1.2+/-0.2 l min(-1)), HR (14+/-2 beats min(-1)), TPC (21+/-3 ml min( -1) mmHg(-1)), Fmax (2.3+/-0.8 l min(-1)) and dF/dt (86+/-21 l min(-1) s(-1)) in normal sheep. In animals with alpha/beta blockade, similar changes were observed with ADM. However, during muscarinic blockade, t he increases in HR (32+/-4 beats min(-1)), CO (2.1+/-0.41 min(-1)), TP C (31+/-4 ml min(-1) mmHg(-1)), Fmax (4.0+/-0.6 l min(-1)), and dF/dt (150+/-12 l min(-1) s(-1)) produced by ADM were enhanced. During gangl ion blockade, ADM produced a greater reduction in MAP (-10+/-2 mmHg) c ompared to controls (-3+/-1 mmHg). However, there was no increase in H R. The changes in CO, TPC and contractility were similar to those obse rved in control animals. 4 These results suggest that the vasodilator effects of ADM on the periphery and its ability to increase CO and car diac contractility are not mediated by the autonomic nervous system, b ut are probably the result of direct actions of ADM on the heart and v asculature.