Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels

Abstract

AimsThe haemodynamic effects of adrenomedullin and calcitonin gene-related peptide (CGRP) were studied in resistance and capacitance vessels of healthy volunteers. Methods Adrenomedullin and CGRP were infused into the brachial artery of eight healthy subjects on two separate occasions at doses between 0.3-30 pmol min −1 .Forearm blood flow was measured using venous occlusion plethysmography. Venodilatation to adrenomedullin and CGRP was assessed in a further eight subjects by infusing the peptides at doses between 0.3-10 pmol min −1 into a dorsal hand vein preconstricted with noradrenaline. Venodilator responses were measured as percentage reduction in noradrenaline preconstriction. Results Adrenomedullin and CGRP at a dose of 30 pmol min −1 , produced an increase in forearm blood flow of 288±42% and 252±30% respectively (mean±s.e. mean, P<0.001). At doses between 3 and 10 pmol min −1 adrenomedullin was significantly more potent than CGRP. The vasodilatation to both peptides was of similar duration with a biological half-life of approximately 18 min. Adrenomedullin reversed constriction in dorsal hand veins by 84±2% (P<0.001) at a dose of 10 pmol min −1 . CGRP produced a similar effect reversing constriction by 72±12%at the same dose (P<0.01). In veins, adrenomedullin was also more potent than CGRP at doses between 0.3 and 3 pmol min −1 . ConclusionsThe lowest dose of adrenomedullin producing significant arteriolar dilatation was calculated to produce plasma levels similar to those found in heart failure. These findings suggest that in pathophysiological conditions such as heart failure circulating levels of adrenomedullin may be within a range capable of influencing vascular resistance directly.

Adrenomedullin increases cardiac sympathetic nerve activity in normal conscious sheep

“…Furthermore, NP is predominantly a venodilator and has no direct inotropic effect, both of which limit the cardiac output response to hypotension (Miletich & Ivankovich 1978, Bauer & Fung 1996. In contrast, AM is mainly an arterial vasodilator (Champion et al 1997, Cockcroft et al 1997 and may increase cardiac contractility (Parkes & May 1995, Szokodi et al 1998. The exaggerated heart rate response to AM observed in the present study may be due to increased sympathetic outflow from the central nervous system resulting in a greater rise in heart rate than that expected by baroreceptor activation alone.…”

“…Accordingly, CTPR fell more for a given fall in arterial pressure with AM than NP. The available evidence points to AM being a potent vasodilator (Champion et al 1997, Cockcroft et al 1997. A likely explanation for cardiac output being increased more with AM is that, compared with NP, AM has less venodilatory action.…”

Adrenomedullin modulates the neurohumoral response to acute volume loading in normal conscious sheep

“…As with previous studies in euvolemic animals, there was a reduction in CTPR which would also tend to promote increased cardiac output due to reduced afterload. Thus, available evidence points to ADM being a potent vasodilator probably via a direct action of ADM on arterial tone (Champion et al 1997, Cockcroft et al 1997. Although extrapolation from acute to chronic states should be made with caution, these findings suggest that the elevated levels of ADM observed in heart failure may provide a compensatory effect maintaining cardiac output and reducing afterload in the face of inappropriate volume expansion.…”

Long-Term Adrenomedullin Administration in Experimental Heart Failure

“…9,10 The hypotensive action of AM in the present study, of rapid onset and persistent, is likely to be primarily owing to a direct affect on arterial tone, 14 as reflected in concomitant reductions in CTPR. In addition, inhibitory effects of AM on the procontractile activities of factors such as angiotensin II 15 and endothelin-1 16 may have played a contributory role in this setting, in which these systems are activated.…”