Comparison of responses to rat and human adrenomedullin in the hindlimb vascular bed of the cat

The sympathetic nervous system and adrenomedullin (AM) both participate in the regulation of cardiac and circulatory function but their interaction remains uncertain. We have examined the effects of AM on cardiac sympathetic nerve activity (CSNA) and hemodynamics and contrasted these effects with pressure-matched nitroprusside (NP) administration in normal conscious sheep. Compared with vehicle control, arterial pressure fell similarly with AM (P=0·04) and NP (P<0·001). Heart rate rose in response to both AM (P<0·001) and NP (P=0·002) but the rise with AM was significantly greater than that induced by NP (P<0·001). Cardiac output increased in response to AM compared with both control and NP (both P<0·001). CSNA burst frequency (bursts/ min) were increased in response to both AM (P<0·001) and NP (P=0·005) with the rise in burst frequency being greater with AM compared with NP (P<0·001). CSNA burst area/min was also raised by both AM (P=0·03) and NP (P=0·002) with a trend for burst area being greater with AM than NP (P=0·07). CSNA burst incidence (bursts/100 beats) showed no significant differences between any treatment day. In conclusion, we have demonstrated that AM is associated with a greater increase in CSNA and heart rate for a given change in arterial pressure than seen with the classic balanced vasodilator NP.

Section: Discussionmentioning

confidence: 58%

“…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.…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin increases cardiac sympathetic nerve activity in normal conscious sheep

Charles¹,

Jardine²,

Nicholls³

et al. 2005

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Charles¹,

Nicholls²,

Rademaker³

et al. 2002

The physiological role of adrenomedullin (ADM) in volume and pressure homeostasis remains unclear. Accordingly, we assessed possible modulatory actions of ADM infusions on the neurohumoral response to acute volume loading with dextran in normal conscious sheep. Dextran (15 ml/kg), given with concurrent ADM (5·5 pmol/kg per min -raising plasma ADM from below detection to approximately 10 pmol/l) or vehicle control infusions, induced matched significant (P<0·001 by ANOVA) falls in hematocrit (27-30%) during both ADM and control and similar increases in right atrial pressure (approximately 10 mmHg). Compared with control, both systemic (P=0·033) and pulmonary (P=0·005) arterial pressure and peripheral resistance (P=0·004) were reduced during ADM but were raised post-infusion. The dextran-induced increase in cardiac output was augmented by ADM (P=0·048). Dextran-induced increases in plasma atrial natriuretic peptide (ANP; P=0·008), brain natriuretic peptide (BNP; P=NS) and cyclic guanosine monophosphate (cGMP; P=0·003) were augmented post-ADM infusions. The dextran-induced fall in plasma renin activity (PRA) was attenuated by ADM (P=0·039) whereas plasma aldosterone levels were unaltered. ADM augmented the increase in urinary volume during the second 2-h clearance period post-dextran.Our data indicate that ADM modifies the hemodynamic and hormonal response to an acute volume challenge, enhances natriuretic peptide secretion and reduces systemic vascular resistance. These results provide further evidence that ADM plays a physiological role in volume and pressure homeostasis.

“…Adrenomedullin has vasorelaxant properties in animal models (Champion et al 1997) and in humans (Cockcroft et al 1997, Lainchbury et al 2000, Troughton et al 2000. CNP also has vasodilator properties, but its precise role under physiological and pathophysiological circumstances remains ill defined (Espiner et al 1995).…”

Section: Introductionmentioning

confidence: 99%

Effects of endothelin-1 on release of adrenomedullin and C-type natriuretic peptide from individual human vascular endothelial cells

Ah²,

Yandle³

et al. 2002

Regulation of cardiovascular system activity involves complex interactions amongst numerous factors. Three of these vasoactive factors are adrenomedullin, C-type natriuretic peptide (CNP) and endothelin-1 (ET-1), each of which is claimed to have important local effects. To investigate paracrine/autocrine regulation of the secretion of these peptides we used a cell immunoblot method. We postulated that basal release of adrenomedullin and CNP by endothelial cells is modulated by ET-1. Dispersed human aortic endothelial cells were attached to a protein binding membrane and incubated for 1 or 4 h with control medium or with ET-1, endothelin receptor antagonists or antibody to ET-1, and then submitted to immunohistochemical staining. Peptides (adrenomedullin, CNP and ET-1) within individual cells were stained, as was peptide secreted and adjacent to the cell. It was demonstrated that adrenomedullin, CNP and ET-1 can be contained within the same cell. In addition, we observed that individual endothelial cells can secrete all three peptides.The endothelin ET-A/ET-B receptor antagonist, bosentan, the ET-B receptor antagonist, BQ-788, and anti-ET-1 serum decreased the percentage of endothelial cells that secreted adrenomedullin and CNP relative to control. Conversely, the addition of ET-1 induced an increase in the number of endothelial cells that secreted adrenomedullin and CNP. These results provide strong evidence that endogenous ET-1, from human vascular endothelial cells, acts in a paracrine/autocrine manner to modulate the basal release of adrenomedullin and CNP. Our observations of this modulation suggest that vascular endothelial cells of humans constitute an important component of a self-responsive vasoregulatory system.