Comparative actions of adrenomedullin and nitroprusside: interactions with ANG II and norepinephrine

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.

Section: Discussionmentioning

confidence: 69%

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

Charles¹,

Nicholls²,

Rademaker³

et al. 2002

“…These actions include lowering of arterial pressure associated with increases in cardiac output and falls in peripheral resistance (Charles et al 1997, Lainchbury et al 2000, Troughton et al 2000. We have previously reported the effects of AM compared with pressure-matched NP in another group of sheep undergoing similar experiments but without concurrent CSNA recordings (Charles et al 2001). Less clear is whether baroreceptor-mediated increases in sympathetic activity (for a given change in blood pressure) are altered by AM compared with NP, a standard agent used for assessing baroreflex-modulated responses to vasodilation (Casadei & Paterson 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Each animal was studied on three occasions receiving vehicle (haemaccel) control, AM and NP using a study design similar to our previous study (Charles et al 2001). AM was infused i.v.…”

Section: Methodsmentioning

confidence: 99%

Adrenomedullin increases cardiac sympathetic nerve activity in normal conscious sheep

Charles¹,

Jardine²,

Nicholls³

et al. 2005

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.

“…CGRP activates CL-R-RAMP1 while AM and AM-2 activate the CL-R-RAMP2 and CL-R-RAMP3 receptor complexes. Activation of these receptor complexes by CGRP (Gnaedinger et al 1989), AM (Charles et al 2001), and AM-2 (Charles et al 2006) results in a number of hemodynamic actions including lowering blood pressure and peripheral resistance while increasing heart rate and cardiac output. These changes are also associated with significant activation of PRA.…”

Section: Discussionmentioning

confidence: 99%

“…of the study. Repeated-measures ANOVA is appropriate as it simultaneously incorporates the time and treatment (within animal) effects without direct recourse to numerous pairwise comparisons, and is thus routinely used in this context with group sizes of five to eight using similar experimental design (Charles et al 1990(Charles et al , 1991(Charles et al , 2001(Charles et al , 2006. The appropriateness of the parametric analysis has been confirmed with attention to graphical displays of the residuals from the models confirming appropriate normality.…”

Section: Bioactivity Of Ovine Crsp-1 In Conscious Sheepmentioning

confidence: 98%

Identification and biological activity of ovine and caprine calcitonin receptor-stimulating peptides 1 and 2

Charles

Katafuchi²,

Yandle

et al. 2008

We have recently reported the isolation of three new members of the calcitonin (CT) gene-related peptide family of peptides, the CT receptor (CT-R)-stimulating peptides (CRSPs). We now report the sequencing and characterization of ovine/caprine CRSP-1 and caprine CRSP-2. Mature ovine and caprine CRSP-1 are identical and have strong structural homology to CRSP-1s identified to date from other species. As with other CRSP-1s, ovine/caprine CRSP-1 binds to and activates the CT-R but not the CT-like receptor (CL-R) in combination with the receptor activity-modifying proteins (RAMPs). By contrast, caprine CRSP-2 does not activate any of these receptor-RAMP complexes. Intravenous infusions of ovine CRSP-1 to normal conscious sheep induced dose-dependent reduction in plasma total Ca levels (PZ0 . 02) and corrected Ca levels (PZ0 . 017) associated with increases in plasma cAMP (PZ0 . 002). CRSP-1 reduced both plasma amino-terminal pro-C-type natriuretic peptide levels (PZ0 . 006) and plasma renin activity (PZ0 . 028). There were no significant effects observed on hemodynamic or renal indices measured. In conclusion, we have sequenced ovine/caprine CRSP-1 and caprine CRSP-2 precursors. This newly identified CRSP-1 has been shown to share the structural and biological features of CRSP-1s known to date. In vivo studies confirm that ovine CRSP-1 reduces plasma Ca levels in sheep, presumably via a cAMP-mediated mechanism. By contrast, caprine CRSP-2 did not stimulate any combination of CT-R, CL-R, and RAMPs. Accession numbers of cDNA determined in this study are caprine CRSP-1, AB364646; caprine CRSP-2, AB364647; and ovine CRSP-1, AB364648.