Hemodynamic, Hormonal, and Renal Actions of Adrenomedullin-5 in Normal Conscious Sheep

Abstract

Although blood pressure effects have been reported for adrenomedullin 5 (AM-5), a newly identified member of the calcitonin gene-related peptide superfamily, little is known about other biological actions. We report the integrated hemodynamic, hormonal, and renal actions of AM-5 (10 and 100 ng·kg·min each for 90 minutes) in normal conscious sheep. AM-5 reduced the mean arterial pressure by 12 mm Hg at the end of the high dose (P < 0.001) in association with dose-dependent increments in the heart rate (40 beats/min--high dose, P < 0.001) and cardiac output (50%-high dose, P < 0.001) and dose-dependent falls in calculated total peripheral resistance (P < 0.001). Plasma renin activity (4-fold increment, P < 0.001), aldosterone (2-fold increment, P = 0.014), and cyclic adenosine monophosphate (50% increment, P < 0.001) all rose in response to high dose AM-5. Urine volume and sodium excretion were unchanged. In conclusion, it is observed that intravenous infusions of AM-5 administered to normal conscious sheep induced significant hemodynamic actions including reduced mean arterial pressure and calculated total peripheral resistance and increased heart rate and cardiac output. Concurrently, AM-5 activated plasma cyclic adenosine monophosphate, plasma renin activity, and aldosterone. These actions are similar to those previously reported for AM and AM-2. Thus, AM-5 may be an another important regulator of volume and pressure homeostasis and may play a role in the pathophysiology of heart disease.

Haemodynamic, endocrine and renal actions of adrenomedullin 5 in an ovine model of heart failure

“…As observed previously in normal sheep [18], AM5 induced significant and dose-dependent augmentation of CO in the setting of HF. Although this effect is probably attributable in part to the attendant reduction in cardiac afterload (evidenced by falls in CTPR and MAP), it is plausible that AM5 also exhibits positive inotropic activity as the rise in CO was associated with prominent increases in LV d P /d t (max).…”

“…The hypotensive actions of AM and AM2 are reported to be due to direct vasodilatory actions both receptor mediated and via stimulation of nitric oxide [7], and the concurrent falls in MAP and peripheral resistance seen with AM5 in the present study also suggest a direct affect of this peptide on arterial tone. A similar correlation between falls in BP and CTPR was noted in normal sheep with AM5 administration [18] (Table 2). In comparison with AM, where reductions in MAP persisted for 1 h post-infusion [11], MAP responses were more transient with AM5 (the present study) and AM2 [12] (absent after 30 min for both peptides).…”

“…A decrease in blood volume cannot be implicated as the significant decline in LAP seen during the LD AM5 infusion occurred well before the increase in urine output and in the face of a fall in haematocrit. A reduction in haematocrit has been recorded previously following AM5 administration in normal sheep [18] as well as during AM2 infusion in HF animals [12], and suggests a shift of fluid from the extravascular to intravascular compartment. The mechanisms underlying this effect are yet to be determined for any of the AM peptides.…”

“…Despite continued haemodynamic improvement during HD AM5, cAMP levels rose, suggesting that AM5 did activate this second messenger and may indeed signal via the same receptors as AM and AM2. Of note, AM5 administration in normal sheep was associated with significant increases in circulating cAMP [18], albeit by amounts less than half that seen with equivalent doses of AM [19] and AM2 [20] (Table 2). …”

“…Bioactivity reported for AM5 to date includes potent osmoregulatory effects in fish (with a greater efficacy than AM1) [17], whereas intravenous administration in normal rats [16] and sheep [18] produces significant haemodynamic actions including decreases in peripheral resistance and arterial pressure together with increases in HR (heart rate) and CO (cardiac output) with a potency comparable with that seen with AM and AM2 [16,19,20]. Although these findings point towards a role for AM5 in the regulation of the cardiovascular system and body fluids in health, there have been no studies investigating the effects of AM5 in heart disease.…”