Mechanisms involved in the regional haemodynamic effects of intermedin (adrenomedullin 2) compared with adrenomedullin in conscious rats

Abstract

Background and purpose: Intermedin (IMD) is a newly identified member of the calcitonin family of peptides that shares structural and functional homology with adrenomedullin (AM). In vivo cardiovascular effects of AM have been described, but relatively little is known of the in vivo actions of IMD. The purpose of this study was to compare the regional haemodynamic effects of IMD with those of AM in conscious rats, and investigate possible underlying mechanisms.

Experimental approach: Measurements of blood pressure, heart rate and renal, mesenteric and hindquarters haemodynamics were made in conscious, chronically-instrumented rats.

Key results: IMD caused tachycardia and vasodilatation in all three vascular beds, associated with modest hypotension. At an equimolar dose (1 nmol.kg(-1)), most of the cardiovascular effects of IMD were greater than those of AM. The AM receptor antagonist, AM(22-52), was equally effective in attenuating the renal and mesenteric vasodilator effects of IMD (1 nmol.kg(-1)) and AM (3 nmol.kg(-1)), but inhibition of NO synthase was more effective at reducing the vasodilator effects of IMD than AM. Vascular K(ATP) channel blockade with U-37883A did not inhibit the vasodilator effects of either peptide.

Conclusions and implications: In vivo, the regional haemodynamic profile of IMD resembles that of AM, and some of the vasodilator effects of IMD are mediated by AM receptors and NO, but not by K(ATP) channels. The cardiovascular effects of AM have been implicated in various pathological conditions, but whether or not endogenous IMD fulfils a similar role remains to be determined.

Figure 1

Cardiovascular responses to IMD [1 nmol·kg⁻¹, n= 8 (A) or 11 (B)] and AM [1 nmol·kg⁻¹, n= 9 (A) or 3 nmol·kg⁻¹, n= 10 (B)] in conscious rats. Values are mean and vertical bars represent SEM. *P < 0.05 versus baseline (Friedman's test), #P < 0.05 for integrated (0–30 min) changes (Mann–Whitney U-test). AM, adrenomedullin; IMD, intermedin.

Figure 2

Cardiovascular responses to (A) IMD (1 nmol·kg⁻¹) or (B) AM (3 nmol·kg⁻¹) following administration of saline (0.4 mL·h⁻¹) or AM_22–52 (500 nmol·kg⁻¹·h⁻¹). Values are mean and vertical bars represent SEM, n= 6–8 per group. *P < 0.05 versus baseline (Friedman's test), #P < 0.05 for integrated (0–30 min) changes (Mann–Whitney U-test). AM, adrenomedullin; IMD, intermedin.

Figure 3

Cardiovascular responses to (A) IMD (1 nmol·kg⁻¹) or (B) AM (3 nmol·kg⁻¹) in the presence of angiotensin II (AII, 200 ng·kg⁻¹·h⁻¹) + AVP (20 ng·kg⁻¹·h⁻¹) or L-NAME (3 mg·kg⁻¹·h⁻¹). Values are mean and vertical bars represent SEM, n= 8 *P < 0.05 versus baseline (Friedman's test), #P < 0.05 for integrated (0–30 min) changes (Wilcoxon's test). AM, adrenomedullin; AVP, arginine vasopressin; IMD, intermedin.

Figure 4

Cardiovascular responses to (A) IMD (1 nmol·kg⁻¹) or (B) AM (3 nmol·kg⁻¹) following administration of saline (1 mL infused over 30 min) or U-37883A (5 mg·kg⁻¹). Values are mean and vertical bars represent SEM, n= 9 *P < 0.05 versus baseline (Friedman's test), #P < 0.05 for integrated (0–30 min) changes (Wilcoxon's test). AM, adrenomedullin; IMD, intermedin.

Figure 5

Cardiovascular responses to (A) IMD (1 nmol·kg⁻¹) or (B) AM (3 nmol·kg⁻¹) following administration of saline (0.1 mL) or losartan (10 mg·kg⁻¹). Values are mean and vertical bars represent SEM, n= 9 *P < 0.05 versus baseline (Friedman's test), #P < 0.05 for integrated (0–30 min) changes (Wilcoxon's test). AM, adrenomedullin; IMD, intermedin.