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 ), but inhibition of NO synthase was more effective at reducing the vasodilator effects of IMD than AM. Vascular KATP 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 KATP 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.

Cardiac sympathetic afferent reflex response to intermedin microinjection into paraventricular nucleus is mediated by nitric oxide and γ-amino butyric acid in hypertensive rats

“…30,45 NO mediates the effects of IMD in the PVN on the RSNA and MAP in 2K1C rats and peripheral vasodilatation. 6,28,29,38 In this study, our results showed that non-selective NOS inhibitor L-NAME prevented IMD-induced decrease in the CSAR and IMD microinjection into the PVN significantly increased NO content in 2K1C, 38 which indicates that IMD may activate NO-producing neurons and increase NO production in the PVN, and that NO, in turn, decreases the CSAR.…”

Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases

“…The i.v. infusion of ADM2/IMD 1–47 increases the blood flow and decreases the vascular resistance of the heart, lungs, kidneys, liver, stomach, small intestine, adrenal glands and testes (Fujisawa et al , ), more potently than ADM (Jolly et al , ). The modified cardiac function, vasodilation, renal function and neuroendocrine effect are involved in the haemodynamic regulation by ADM2 (Figure ).…”

“…ADM2 has a hypotensive effect, but the potency comparisons have produced variable results. The overall rank of the hypotensive potency is ADM2/IMD 1–53 > ADM > ADM2/IMD 1–47 = CGRP > ADM2/IMD 1–40 , which can be blocked by CGRP receptor antagonist (Roh et al , ; Taylor et al , ; Jolly et al , ). However, other studies have reported a different potency ranking for the hypotensive effect: ADM2/IMD 1–47 = ADM2/IMD 1–40 ≥ ADM = ADM2/IMD 1–53 (Takei et al , ; Pan et al , ; Fujisawa et al , ; Ren et al , ).…”

Intermedin/adrenomedullin2: an autocrine/paracrine factor in vascular homeostasis and disease

“…IMD had a negative inotropic effect on the isolated myocardium because of NO-cGMP pathway activation with concomitant thin myofilament desensitization by increased cTnI phosphorylation [25], which provides a coherent explanation for the previously reported contradictory results (positive or negative inotropic effect). In conscious rat models, the regional haemodynamic profile of IMD resembled that of ADM [30], and some of the vasodilator effects of IMD were mediated by ADM receptors and NO but not by K(ATP) channels. Using anaesthetic rat models, Abdelrahman et al found that IMD dose-dependently decreased mean arterial pressure and increased heart rate; the depressive effect of IMD was not mediated via the L-arginine-NO pathway, production of prostanoids or opening of tetraethylammonium-sensitive K + channels but was opposed by activity of the sympathetic nervous system [33].…”

“…IMD treatment increased the activity of NO synthase (NOS) and content of NO in tissues and augmented the uptake of L-arginine by cells [29]. NO activates GC and elevates intracellular cGMP levels for multiple effects such as vasodilation, anti-oxidative stress, and inhibition of cell apoptosis [8,30,31]. IMD153 significantly increased NO production and endothelial NOS (eNOS) activity in rat aortas and was more potent than equivalent ADM [32].…”