Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats

Abstract

Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.

Direct coronary vasodilator action of adrenomedullin is mediated by nitric oxide

“…This complete prevention of the vasodilator response, in comparison with the partial prevention reported in other studies, may reflect a more complete inhibition of NOS by the 2 h pretreatment with L-NNA given directly into the coronary arteries in our study. Our observation that NOS inhibition prevented the vasodilator action of ADM in the coronary arteries of sheep is consistent with the reports that NOS inhibition blocks the effect of ADM in most, but not all, vascular beds (Feng et al, 1994;Majid et al, 1996;Nossaman et al, 1996). In the present study, ADM (0.5 mg kg À1 h À1 ) infused i.c., but not i.v., caused a small increase in HR, suggesting that ADM has a direct chronotropic action.…”

“…It has been proposed that the vasodilator action of ADM is mediated by a number of mechanisms, including a direct action on vascular smooth muscle cells via cAMP and Ca 2 þ mobilisation (Ishizaka et al, 1994;Shimekake et al, 1995), and by stimulation of nitric oxide (NO). Inhibition of nitric oxide synthase (NOS) has been shown to prevent the vasodilator action of ADM in dog kidney (Majid et al, 1996), rat hindquarters (Feng et al, 1994) and in the pulmonary circulation of the rat but not the cat (Nossaman et al, 1996).…”

Effects of Adrenomedullin Inhalation on Hemodynamics and Exercise Capacity in Patients With Idiopathic Pulmonary Arterial Hypertension

“…[25][26][27] The vasodilatory effect is mediated by cAMP-dependent and nitric oxide-dependent mechanisms. 28,29 Endogenous AM production is enhanced in a variety of cardiovascular diseases through a compensatory mechanism.…”

Adrenomedullin

“…For example, pulmonary vasodilator responses were reduced by N-nitro-L-arginine methyl ester (L-NAME) in rats, but not in cats. 27 Currently, there is little data available on the vasodilator effect on veins, whereas Barder et al reported that vasodilatation of femoral veins in canines was endotheliumdependent, but independent of cAMP and cGMP. 28 Thus, the mechanism by which AM achieves direct vasodilatation appears to differ depending on species, the size of blood vessels, or regions where the vessels are isolated.…”