Species comparison of cardiovascular responses to adrenomedullin and related peptides: Role of vascular endothelium and nitric oxide
Description
Adrenomedullin is a recently discovered member of the CGRP family of peptides which has been demonstrated to be involved in regulating many organ systems. Moreover, it has been suggested that, while the presence of these peptides is well conserved, there may exist important species differences in the mechanism(s) of action This study was designed to investigate the systemic and regional hemodynamic responses to adrenomedullin and related peptides in the cat, rat, and mouse in order to test the hypothesis that there exists species differences in the activity and mechanism of action of these peptides. The structure-activity relationships of adrenomedullin and CGRP were studied through the alteration of the peptide sequences. The effect of local modulators on responses to adrenomedullin and related peptides was investigated The hypothesis that endothelial nitric oxide synthase (eNOS) may play a role in mediating pulmonary vasodepressor responses to adrenomedullin, but not CGRP, was additionally tested using adenoviral-mediated gene-transfer of eNOS to the lung of the mouse. Gene-transfer of eNOS was accomplished and verified by increased protein expression of eNOS, increased cGMP levels, and increased L-arginine to L-citrulline conversion activity. Responses to adrenomedullin and CGRP were compared to responses in animals receiving a blank viral vector The hypothesis that elevated levels of adrenomedullin and CGRP can be achieved through gene-transfer technology was tested in the pulmonary vascular bed of the mouse. This series of experiments utilized adenoviral gene-transfer technology to deliver the genes encoding adrenomedullin and CGRP to the lung where the effect on cAMP, cGMP, and pulmonary and systemic vascular function was studied These studies demonstrate that adrenomedullin and CGRP are potent vasodilators in the systemic and regional vascular beds of the cat, rat, and mouse. The data from experiments in the pulmonary vascular bed of the mouse provide support for the hypothesis that adrenomedullin is an endothelium-dependent vasodilator in the lung of the mouse. (Abstract shortened by UMI.)