Responses to human CGRP, ADM, and PAMP in human thymic arteries

Abstract

. Responses to human CGRP, ADM, and PAMP in human thymic arteries. Am J Physiol Regul Integr Comp Physiol 284: R531-R537, 2003; 10.1152/ajpregu.00337.2002Responses to human CGRP, adrenomedullin (ADM), and proadrenomedullin NH2-terminal 20 peptide (PAMP) were studied in small human thymic arteries. CGRP, ADM, and PAMP produced concentrationdependent vasodilator responses in arteries preconstricted with the thromboxane mimic U-46619. Responses to ADM and PAMP were attenuated, whereas responses to CGRP were not altered by endothelial denudation. Inhibitors of nitric oxide synthase and guanylyl cyclase attenuated responses to ADM and PAMP but not to CGRP. The CGRP1 receptor antagonist CGRP(8-37) attenuated responses to CGRP and ADM but not to PAMP. Responses to CGRP were reduced by SQ-22536 and Rp-cAMPS, inhibitors of adenylyl cyclase and PKA. These data suggest that responses to CGRP and ADM are mediated by CGRP(8-37)-sensitive receptors and that the endothelial ADM receptor induces vasodilation by a nitric oxide-guanylyl cyclase mechanism, whereas a smooth muscle CGRP receptor signals by a cAMP-dependent mechanism. A different endothelial receptor recognizes PAMP and signals by a nitric oxide-dependent mechanism. CGRP1 receptor; vascular endothelium; vascular tone; human thymus ADRENOMEDULLIN (ADM) and proadrenomedullin NH 2 -terminal 20 peptide (PAMP) are distinct products encoded by the ADM gene (20-23). The human form of ADM consists of 52 amino acids and a six-membered ring structure that shares homology with CGRP and amylin (20)(21)(22)(23). PAMP consists of 20 amino acids and does not share the six-membered ring structure (20)(21)(22). ADM was discovered in human pheochromocytoma cells and has been localized in many tissues, including vascular smooth muscle cells and the endothelium (11,13,15,16,20). ADM plasma levels are increased in disorders, such as hypertension, heart and renal failure, and hypoxia, and ADM induces a different spectrum of hemodynamic effects than do nitrovasodilators (8, 12-14, 18, 23, 26, 35). PAMP is found in the NH 2 -terminal portion of the precursor for ADM and has a similar distribution, including vascular smooth muscle and the endothelium (17,20,24,36).

Decrease in arterial pressure induced by adrenomedullin in the hypothalamic paraventricular nucleus is mediated by nitric oxide and GABA

“…The most likely cascade is an ADM-NO-GABA cascade. In support of this suggestion, endothelial cells have been shown to produce and release NO in response to ADM [13,44]. In addition, our data provide anatomical support for the idea that PVN neurons can produce NO upon stimulation by ADM.…”

“…It has been shown that ADM activates NOS in endothelial cells of blood vessels to produce NO [13,44], and we have found that endothelial cells of blood vessels are the only endothelial NOS-positive cells in the PVN (unpublished data). Based on these data, we speculate that ADM in the PVN evokes the production and release of NO at least in part by activating endothelial NOS within the blood vessels.…”

Antiproliferative effects of calcitonin gene-related peptide in aortic and pulmonary artery smooth muscle cells

“…cAMP has been implicated in several studies as the primary intracellular signaling molecule used by CGRP (8,13,15,23,25,37). A significant increase in cAMP following AdCMVCGRP transfection has been observed in both cell types.…”

“…Whereas NO is known to signal through a cGMP-protein kinase A (PKA)-p53 pathway in aortic smooth muscle (12,37), the mechanism by which CGRP elicits its beneficial effect is unknown. It is proposed that CGRP signals through a cAMP pathway (8,13,15,23,25,37). In arterial smooth muscle, vasodilator agents increase cAMP and inhibit smooth muscle proliferation by arresting the cells primarily in G 1 phase (4,39).…”

Progression of vascular and neural dysfunction in sciatic nerves of Zucker diabetic fatty and Zucker rats

“…If the expression of one or more of these proteins is compromised by diabetes/hyperglycemia, the function of the CGRP receptor would likely be affected. The vasodilatory response to CGRP involves the formation of cAMP and activation of Ca 2ϩ signaling pathways (1,7,18,35). It is also possible that the signaling mechanism(s) activated by the CGRP receptor may be impaired in diabetes/hyperglycemia, thereby causing a decrease in vasodilation in response to exogenous CGRP.…”