Effects of Adrenomedullin, Calcitonin Gene-Related Peptide, and Amylin on Cerebral Circulation in Dogs

Abstract

The effect of human adrenomedullin on cerebral circulation was investigated in dogs in vivo and in vitro. Bolus administration of adrenomedullin or its homologous peptides, calcitonin gene-related peptide (CGRP) and amylin, into the vertebral artery induced a dose-dependent increase in vertebral blood flow. The potencies of adrenomedullin and CGRP were similar and approximately 100 times more than that of amylin. The effects of adrenomedullin and CGRP were inhibited by CGRP8-37, an antagonist of CGRP. In contrast to substance P, adrenomedullin did not induce an increase in blood flow after prior administration of CGRP. Pretreatment with either NG-nitro-L-arginine methyl ester or indomethacin did not affect the adrenomedullin-induced increase in blood flow. Intracisternal administration of adrenomedullin induced dilation of the basilar and other major cerebral arteries in a dose-dependent manner, accompanied by an increase in the concentration of cyclic AMP in the cerebrospinal fluid. Adrenomedullin also induced relaxation of isolated basilar and middle cerebral arterial rings. These data suggest that adrenomedullin induces vasodilation of cerebral arteries and an increase in vertebral blood by acting at CGRP receptors positively coupled to adenylate cyclase, and that these effects are not dependent on nitric oxide or prostaglandin formation.

Circulating Adrenomedullin Is Increased in Preterm Newborns Developing Intraventricular Hemorrhage

“…The main events causing loss of vascular autoregulation, which can lead to IVH, are commonly identified in hypotension, cerebral ischemia, and reperfusion hyperemia (3)(4)(5). In vitro and in vivo studies have shown that adrenomedullin is secreted by endothelial cells (7) and participates in the regulation of cerebral blood flow (10,11); adrenomedullin infusion in dogs increases cerebral blood flow in a dose-dependent manner without affecting systemic blood pressure and other cardiovascular parameters (19). Recently, we have shown that adrenomedullin contributes to the hemodynamic modifications that determine the occurrence of the brain-sparing effect in growth retarded fetuses, confirming an important role of this peptide in the regulation of fetal cerebral blood flow in humans (15).…”

Role of Nitric Oxide–cGMP Pathway in Adrenomedullin-Induced Vasodilation in the Rat

“…However, it is still controversial whether it is endothelium-dependent 6 -8 or -independent. 9,10 Most studies evaluated the endothelium-dependency of AM-induced vasodilation with NOS inhibitors such as L-NMMA. However, because the NOS inhibitors sometimes increase baseline vascular tone, it is difficult to get a clear-cut conclusion.…”

Adrenomedullin Blood Concentrations in Infants Subjected to Cardiopulmonary Bypass: Correlation with Monitoring Parameters and Prediction of Poor Neurological Outcome

“…We investigated whether open heart surgery with CPB changes cerebrovascular resistance and adrenomedullin (AM) secretion, and whether AM measurement is useful for monitoring cerebral distress during CPB. AM, a 6-kD vasoactive peptide (2 ), affects cerebral circulation and vasodilates cerebral arterioles without modifying systemic blood pressure or other cardiovascular variables (3 ). AM plays a role in fetal cerebral hemodynamic modifications due to hypoxia (4 ), and in preterm newborns who develop intraventricular hemorrhage, an early increase of AM is related to a series of events causing loss of the cerebral vascular autoregulation system, leading to cerebral bleeding due to reperfusion (5 ).…”

“…AM infusion in animals increases cerebral blood flow in a dose-dependant manner (3,10 ), suppresses the reduction in regional cerebral blood flow, and prevents ischemic brain injury after middle cerebral artery occlusion (in vivo in rats) (10 ). In humans AM is involved in the regulation of fetal cerebral vascular hemodynamic mechanisms for adaptation to hypoxia (4 ) and participates in the ischemia-reperfusion mechanisms leading to intraventricular hemorrhage in preterm newborns (5 ).…”