✓ Increasing evidence suggests that disturbances in the modulatory influence of the vasoactive peptide, calcitonin gene—related peptide (CGRP), contribute to the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). However, only limited success has been achieved in trials attempting to ameliorate vasospasm by modifying CGRP function. To better understand the potential utility of targeting CGRP-mediated relaxation, it is important both to identify the interactions CGRP may have with other elements of the vasospastic response and to characterize the mechanisms through which CGRP elicits vasodilative effects. The present studies examined the effects of CGRP on vascular responsiveness using tension measurements of ring strips of rabbit basilar artery maintained in vitro. Pretreatment of vessels with CGRP (100 nM) inhibited vasoconstrictor responses to the potent protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDB). This particular contractile response was selected because PKC-mediated vasoconstriction is a critical component of the vasospastic response after SAH. In a posttreatment paradigm, CGRP was also found to reverse established constriction responses to PDB (2 nM) and histamine (3 µM) in a dose-dependent manner.
When tested against the maximum effective dose of PDB (30 nM) in the posttreatment paradigm, CGRP (100 nM) did not elicit significant relaxation. However, after washing both of these drugs out of the test chamber, a persistent effect of CGRP was revealed: the decay of PDB-induced contraction was accelerated in vessels that had previously been treated with CGRP. These findings indicate that CGRP elicits both immediate and sustained influences on contractile responses mediated by PKC.
Finally, two potential mechanisms for the vascular response to CGRP were examined. Adenosine triphosphate (ATP)—sensitive K+ channels do not appear to participate in CGRP-mediated dilation; inhibitors of these channels, glibenclamide and tolbutamide, did not block CGRP-induced relaxation. In contrast, a possible role for the nucleotide cyclic adenosine monophosphate (cAMP) in the vascular response to CGRP was indicated by the dose-dependent elevation of cAMP levels by CGRP.
Together these studies indicate that CGRP can modulate the contractile response to PKC activation. These effects are associated with increases in the levels of cAMP, but occur independently of fluxes through ATP-sensitive K+ channels.
Effects of Adrenomedullin, Calcitonin Gene-Related Peptide, and Amylin on Cerebral Circulation in Dogs