Mechanisms of Adrenomedullin-Induced Dilatation of Cerebral Arterioles

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Abstract
Adrenomedullin is a recently discovered vasoactive peptide that is structurally related to calcitonin gene-related peptide (CGRP). Adrenomedullin is produced by vascular endothelium and smooth muscle and is present in the brain. The goals of this study were to determine (1) whether adrenomedullin produces dilatation of cerebral arterioles and whether this effect is mediated by activation of CGRP receptors and (2) whether vasodilatation to adrenomedullin was mediated by K+ channels. Diameter of cerebral arterioles (mean +/- SE baseline, 46 +/- 1 microns) was measured using a closed cranial window in anesthetized rats. Application of rat adrenomedullin (10(-7) and 10(-6) mol/L) increased vessel diameter by 16 +/- 3% and 45 +/- 8% (n = 5), respectively. Vasodilator responses to repeated application of adrenomedullin were reproducible. Pretreatment of cerebral arterioles with the specific CGRP1 receptor antagonist CGRP-(8-37) (5 x 10(-7) mol/L) selectively inhibited the vasodilator responses to adrenomedullin without inhibiting responses to ADP (10(-5) to 10(-3) mol/L). Responses to adrenomedullin (10(-7) and 10(-6) mol/L) were 14 +/- 1% and 40 +/- 3% before and 2 +/- 2% and 6 +/- 1% after CGRP-(8-37), respectively (P < .01). Glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive K+ channels, reduced the responses to adrenomedullin without attenuating responses to ADP. Responses to adrenomedullin were 19 +/- 4% and 35 +/- 6% before and 6 +/- 3% and 19 +/- 5% after glibenclamide, respectively (P < .05). Iberiotoxin (10(-7) mol/L), an inhibitor of calcium-dependent K+ channels, also significantly attenuated responses to adrenomedullin and did not inhibit vasodilatation to papaverine. Responses to adrenomedullin were 16 +/- 2% and 55 +/- 8% before and 12 +/- 4% and 26 +/- 3% after iberiotoxin, respectively (P < .01 for 10(-6) mol/L adrenomedullin). Adrenomedullin produces substantial dilatation of cerebral arterioles in vivo, and the response is mediated in large part by activation of CGRP1 receptors. Cerebral vasodilatation to adrenomedullin appears to be dependent on activation of K+ channels.

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