NK 1 and CGRP receptor-mediated dilatation of the carotid arterial bed of the anaesthetized rabbit

Abstract

The present study has investigated the effects of α and β calcitonin gene-related peptide (CGRP), and the tachykinin neurokinin 1 (NK 1) receptor agonist, substance P methyl ester (SPOMe), on carotid vascular resistance, following their injection into the carotid artery bed of the anaesthetized rabbit. The involvement of CGRP and NK 1 receptors in nicotine-induced alterations in carotid vascular resistance has also been characterized. α-or βCGRP (1 and 10 pmolkg −1 i.a.) and SPOMe (0.01 and 0.1 pmolkg −1 i.a.) caused dose-related increases in carotid arterial blood flow associated with decreases in carotid arterial vascular resistance with little effect on arterial blood pressure. The selective CGRP receptor antagonist, CGRP 8–37 (0.34 μmolkg −1 i.v.), caused a rightward displacement of the dose-response curves to both α- and βCGRP; mean dose-ratios, 5 min after antagonist administration, were 14 and 24 respectively. The selective NK 1 receptor antagonist, CP99 994 (0.23 μmolkg −1 i.v.), caused a rightward shift in the dose-response curve to SPOMe; mean dose-ratios, 15 and 75 min after antagonist administration, were 42 and 16 respectively. CGRP 8–37 (0.34 μmolkg −1) had no effect on decreases in carotid arterial vascular resistance produced by SPOMe, and CP99 994 (0.23 μmolkg −1 i.v.) had no effect on vasodilator responses produced by either α-or βCGRP. Intracarotid injection of nicotine (0.002–2 μmolkg −1) caused dose-dependent transient, followed by a more prolonged, increase in carotid blood flow and reduction in arterial vascular resistance. The prolonged carotid vasodilator response produced by nicotine (0.2 μmolkg −1) was markedly attenuated by CGRP 8–37 (0.34 μmolkg −1 i.v.) but unaffected by CP99 994 (1.15 μmolkg −1 i.v.) suggesting a role for CGRP, and not substance P, in this vasodilatation. Neither receptor antagonist affected the transient response produced by nicotine. This study has demonstrated that intracarotid injection of NK 1 and CGRP receptor agonists to the anaesthetized rabbit results in an increase in carotid blood flow and a reduction in vascular resistance, indicative of vasodilatation of this artery bed. CGRP mediates the nicotine-induced dilatation of the carotid vascular bed, consistent with its release from sensory nerves. This model should prove useful for the in vivo characterization of NK 1 or CGRP receptor agonist and antagonist activities, and in the study of neurogenically induced vasodilatation.