NK1 AND CGRP RECEPTOR-MEDIATED DILATATION OF THE CAROTID ARTERIAL BEDOF THE ANESTHETIZED RABBIT

The present study has investigated the effects of alpha and beta calci tonin gene-related peptide (CGRP), and the tachykinin neurokinin(1) (N K1) receptor agonist, substance P methyl ester (SPOMe), on carotid vas cular resistance, following their injection into the carotid artery be d of the anaesthetized rabbit. The involvement of CGRP and NK1 recepto rs in nicotine-induced alterations in carotid vascular resistance has also been characterized. alpha-or beta CGRP (1 and 10 pmolkg(-1) i.a.) and SPOMe (0.01 and 0.1 pmolkg(-1) i.a.) caused dose-related increase s in carotid arterial blood flow associated with decreases in carotid arterial vascular resistance with little effect on arterial blood pres sure. The selective CGRP receptor antagonist, CGRP(8-37) (0.34 mu molk g(-1) i.v.), caused a rightward CGRP displacement of the dose-response curves to both alpha- and beta CGRP; mean dose-ratios, 5 min after an tagonist administration, were 14 and 24 respectively. The selective NK 1 receptor antagonist, CP99 994 (0.23 mu molkg(-1) i.v.), caused a rig htward shift in the dose-response curve to SPOMe; mean dose-ratios, 15 and 75 min after antagonist administration, were 42 and 16 respective ly. CGRP(8-37) (0.34 mu molkg(-1)) had no effect on decreases in carot id arterial vascular resistance produced by SPOMe, and CP99 994 (0.23 mu molkg(-1) i.v.) had no effect on vasodilator responses produced by either alpha- or beta CGRP. Intracarotid injection of nicotine (0.002- 2 mu molkg(-1)) caused dose-dependent transient, followed by a more pr olonged, increase in carotid blood flow and reduction in arterial vasc ular resistance. The prolonged carotid vasodilator response produced b y nicotine (0.2 mu molkg(-1)) was markedly attenuated by CGRP(8-37) (0 .34 mu molkg(-1) i.v.) but unaffected by CP99 994 (1.15 mu molkg(-1) i .v.) suggesting a role for CGRP, and not substance P, in this vasodila tation. Neither receptor antagonist affected the transient response pr oduced by nicotine. This study has demonstrated that intracarotid inje ction of NK1 and CGRP receptor agonists to the anaesthetized rabbit re sults in an increase in carotid blood flow and a reduction in vascular resistance, indicative of vasodilatation of this artery bed. CGRP med iates the nicotine-induced dilatation of the carotid vascular bed, con sistent with its release from sensory nerves. This model should prove useful for the in vivo characterization of NK1 or CGRP receptor agonis t and antagonist activities, and in the study of neurogenically induce d vasodilatation.