title: NK1 and CGRP receptor-mediated dilatation of the carotid arterial bed of the anaesthetized rabbit.
abstract: The present study has investigated the effects of alpha and beta calcitonin gene-related peptide (CGRP), and the tachykinin neurokinin1 (NK1) 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 NK1 receptors 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 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, CGRP8-37 (0.34 mumolkg-1 i.v.), caused a rightward displacement of the dose-response curves to both alpha- and beta CGRP; mean dose-ratios, 5 min after antagonist administration, were 14 and 24 respectively. The selective NK1 receptor antagonist, CP99 994 (0.23 mumolkg-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. CGRP8-37 (0.34 mumolkg-1) had no effect on decreases in carotid arterial vascular resistance produced by SPOMe, and CP99 994 (0.23 mumolkg-1 i.v.) had no effect on vasodilator responses produced by either alpha- or beta CGRP. Intracarotid injection of nicotine (0.002-2 mumolkg-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 mumolkg-1) was markedly attenuated by CGRP8-37 (0.34 mumolkg-1 i.v.) but unaffected by CP99 994 (1.15 mumolkg-1 i.v.) suggesting a role for CGRP, and not substance P, in this vasodilation. Neither receptor antagonist affected the transient response produced by nicotine. This study has demonstrated that intracarotid injection of NK1 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 NK1 or CGRP receptor agonist and antagonist activities, and in the study of neurogenically induced vasodilation.
authors.affiliation: Glaxo Wellcome Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Perren
authors.forename: H E
authors.initials: HE
authors.lastname: Connor
authors.forename: D T
authors.initials: DT
authors.lastname: Beattie
mesh_terms: D000758:Anesthesia; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002339:Carotid Arteries / Q000502:physiology*; D005260:Female; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D011817:Rabbits; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018015:Receptors, Calcitonin Gene-Related Peptide; D018040:Receptors, Neurokinin-1; D013373:Substance P; D009538:Nicotine; C033611:substance P, methyl ester-; D015740:Calcitonin Gene-Related Peptide