THE INFLUENCE OF NEUROKININS AND CALCITONIN GENE-RELATED PEPTIDE ON CEREBRAL BLOOD-FLOW IN ANESTHETIZED GUINEA-PIGS

The effects of systemically-administered human alpha calcitonin gene-r elated peptide (h.alphaCGRP), substance P and the selective neurokinin receptor agonists, GR73632 (NK1) and GR64349 (NK2) on cerebral blood flow (CBF) were studied in anaesthetized guinea-pigs using a laser-Dop pler flowmeter. h.alphaCGRP (0.1 and 0.3 nmol/kg), substance P (0.03-1 .0 nmol/kg), GR73632 (0.03-0.3 nmol/kg) and GR64349 (0.3 nmol/kg) each , following intra-carotid artery injection, reduced transiently (< 5mi n) blood pressure and CBF. GR73632 (0.1 and 0.3 nmol/kg) and GR64349 ( 0.3 nmol/kg), but not h.alphaCGRP (0.01-0.3 nmol/kg) or substance P(0. 01-1.0 nmol/kg), then produced a more prolonged increase in CBF, the p eak effect occurring 10-15 min after injection. It is likely that this increase in CBF was due to their bronchoconstrictor activity, rather than a direct effect on the cerebrovasculature; arterial PaCO2 levels were increased and PaO2 decreased by both compounds. Following pretrea tment with urea (5 M) to disrupt the blood brain barrier, h.alphaCGRP (0.1 nmol/kg) produced a significant increase in CBF (13 +/- 4%), impl ying that access to its receptors on the cerebrovascular smooth muscle had been achieved. Substance P (0.1 nmol/kg) remained inactive. The s tudy has demonstrated that compounds acting on neuropeptide receptors have little direct influence on CBF following systemic administration. CGRP requires access to its receptors on the cerebrovascular smooth m uscle, while selective NK1 and NK2 receptor agonists increase CBF, pro bably indirectly via their bronchoconstrictor activity. The lack of ef fect of substance P may be due to its rapid breakdown by peptidases, a property not shared by the selective neurokinin agonists.