Cardiovascular responses to intrathecal neuropeptide gamma in conscious rats: receptor characterization and mechanism of action.
1. In the conscious rat, cardiovascular responses to intrathecally (i.t.) administered neuropeptide gamma (NP gamma) were studied prior to and after the i.t. pretreatment with selective antagonists at NK1 ((+/-)-CP 96345 and RP 67580), NK2 (SR 48968) and NK3 (R 486) receptors. Pretreatment with a mixture of peptidase inhibitors (phosphoramidon, captopril, bacitracin, phenanthroline) was also tested to ascertain whether or not the effect of NP gamma was mediated by a metabolite. The involvement of peripheral catecholamines was examined with intravenous injection of alpha-adrenoceptor (phentolamine) and beta-adrenoceptor (propranolol) antagonists. 2. NP gamma (0.078-78 nmol) induced dose-dependent increases in heart rate (HR) and mean arterial blood pressure (MAP). The highest dose of 78 nmol did not induce an increase of MAP greater than that with 7.8 nmol but was preceded by a transient decrease of MAP (1-3 min). No desensitization was observed when three injections of 7.8 nmol NP gamma were given at 90 min intervals. 3. Cardiovascular and behavioural (biting/scratching) effects evoked by 0.78 nmol NP gamma were significantly reduced by the NK1 antagonists, (+/-)-CP 96345 (65 nmol) or RP 67580 (7.8 and 78 nmol). However, cardiovascular responses to NP gamma were not affected by (+/-)-CP 96345 (6.5 nmol), SR 48968 (7.8 and 78 nmol) or R 486 (25 nmol). Pretreatment with peptidase inhibitors significantly enhanced the cardiovascular and behavioural responses to NP gamma. 4. The pressor response to 7.8 nmol NP gamma was converted to a vasodepressor response by pretreatment with phentolamine (2 mg kg-1, i.v.) while the chronotropic response was markedly reduced by propranolol (2 mg kg-1, i.v.). 5. These results suggest that the cardiovascular responses to i.t. NP gamma are mediated by NK1 receptors in the spinal cord leading to the peripheral release of catecholamines from sympathetic fibres or the adrenal medulla. It is unlikely that the spinal action of NP gamma results from its metabolic conversion into neurokinin A or another major metabolite.
Poulat
P
P
Department of Physiology, Université de Montréal, Québec, Canada.
de Champlain
J
J
Couture
R
R
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007278:Injections, Spinal; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015320:Tachykinins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018013:Receptors, Neuropeptide; D015320:Tachykinins; C059905:tachykinin neuropeptide gamma