Integrated autonomic and behavioral responses to L/N Ca2(+)-channel blocker omega-conotoxin in conscious rats.
omega-Conotoxin (omega-ctx) was used as a probe for studying the putative role of brain L/N-type Ca2+ channels in regulation of autonomic functions. Rats were injected intracerebroventricularly (icv) with omega-ctx, and hemodynamic, biochemical and behavioral variables were monitored. omega-Ctx (0.032-10 nmol/kg) caused a persistent, dose-dependent shaking behavior, complex thermoregulatory changes, and motor deficits lasting up to 48 h. Cardiovascular responses to omega-ctx included tachycardia (+71 +/- 16%, P less than 0.01) and elevated arterial blood pressure (+16 +/- 1%, P less than 0.05) associated with increased circulating levels of norepinephrine and epinephrine. Higher doses, 1 or 10 nmol/kg, resulted in circulatory shock and death. Central administration of 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8), diltiazem (100 or 1,000 nmol/kg), neomycin (100 nmol/kg, each), nifedipine (10 nmol/kg), and CdCl2 (100 nmol/kg), which represent intracellular, non-specific N-, L-, and L/N-type Ca2(+)-channel blockers, respectively, did not cause any behavioral or hemodynamic effects, whereas the L-channel agonist BAY K 8644 (100 nmol/kg icv) caused a mild transient pressor response. Pretreatment with the gamma-aminobutyric acid (GABA) agonist muscimol (icv) or a combined intravenous pretreatment with propranolol and N-methylatropine blocked the omega-ctx effects. Our data suggest that omega-ctx actions in the brain involve central GABAergic mechanisms modulated by yet a different type of Ca2+ channels not characterized by any of the known voltage-operated Ca2+ channels.
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001774:Blood Chemical Analysis; D001831:Body Temperature / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002395:Catecholamines / Q000097:blood; D004110:Diltiazem / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009420:Nervous System / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D002395:Catecholamines; D010456:Peptides, Cyclic; D020960:omega-Conotoxins; C053423:Conus magus toxin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D004110:Diltiazem