Prolonged cardiovascular effects of the N-type Ca2+ channel antagonist omega-conotoxin GVIA in conscious rabbits.
omega-Conotoxin GVIA (omega-CTX) is an N-type Ca2+ channel antagonist that is considered to be only partially reversible in vitro. In vivo, its effects after 24 h are unknown. To assess the duration of action of this peptide in vivo, the effects of a single intravenous injection of omega-CTX on mean arterial pressure (MAP), heart rate (HR), postural adaptation, and the baroreflex were investigated in conscious rabbits. MAP, HR, the baroreflex induced by i.v. glyceryl trinitrate (0.4-20 micrograms/kg) and phenylephrine (0.1-15 micrograms/kg) and orthostatic responses to 1 min 90 degrees head-up tilt were assessed before (0 h) and 2-168 h after administration of omega-CTX (10 micrograms/kg i.v. bolus: n = 6-9) or vehicle (0.9% saline; n = 6). Acute phase I: By 2 h after omega-CTX administration, MAP had decreased from 75 +/- 3 mm Hg to 60 +/- 2 mm Hg; HR increased from 220 +/- 7 beats/min to 249 +/- 5 beats/min (n = 9). There was marked attenuation of the baroreflex curve (HR range decreasing by 61%). By 24 h. MAP and HR had returned to control values, but the HR range was still 18% less than that of control. Phase II: MAP and HR then decreased steadily over the next 96 h to significantly lower values by 120 h after omega-CTX administration (delta-8 +/- 2 mm Hg and -29 +/- 2 beats/min, respectively; n = 6). Thereafter, MAP and HR values increased and by 168 h these parameters, and the baroreflex, were similar to control values. In response to 90 degrees tilt, there was no change in MAP at 0 h; however, 1 h after omega-CTX, significant postural hypotension was observed with decreases of 14 +/- 1 mm Hg(n = 9). Smaller orthostatic responses were still observed 48 h after omega-CTX administration: however, by 72 h, head-up tilt no longer induced a significant change in MAP. In the vehicle-treatment group, there were no changes in cardiovascular parameters during 0-168 h. Thus omega-CTX (10 micrograms/kg i.v.) causes acute hypotension, as well as postural hypotension, and has sympatholytic and vagolytic effects that are mostly reversed after 48 h in the conscious rabbit. However, a second hypotensive and bradycardic phase lasting a further 96 h ensues, suggesting that other prolonged effects from central neural or hormonal mechanisms or fluid shifts may occur.
Wright
C E
CE
Department of Pharmacology, University of Melbourne, Australia.
Angus
J A
JA
D000818:Animals; D017704:Baroreflex / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011187:Posture; D011817:Rabbits; D020866:omega-Conotoxin GVIA
D002121:Calcium Channel Blockers; D010455:Peptides; D020866:omega-Conotoxin GVIA