Cardiac hypertrophy in rats after intravenous administration of CI-959, a novel antiinflammatory compound: morphologic features and pharmacokinetic and pharmacodynamic mechanisms.
CI-959 is an antiallergic/antiinflammatory agent currently in development. In rats, daily bolus intravenous administration of CI-959 at doses > or = 10 mg/kg was associated with development of cardiac hypertrophy. There was no morphologic or biochemical evidence of myocyte injury, and cardiac hypertrophy rapidly reversed after treatment was discontinued. Cardiac hypertrophy was not evident when CI-959 was given orally or by continuous intravenous infusion with ALZA osmotic pumps. Maximum plasma drug concentrations (Cmax) were significantly higher when CI-959 was given by bolus intravenous injection, suggesting that cardiac effects were dependent on high Cmax concentrations. When neonatal rat cardiomyocytes were exposed to CI-959 in vitro, there was no evidence of myocyte enlargement or increased protein content. Cardiac hypertrophy was prevented by pretreatment with nonselective beta- and beta 1-selective adrenoceptor blockers as well as with central sympatholytics. beta 2- and alpha-adrenoceptor blockers were ineffective in preventing cardiac hypertrophy. Bolus intravenous CI-959 administration resulted in prolonged hypotension and associated increase in plasma catecholamine levels, with apparent inhibition of reflex tachycardia. We conclude that CI-959-associated cardiac hypertrophy in rats was not a direct drug effect but instead was probably mediated by endogenous catecholaminergic stimulation of cardiac beta 1-adrenoceptors.
Low
J E
JE
Parke-Davis Pharmaceutical Research Division, Warner-Lambert, Ann Arbor, MI 48105, USA.
Metz
A L
AL
Mertz
T E
TE
Henry
S P
SP
Knowlton
P
P
Loewen
G
G
Sommers
C S
CS
Robertson
D G
DG
Olszewski
B J
BJ
Schroeder
R L
RL
D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced* / Q000517:prevention & control; D002395:Catecholamines / Q000097:blood; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D006003:Glycogen / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D015918:Infusion Pumps, Implantable; D007262:Infusions, Intravenous; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008854:Microscopy, Electron; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002395:Catecholamines; D013777:Tetrazoles; D013876:Thiophenes; C061662:CI 959; D006003:Glycogen; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase