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 developm ent. In rats, daily bolus intravenous administration of CI-959 at dose s greater than or equal to 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 tre atment was discontinued. Cardiac hypertrophy was not evident when CI-9 59 was given orally or by continuous intravenous infusion with ALZA os motic pumps. Maximum plasma drug concentrations (C-max) were significa ntly higher when CI-959 was given by bolus intravenous injection, sugg esting that cardiac effects were dependent on high C-max concentration s. When neonatal rat cardiomyocytes were exposed to CI-959 in vitro, t here was no evidence of myocyte enlargement or increased protein conte nt. Cardiac hypertrophy was prevented by pretreatment with nonselectiv e beta- and beta(1)-selective adrenoceptor blockers as well as with ce ntral sympatholytics. beta(2)- and alpha-adrenoceptor blockers were in effective in preventing cardiac hypertrophy. Bolus intravenous CI-959 administration resulted in prolonged hypotension and associated increa se 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 b y endogenous catecholaminergic stimulation of cardiac beta(1)-adrenoce ptors.