POSSIBLE MECHANISMS OF SUDDEN-DEATH AND HEMOCONCENTRATION INDUCED BY ENDOTHELIN-1 AND BIG ENDOTHELIN-1 IN MICE

We investigated the profiles of sudden death and hemoconcentration ind uced by endothelin-1 (ET-1) and big endothelin-1 (big ET-1) in mice us ing various compounds as pharmacological tools. In ET-1-induced sudden death (5 nmol/kg, i.v.), pretreatment with the Ca2+-channel blockers, diltiazem, nifedipine or verapamil at a dose of 2 mg/kg, i.v. signifi cantly inhibited the mortality and prolonged the latency to death. The se Ca2+-channel blockers, however, failed to inhibit the rise in hemat ocrit(Ht), namely hemoconcentration, induced by ET-1 (2.5 nmol/kg). A beta-adrenoceptor agonist, isoproterenol (I mg/kg) tended to prolong t he latency, whereas, a beta-adrenoceptor blocker, propranolol (2 mg/kg ), and an alpha- and beta-adrenoceptor blocker, labetalol (5 mg/kg), a ggravated the sudden death. Esculetin (10 mg/kg) and fenbufen (10 mg/k g), which are enzyme inhibitors in the arachidonate cascade, prevented only the hemoconcentration. Anti-arrythmic drugs, lidocaine (1 mg/kg) and disopyramide (20 mg/kg) did not improve any parameters. Big ET-1 also caused sudden death (20 and 25 nmol/kg, i.v.) and hemoconcentrati on (10 nmol/kg, i.v.). Of several proteinase inhibitors, only a metall oproteinase inhibitor, phosphoramidon (2 mg/kg i.v.), prevented the su dden death and the hemoconcentration induced by big ET-1 but not by ET -1. Ca2+-channel blockers exerted their protective effects only when a lower dose of big ET-1 was employed. These results indicate that the sudden death caused by both peptides is mainly due to myocardial ische mia and respiratory disorder, and that hemoconcentration caused by the m is due not to their vasoconstrictor action but to their effects on t he vascular permeability via secondary endogenous factors.