Mechanism and metabolic disposition of verapamil-evoked overflow of radioactivity from isolated atria preloaded with [3H]norepinephrine.

In this study the mechanism and metabolic profile of verapamil-evoked release of radioactivity was investigated in the rat isolated atria preloaded with [3H]norepinephrine [( 3H]NE). Verapamil (10(-7) to 10(-3) M) caused a dose-related increase in the outflow (or the fractional release) of 3H. The fractional 3H-release produced by verapamil was reduced markedly in tissues which had been preloaded with [3H]NE in the presence of cocaine (10 microM) or after pretreatment of animals with reserpine (5 mg/kg i.p., 24 hr before sacrifice). Verapamil-evoked fractional 3H-release was unchanged in the presence of tetrodotoxin (5 X 10(-6) M) or in Ca++-free Krebs' medium containing 2 mM ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid. Whereas greater than 90% of tissue 3H-content consisted of unchanged [3H]NE, 60 to 75% of the spontaneous outflow and the verapamil-evoked overflow consisted of [3H]-3,4-dihydroxyphenylglycol and 2 to 10% was unchanged [3H]NE. When both cocaine (10 microM) and hydrocortisone (28 microM) (uptake-1 and uptake-2 blockers, respectively) were present, although the spontaneous outflow, as well as verapamil-evoked overflow, of radioactivity was increased, the metabolic profiles remained essentially unchanged. The addition of pargyline (10 microM), a monoamine oxidase inhibitor, in addition to the uptake-1 and uptake-2 blockers to the Krebs' solution significantly depressed both the spontaneous outflow and verapamil-evoked overflow of 3H; the verapamil-evoked overflow under this condition, however, consisted of unchanged [3H]NE (greater than 90%).(ABSTRACT TRUNCATED AT 250 WORDS)