Uptake and metabolism of histamine in guinea-pig isolated atria and their relationship to the pharmacological responses.

1. The uptake of radiolabelled 14C-histamine into guinea-pig isolated left atria was determined. 2. Mepyramine up to 10(-7) M had no significant effect upon the uptake of total radioactivity. Metiamide (10(-4) M) produced a small but not significant inhibition of uptake. SK & F 91581 (10(-4) M) and amodiaquine (10(-4) M) both significantly inhibited uptake by 48.2 +/- 4.2 and 56.7 +/- 1.2% respectively. 3. The metabolism profiles of radiolabelled histamine after 5 and 30 min incubation were examined by thin-layer chromatography. 4. SK & F 91581 (10(-4) M) and amodiaquine (10(-4) M) reduced the proportion of N tau-methylhistamine and acid metabolites after a 30 min incubation. The levels of unmetabolized histamine were elevated. This may explain their inhibitory action upon histamine uptake. 5. The effects of mepyramine, metiamide, SK & F 91581 and amodiaquine were then examined upon the positive inotropic and chronotropic responses of isolated left and right atria to histamine. 6. Mepyramine (10(-7) M) inhibited the positive inotropic responses only (H1), whereas metiamide (10(-4) M) inhibited the positive chronotropic responses only (H2). SK & F 91581 (10(-4) M) had no effect upon these responses and amodiaquine (10(-5) M) depressed the maxima of the rate response dose-response curves. 7. The relationship between uptake and metabolism of histamine and its pharmacological response is discussed.