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Radioligand binding studies of α1‐adrenoceptor subtypes in rat heart

1 In order to characterize the α1‐adrenoceptor subtypes mediating positive inotropic effects of adrenaline (in the presence of propranolol) in rat right ventricular strips and the Ca2+ sources used to elicit them, we have used radioligand binding to identify the α1‐adrenoceptor subtypes present in rat heart and the α1‐adrenoceptor affinity and subtype‐selectivity of various pharmacological tools. 2 Amitryptiline, mianserin, trimipramine, oxaprotiline, clonidine, chloroethylclonidine, phenoxybenzamine, BE 2254 and 8‐OH‐DPAT competed for [3H]‐prazosin binding in rat heart, vas deferens, liver, spleen, cerebral cortex and hippocampus but none of them displayed detectable α1‐adrenoceptor subtype‐selectivity; nitrendipine did not compete for [3H]‐prazosin binding in concentrations up to ***5 μmoll−1. 3 The α1A‐adrenoceptor‐selective, 5‐methyl‐urapidil, (+)‐niguldipine, and to a lesser extent (–)‐niguldipine competed for [3H]‐prazosin binding in rat heart, vas deferens, cerebral cortex and hippocampus with shallow and biphasic curves; analysis of these curves demonstrated that rat heart contains α1A‐ and α1B‐adrenoceptors in a 20:80 ratio. 4 Treatment of rat right ventricular strips with 100 μmoll−1 chloroethylclonidine for 30 min at 30°C followed by 60 min washout reduced the number of α1‐adrenoceptors, as assessed by [3H]‐prazosin saturation experiments, by 74%. Treatment with 100 μmol 1−1 CdCl2 did not affect number or affinity of cardiac α1‐adrenoceptors and combined treatment with chloroethylclonidine and CdCl2 reduced α1‐adrenoceptor number by 90%. 5 Treatment of rat right ventricular strips with chloroethylclonidine steepened 5‐methyl‐urapidil competition curves and increased the relative contribution of α1A‐adrenoceptors from 26 to 89%. Treatment with CdCl2 did not affect 5‐methyl‐urapidil competition curves and combined treatment with chloroethylclonidine and CdCl2 increased the relative contribution of α1A‐adrenoceptors to 66%. 6 We conclude that rat heart contains α1A‐ and α1B‐adrenoceptors in a 20:80% ratio. Treatment with chloroethylclonidine reduces α1B‐adrenoceptor number by 96% but has only minor effects on α1A‐adrenoceptor density. Treatment with CdCl2 does not affect the number of either α1‐adrenoceptor subtype.