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The pharmacological specificity of beta-1 and beta-2 adrenergic receptors in rat heart and lung in vitro.

The potency and selectivity of a variety of agonists and antagonists were determined for β-1 and β-2 adrenergic receptors on membranes prepared from rat ventricular muscle and lung. Activation or inhibition of β-adrenergic receptor stimulated adenylate cyclase activity and inhibition of specific (125I)-iodohydroxybenzylpindolol binding were used as in vitro measurements of receptor occupancy. With both assays the relative potencies of isoproterenol, epinephrine and norepinephrine with cardiac membranes was approximately 1:10:10, indicating a population of mainly β-1 adrenergic receptors. With membranes from lung the order of potency of these compounds was approximately 1:10:100, indicating a population mainly of β-2 adrenergic receptors. Several drugs previously reported to be β-2 selective agonists (salbutamol, soterenol, salmefamol, zinterol and fenoterol) activated adenylate cyclase in the lung but not in the heart. These compounds turned out to be partial agonists and isoproterenol-stimulated adenylate cyclase activity was inhibited by them in both tissues. Several compounds previously reported to be either β-1 (dobutamine) or β-2 (terbutaline and metaproterenol) selective agonists had similar potencies for stimulation of adenylate cyclase from both tissues. A series of compounds reported to be β-1 selective antagonists were also investigated. Metoprolol and practolol were 10-fold, and atenolol was 3-fold more potent in the heart than the lung. Butoxamhe, a β-2 antagonist, was 2-4 fold more potent in the lung than the heart, while H35/25 showed no specificity. The ability of antagonists to inhibit [125I]-iodohydroxybenzylpindolol binding to membranes prepared from the heart and lung agreed well with their effects on adenylate cyclase. The β-2 selective agonists zinterol and salmefamol also showed a 10-50 fold greater potency in inhibiting [125I]-iodohydroxybenzylpindolol binding in the lung than the heart. However salbutamol, soterenol and fenoterol, which selectively activated adenylate cyclase in the lung, inhibited [125I]-iodohydroxybenzylpindolol binding in the two tissues with equal potency. This apparent discrepancy appears to be due to the fact that these drugs which are partial agonists in the lung are competitive antagonists in the heart, and that the Ki values in the heart are very similar to the K act values in the lung.