Activation of myocardial ?-adrenoceptors by the nitrogen-free low affinity ligand 3?,4?-dihydroxy-?-methylpropiophenone (U-0521)

Abstract

The effect of 3′,4′-dihydroxy-α-methylpropiophenone (U-0521) on the rate of spontaneously contracting cultured rat heart cells and right atria of rats and kittens was investigated. The action of U-0521 on the cellular content of cyclic AMP and on the adenylyl cyclase of heart membrane particles was also studied. 1. U-0521 caused positive chronotropic effects on single cultured heart cells and right atria of the rat. U-0521 was about 10⁵ times less potent than (-)-isoprenaline. The maximum effect of U-0521 was smaller than the maximum effect of (-)-isoprenaline. A small positive chronotropic effect of U-0521 was also observed on kitten atria. 2. The β-adrenoceptor blocker (-)-bupranolol antagonized the positive chronotropic effects of U-0521 to the same extent as the effects of (-)-isoprenaline on single cells and atria of the rat. The effects of both U-0521 and (-)-isoprenaline appear therefore mediated through the same β-adrenoceptors. The positive chronotropic effects of U-0521 on kitten atria were also blocked by (-)-bupranolol. 3. Up to 0.1 mM U-0521 did not block the effects of (-)-isoprenaline on rat atria, not even in the presence of corticosterone or hydrocortisone. 4. 1 min incubations with equieffective (increase in cellular beating rate) concentrations of U-0521 (0.1 mM) and (-)-isoprenaline (1 nM) caused a significant increase in the cellular content of cAMP; this effect of both drugs was antagonized by 10 nM (-)-bupranolol. 5. 0.1–3.3 mM U-0521 did not stimulate the adenylyl cyclase of cell-free membrane particles of kitten ventricles. The cyclase was depressed by 10 mM U-0521. 3.3 mM U-0521 caused a 20% decrease of the maximum cyclase-stimulating effect of (-)-isoprenaline and a 1.6-fold increase of its apparent K_m. 6. The results with U-0521 suggest that β-adrenoceptors can be activated by agonists devoid of nitrogen. However, the affinity of U-0521 for the β-adrenoceptor is very low (K_U-0521 ≈ 5.5 mM). The concentration of U-0521 (0.1 mM) causing maximal increases in beating rate of cultured cells probably occupies less than 7% of the available β-adrenoceptors.