Mediation of the positive chronotropic effect of CGP 12177 and cyanopindolol in the pithed rat by atypical β‐adrenoceptors, different from β3‐adrenoceptors

Abstract

1 The influence of β₁, β₂, and β₃-adrenoceptor agonists and of CGP 12177 and cyanopindolol on heart rate and diastolic blood pressure was studied in the pithed rat. 2 The β₁-adrenoceptor agonist, prenalterol, increased heart rate and the β₂-adrenoceptor agonist, fenoterol, caused a fall in blood pressure. The effect of prenalterol was antagonized by the β₁-adrenoceptor antagonist, CGP 20712 0.1 μmol kg⁻¹ and the action of fenoterol was attenuated by the β₂-adrenoceptor antagonist, ICI 118551 0.1 μmol kg⁻¹. Both effects were markedly diminished by the non-selective β-adrenoceptor antagonist, bupranolol 0.1 μmol kg⁻¹. 3 The non-selective β-adrenoceptor agonist, isoprenaline, three β₃-agonists as well as CGP 12177 and cyanopindolol elicited a positive chronotropic effect, exhibiting the following pED_A60 values (negative log values of the doses increasing heart rate by 60 beats min⁻¹): isoprenaline 10.4, CGP 12177 8.3, cyanopindolol 7.2, BRL 37344 6.9, ZD 2079 5.2 and CL 316243 −1, given together with ICI 118551 0.1 μmol kg⁻¹, markedly attenuated the positive chronotropic effect of isoprenaline, BRL 37344, ZD 2079 and CL 316243 without affecting the increase in heart rate produced by CGP 12177 and cyanopindolol. 5 The positive chronotropic effect of CGP 12177 and cyanopindolol was attenuated by CGP 20712, 1 and 10 μmol kg⁻¹ and bupranolol, 10 μmol kg⁻¹ but was not affected by ICI 118551, 10 μmol kg⁻¹. The effect of CGP 12177 was also not changed by BRL 37344 1 μmol kg⁻¹, ZD 2079 10 μmol kg⁻¹, CL 316243 10 μmol kg⁻¹, the α₁-adrenoceptor antagonist, prazosin 1 μmol kg⁻¹ and the 5-hydroxytryptamine 5-HT_2A receptor antagonist, ketanserin 3 μmol kg⁻¹. 6 CGP 12177 0.002 μmol kg⁻¹ and cyanopindolol 0.003 μmol kg⁻¹ shifted to the right the dose-response curve of prenalterol for its positive chronotropic effect. The -log values of the doses causing a twofold shift to the right were 9.6 and 9.5, respectively. 7 Isoprenaline 0.00001-0.001 μmol kg⁻¹, BRL 37344 0.01-1 μmol kg⁻¹ and CGP 12177 0.1 μmol kg⁻¹ caused a fall in diastolic blood pressure which was markedly attenuated by combined administration of CGP 20712 and ICI 118551, 0.1 μmol kg⁻¹ each. 8 CGP 12177 0.01 and 0.1 μmol kg⁻¹ and cyanopindolol 1 μmol kg⁻¹ elicited an increase in diastolic blood pressure. CGP 20712, ICI 118551, bupranolol and, in the case of CGP 12177, also BRL 37344, ZD 2079, CL 316243, prazosin and ketanserin did not influence this effect. 9 In conclusion, the positive chronotropic effect of CGP 12177 and cyanopindolol is not mediated via β₁-, β₂-, β₃-, α₁-adrenoceptors or 5-HT_2A receptors. This effect may involve atypical β-adrenoceptors, similar or identical to those described by Kaumann (1989) in isolated heart preparations.