The negative chronotropic effects of (±)-propranolol and (±)-4-NO₂-propranolol in the rat isolated right atrium are due to blockade of the 6-nitrodopamine receptor

The positive chronotropic action induced by 6-nitrodopamine (6-ND) is selectively blocked by β₁-adrenoceptor antagonists at concentrations that do not affect the positive chronotropic effect induced by dopamine, noradrenaline, and adrenaline. Here, the effects of ( ±)-propranolol, ( ±)-4-NO₂-propranolol, and ( ±)-7-NO₂-propranolol were investigated in the rat isolated right atrium. The atrium was mounted in glass chambers containing gassed (95%O₂:5%CO₂) and warmed (37 °C) Krebs-Henseleit's solution, and the isometric tension registered (PowerLab system). ( ±)-Propranolol, ( ±)-4-NO₂-propranolol, and ( ±)-7-NO₂-propranolol caused concentration-dependent falls in the spontaneous atrial frequency (pIC₅₀: 4.80 ± 0.10, 4.64 ± 0.10, and 4.95 ± 0.10, respectively). The calculated pA₂ values for ( ±)-propranolol, ( ±)-4-NO₂-propranolol, and ( ±)-7-NO₂-propranol on noradrenaline-induced positive chronotropism were 8.44 ± 0.08, 6.41 ± 0.07, and 9.21 ± 0.29, respectively. The positive chronotropism induced by 6-ND (10 pM) was blocked by ( ±)-propranolol (1 µM) and ( ±)-4-NO₂-propranolol (30 nM), whereas ( ±)-7-NO₂-propranolol (1 µM) had no effect on 6-ND-induced responses. The pIC₅₀ of ( ±)-propranolol, ( ±)-4-NO₂-propranolol, and ( ±)-7-NO₂-propranolol were significantly shifted to the right in L-NAME-treated atria. The discrepancy between pA₂ values of ( ±)-propranolol and its respective pIC₅₀ indicates that the falls in atrial rate induced by ( ±)-propranolol should not be attributed to b-adrenergic antagonism. The reduced chronotropism by ( ±)-propranolol was unaffected by the sodium channel inhibitors tetrodotoxin and lidocaine but that was abolished in atria pre-treated with ( ±)-4-NO₂-propranolol. The finding that ( ±)-propranolol reduces spontaneous atrial rate only in concentrations that affect 6-ND-induced positive chronotropism confirms the role of this catecholamine as an endogenous modulator of heart chronotropism. ( ±)-4-NO₂-Propranolol behaves as a selective antagonist of 6-ND in the rat isolated atrium.