The negative chronotropic effects of (±)-propranolol and (±)- 4-NO 2 -propranolol in the rat isolated right atrium are due to blockade of the 6-nitrodopamine receptor

Abstract

The positive chronotropic action induced by 6-mitrodopamine (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 were 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 obtained for noradrenaline-induced positive chronotropic effects were 8.44±0.08, 6.41±0.07, and 9.21±0.29, respectively. The positive chronotropism induced by 6-ND (10pM) was blocked by (±)-propranolol (1mM), and (±)-4-NO₂-propranolol (30nM). (±)-7-NO₂-propranol (1mM) had no effect on 6-ND (10pM)-induced increases in atrial rate. 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 (10µM) was unaffected by the sodium channel inhibitors tetrodotoxin (1µM) and lidocaine (10µM) but abolished in atria pre-treated with (±)-4-NO₂-propranolol (10µM). The finding that (±)-propranolol causes falls in spontaneous atrial rate only in concentrations that affect 6-ND positive chronotropic effect, confirms the role of this catecholamine as endogenous modulator of heart chronotropism. (±)-4-NO₂-propranolol behaves as a selective antagonist of 6-ND in the rat isolated atrium.