4-Nitro-propranolol selectively inhibits the positive chronotropic effect induced by 6-nitrodopamine in the rat isolated right atrium

Abstract 6-Nitrodopamine (6-ND) is released from isolated atria of rabbit, rat and mice and has significant positive chronotropic action. The positive chronotropic effect induced by 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 right atrium was mounted between two metal hooks in 10-mL custom designed glass chambers containing Krebs-Henseleit’s solution, continuously gassed (95%O2:5%CO2) and heated (37°C). Tissues were allowed to equilibrate under a resting tension of 10 mN for one hour, and the isometric tension was registered using a PowerLab system. 4-NO2-propranol was more potent than propranolol as a negative chronotropic agent. At 30 nM, 4-NO2-propranolol did not affect the chronotropic effect of dopamine, noradrenaline, and adrenaline. The S-isomer of 4- NO2-propranolol, but not the R-isomer, was active. Propranolol induced fall in atrial rate at concentrations higher than those required to block the chronotropic effects of dopamine, noradrenaline and adrenaline, but enough to block the 6-ND effect. 7-NO2-propranolol was only active at very high concentration, and the effect was not stereoselective. The negative chronotropic effects induced by 4-NO2-propranolol (100 nM) and propranolol (300 nM) were not observed in L-NAME treated atria, whereas that induced by 7-NO2-propranolol (10 mM) was unaffected. The potent and selective inhibition observed with (±)-4-NO2-propranolol reinforces the concept that 6-ND is a major mediator of heart chronotropism and the main target of the so-called b-blockers.