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. 2025 Apr;398(4):3965-3976.
doi: 10.1007/s00210-024-03463-3. Epub 2024 Oct 9.

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

Denis Lima Oliveira #  1 , Vinicius Francisco Cardoso #  1 , Jose Britto-Júnior  2 , Vivian Fuguhara  1 , Francesco Frecentese  3 , Rosa Sparaco  3 , Vincenzo Santagada  3 , Giuseppe Caliendo  3 , André Sampaio Pupo  4 , Edson Antunes  1 , Gilberto De Nucci  1   5
Affiliations

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

Denis Lima Oliveira et al. Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr.

Abstract

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.

Keywords: Beta-blocker; Catecholamines; L-NAME; Stereoselectivity.

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Conflict of interest statement

Declarations. Ethical approval: All experimental protocols were authorized by the Ethics Committee in Animal Use of UNICAMP (CEUA/UNICAMP, protocol number 5942–1/2022). Consent to participate: Not applicable. Consent for publication: The authors authorize the submission and publication of this article Naunyn–Schmiedeberg’s Archives of Pharmacology. Competing interests: The authors declare no competing interests.

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