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

Author(s):Show less -

Oliveira, Denis Lima ; Cardoso, Vinicius Francisco ; Britto-Junior, Jose ; Fuguhara, Vivian ; Frecentese, Francesco ; Sparaco, Rosa ; Santagada, Vincenzo ; Caliendo, Giuseppe ; Pupo, Andre Sampaio ; Antunes, Edson ; De Nucci, Gilberto

• Document type: Journal article
• Source: NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY; v. N/A, p. 12-pg., 2024-10-09.

Abstract

The positive chronotropic action induced by 6-nitrodopamine (6-ND) is selectively blocked by beta(1)-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%O-2:5%CO2) and warmed (37 degrees 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 (pIC(50): 4.80 +/- 0.10, 4.64 +/- 0.10, and 4.95 +/- 0.10, respectively). The calculated pA(2) 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 mu M) and ( +/-)-4-NO2-propranolol (30 nM), whereas ( +/-)-7-NO2-propranolol (1 mu M) had no effect on 6-ND-induced responses. The pIC(50) of ( +/-)-propranolol, ( +/-)-4-NO2-propranolol, and ( +/-)-7-NO2-propranolol were significantly shifted to the right in L-NAME-treated atria. The discrepancy between pA(2) values of ( +/-)-propranolol and its respective pIC(50) 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. (AU)

• FAPESP's process: 21/14414-8 - Evaluation of the action of nitro-catecholamines in the cardiovascular system
• Grantee: José Britto Júnior
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/07737-8 - Evaluation of the cardiovascular effect of 6-nitrodopamine in isolated atrium and perfused rat heart
• Grantee: Vivian Fuguhara de Lima
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/15175-1 - Modulation of soluble guanylate cyclase and the intracellular levels of cyclic nucleotides in the lower urinary tract and prostate
• Grantee: Edson Antunes
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/16805-4 - Evaluation of the pathophysiological role of endothelial catecholamines
• Grantee: Gilberto de Nucci
• Support Opportunities: Research Projects - Thematic Grants