Oliveira Denis Lima, Cardoso Vinicius Francisco, Britto-Júnior Jose, Fuguhara Vivian, Frecentese Francesco, Sparaco Rosa, Santagada Vincenzo, Caliendo Giuseppe, Pupo André Sampaio, Antunes Edson, De Nucci Gilberto
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), 126 Tessália Vieira de Camargo St, Campinas, São Paulo, 13083-887, Brazil.
Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr;398(4):3965-3976. doi: 10.1007/s00210-024-03463-3. Epub 2024 Oct 9.
The positive chronotropic action induced by 6-nitrodopamine (6-ND) is selectively blocked by β-adrenoceptor antagonists at concentrations that do not affect the positive chronotropic effect induced by dopamine, noradrenaline, and adrenaline. Here, the effects of ( ±)-propranolol, ( ±)-4-NO-propranolol, and ( ±)-7-NO-propranolol were investigated in the rat isolated right atrium. The atrium was mounted in glass chambers containing gassed (95%O:5%CO) and warmed (37 °C) Krebs-Henseleit's solution, and the isometric tension registered (PowerLab system). ( ±)-Propranolol, ( ±)-4-NO-propranolol, and ( ±)-7-NO-propranolol caused concentration-dependent falls in the spontaneous atrial frequency (pIC: 4.80 ± 0.10, 4.64 ± 0.10, and 4.95 ± 0.10, respectively). The calculated pA values for ( ±)-propranolol, ( ±)-4-NO-propranolol, and ( ±)-7-NO-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-NO-propranolol (30 nM), whereas ( ±)-7-NO-propranolol (1 µM) had no effect on 6-ND-induced responses. The pIC of ( ±)-propranolol, ( ±)-4-NO-propranolol, and ( ±)-7-NO-propranolol were significantly shifted to the right in L-NAME-treated atria. The discrepancy between pA values of ( ±)-propranolol and its respective pIC 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-NO-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-NO-Propranolol behaves as a selective antagonist of 6-ND in the rat isolated atrium.
6-硝基多巴胺（6-ND）诱导的正性变时作用可被β-肾上腺素能拮抗剂选择性阻断，且这些拮抗剂的浓度不会影响多巴胺、去甲肾上腺素和肾上腺素诱导的正性变时作用。在此，研究了（±）-普萘洛尔、（±）-4-NO-普萘洛尔和（±）-7-NO-普萘洛尔对大鼠离体右心房的作用。将心房置于装有充氧（95%O₂:5%CO₂）且加温（37℃）的克雷布斯-亨泽莱特溶液的玻璃小室中，并记录等长张力（PowerLab系统）。（±）-普萘洛尔、（±）-4-NO-普萘洛尔和（±）-7-NO-普萘洛尔导致自发心房频率呈浓度依赖性下降（pIC₅₀分别为4.80±0.10、4.64±0.10和4.95±0.10）。（±）-普萘洛尔、（±）-4-NO-普萘洛尔和（±）-7-NO-普萘洛尔对去甲肾上腺素诱导的正性变时作用的计算pA₂值分别为8.44±0.08、6.41±0.07和9.21±0.29。6-ND（10 pM）诱导的正性变时作用被（±）-普萘洛尔（1 μM）和（±）-4-NO-普萘洛尔（30 nM）阻断，而（±）-7-NO-普萘洛尔（1 μM）对6-ND诱导的反应无影响。在L-NAME处理的心房中，（±）-普萘洛尔、（±）-4-NO-普萘洛尔和（±）-7-NO-普萘洛尔的pIC₅₀显著右移。（±）-普萘洛尔的pA₂值与其各自的pIC₅₀之间的差异表明，（±）-普萘洛尔引起的心房率下降不应归因于β-肾上腺素能拮抗作用。（±）-普萘洛尔引起的变时作用减弱不受钠通道抑制剂河豚毒素和利多卡因的影响，但在用（±）-4-NO-普萘洛尔预处理的心房中被消除。（±）-普萘洛尔仅在影响6-ND诱导的正性变时作用的浓度下降低自发心房率，这一发现证实了这种儿茶酚胺作为心脏变时性内源性调节剂的作用。（±）-4-NO-普萘洛尔在大鼠离体心房中表现为6-ND的选择性拮抗剂。
