Britto-Júnior José, Lima Antonio Tiago, Fuguhara Vivian, Monica Fabiola Z, Antunes Edson, De Nucci Gilberto
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária, 13083-887, Campinas, São Paulo, Brazil.
Department of Pharmacology, Faculty of Medicine, São Leopoldo Mandic, Campinas, SP, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2023 Jun;396(6):1279-1290. doi: 10.1007/s00210-023-02394-9. Epub 2023 Jan 31.
6-Nitrodopamine (6-ND) is released from rat isolated atria being 100 times more potent than noradrenaline and adrenaline, and 10,000 times more potent than dopamine as a positive chronotropic agent. The present study aimed to investigate the interactions of 6-ND with the classical catecholamines, phosphodiesterase (PDE)-3 and PDE4, and the protein kinase A in rat isolated atria. Atrial incubation with 1 pM of dopamine, noradrenaline, or adrenaline had no effect on atrial frequency. Similar results were observed when the atria were incubated with 0.01 pM of 6-ND. However, co-incubation of 6-ND (0.01 pM) with dopamine, noradrenaline, or adrenaline (1 pM each) resulted in significant increases in atrial rate, which persisted over 30 min after washout of the agonists. The increased atrial frequency induced by co-incubation of 6-ND with the catecholamines was significantly reduced by the voltage-gated sodium channel blocker tetrodotoxin (1 µM, 30 min), indicating that the positive chronotropic effect of 6-ND is due in part to activation of nerve terminals. Pre-treatment of the animals with reserpine had no effect on the positive chronotropic effect induced by dopamine, noradrenaline, or adrenaline; however, reserpine markedly reduced the 6-ND (1 pM)-induced positive chronotropic effect. Incubation of the rat isolated atria with the protein kinase A inhibitor H-89 (1 µM, 30 min) abolished the increased atrial frequency induced by dopamine, noradrenaline, and adrenaline, but only attenuated the increases induced by 6-ND. 6-ND induces catecholamine release from adrenergic terminals and increases atrial frequency independently of PKA activation.
6-硝基多巴胺（6-ND）可从大鼠离体心房释放，作为正性变时剂，其效力比去甲肾上腺素和肾上腺素强100倍，比多巴胺强10000倍。本研究旨在探讨6-ND与经典儿茶酚胺、磷酸二酯酶（PDE）-3和PDE4以及大鼠离体心房中的蛋白激酶A之间的相互作用。用1 pM多巴胺、去甲肾上腺素或肾上腺素孵育心房对心房频率无影响。当心房用0.01 pM的6-ND孵育时，观察到类似结果。然而，将6-ND（0.01 pM）与多巴胺、去甲肾上腺素或肾上腺素（各1 pM）共同孵育会导致心房率显著增加，在冲洗激动剂后这种增加持续超过30分钟。电压门控钠通道阻滞剂河豚毒素（1 µM，30分钟）可显著降低6-ND与儿茶酚胺共同孵育诱导的心房频率增加，表明6-ND的正性变时作用部分归因于神经末梢的激活。用利血平预处理动物对多巴胺、去甲肾上腺素或肾上腺素诱导的正性变时作用无影响；然而，利血平显著降低了6-ND（1 pM）诱导的正性变时作用。用蛋白激酶A抑制剂H-89（1 µM，30分钟）孵育大鼠离体心房可消除多巴胺、去甲肾上腺素和肾上腺素诱导的心房频率增加，但仅减弱6-ND诱导的增加。6-ND诱导肾上腺素能末梢释放儿茶酚胺并增加心房频率，且不依赖于PKA激活。
