6-Cyanodopamine as an endogenous modulator of heart chronotropism and inotropism

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2025-04-01 Epub Date: 2025-02-19 DOI:10.1016/j.lfs.2025.123504

José Britto-Júnior , Antonio Tiago Lima , Denis Lima Oliveira , Fernanda V. Mariano , Valéria Barbosa de Souza , André Almeida Schenka , Larryn W. Peterson , Maria Skovbjerg Slot , Rebecca Fjord , Tobias Wang , Edson Antunes , Gilberto De Nucci

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Abstract

Rat isolated atria and ventricles release endothelium-derived 6-nitrodopamine, which induces potent positive chronotropic and inotropic responses. 6-Cyanodopamine is released from rabbit isolated atria and ventricles; however, it is not known whether this novel catecholamine has any action on the isolated heart. Therefore, it was investigated whether rat isolated ventricles release 6-cyanodopamine and its action on the rat isolated heart.

Basal release of 6-cyanodopamine was assessed by LC-MS/MS method. Tyrosine hydroxylase expression was measured by both immunohistochemistry and fluorescence in situ hybridization (FISH). Chronotropic and inotropic effects were evaluated in isolated atria and Langendorff's preparation, respectively.

Rat isolated ventricles presented basal release of 6-cyanodopamine, which was unaffected by pre-treatment with the voltage-gated sodium channel blocker tetrodotoxin. Immunohistochemistry and FISH assays identified tyrosine hydroxylase expression in both endothelium and cardiomyocytes. 6-Cyanodopamine at 10 and 100 pM significantly increased the atrial rate, which was maintained even at 30 min after washing the preparation. In the Langendorff's preparation, 1-min infusion of 6-cyanodopamine (10 and 100 pM) significantly increased heart frequency, left ventricular developed pressure (LVDP), and maximal rate of rise of the left ventricular pressure (dP/dt_max). Bolus injection of noradrenaline at 1 pmol had no effect on any of these parameters; however, in the presence of 6-cyanodopamine (0.01 pM), noradrenaline (1 pmol) significantly increased heart frequency, LVDP, and dP/dt(max).

The results indicate that 6-cyanodopamine is a potent endogenous catecholamine mediating both chronotropism and inotropism in the rat isolated heart. 6-Cyanodopamine may have potential therapeutic effect in heart failure and may be useful as a biomarker of cardio-renal diseases.

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6-氰多巴胺作为心脏变时性和肌力性的内源性调节剂。

大鼠离体心房和心室释放内皮源性6-硝基多巴胺，诱导强效正性变时性和正性肌力反应。6-氰多巴胺从兔离体心房和心室释放；然而，目前尚不清楚这种新型儿茶酚胺是否对离体心脏有任何作用。因此，研究了大鼠离体心室是否释放6-氰多巴胺及其对大鼠离体心脏的作用。采用LC-MS/MS法测定6-氰多巴胺的基础释放量。采用免疫组织化学和荧光原位杂交（FISH）检测酪氨酸羟化酶的表达。分别在离体心房和Langendorff制剂中评估变时性和变肌力作用。大鼠离体心室基底释放6-氰多巴胺，且不受电压门控钠通道阻滞剂河豚毒素预处理的影响。免疫组织化学和FISH检测证实了内皮细胞和心肌细胞中酪氨酸羟化酶的表达。6-氰多巴胺在10 pm和100pM显著增加心房率，即使洗涤制剂后30 min仍保持心房率。在Langendorff制剂中，6-氰多巴胺输注1 min（10和100pM）可显著提高心脏频率、左室发展压（LVDP）和最大左室压上升率（dP/dtmax）。1 pmol去甲肾上腺素对上述参数均无影响；然而，在6-氰多巴胺（0.01pM）存在下，去甲肾上腺素（1 pmol）显著增加心脏频率、LVDP和dP/dt（max）。结果表明，6-氰多巴胺是一种有效的内源性儿茶酚胺，可介导大鼠离体心脏的变时性和肌力性。6-氰多巴胺可能对心力衰竭有潜在的治疗作用，并可能作为心肾疾病的生物标志物。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.