Tetrahydrobiopterin paradoxically mediates cardiac oxidative stress and mitigates ethanol-evoked cardiac dysfunction in conscious female rats

• Published in: European journal of pharmacology 2021-10, Vol.909, p.174406-174406, Article 174406
• Main Authors: Yao, Fanrong, Abdel-Rahman, Abdel A.
• Format: Article
• Language: English
• Subjects: Animals; Arginase; Biopterins - analogs & derivatives; Biopterins - antagonists & inhibitors; Biopterins - pharmacology; Biopterins - therapeutic use; Cardiomyopathies - chemically induced; Cardiomyopathies - drug therapy; Cardiomyopathies - pathology; Disease Models, Animal; Ethanol; Ethanol - adverse effects; Female; Heart - drug effects; Humans; Hypotension; Myocardial dysfunction; Myocardium - pathology; Nitric oxide synthase; Nitric Oxide Synthase Type III - metabolism; Oxidative stress; Oxidative Stress - drug effects; Rats; Reactive Oxygen Species - metabolism; Sugar Acids - pharmacology; Superoxide dismutase; Tetrahydrobiopterin
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174406

Oxidation of tetrahydrobiopterin (BH4), a cofactor of nitric oxide synthase (NOS), by reactive oxidative species (ROS), leads to NOS uncoupling and superoxide production instead of NO. Further, oxidative stress plays a major role in ethanol-evoked cardiac dysfunction in proestrus female rats, and acute ethanol administration reduces brain BH4 level. Therefore, we discerned the unknown role of BH4 in ethanol-evoked cardiac dysfunction by pharmacologically increasing BH4 levels or inhibiting its effect in proestrus female rats. Acute ethanol (1.5 g/kg, i.v, 30 min) caused myocardial dysfunction (lowered dP/dtmax and LVDP) and hypotension, along with increases in myocardial: (i) levels of NO, ROS and malondialdehyde (MDA), (ii) activities of catalase, ALDH2 and NADPH oxidase (Nox), and (iii) phosphorylation of eNOS, nNOS. Further, ethanol suppressed myocardial arginase and superoxide dismutase (SOD) activities and enhanced eNOS uncoupling. While ethanol had no effect on cardiac BH4 levels, BH4 (19 mg/kg, i.v) supplementation paradoxically caused cardiac oxidative stress, but mitigated the cardiac dysfunction/hypotension and most of the adverse molecular responses caused by ethanol. Equally important, the BH4 inhibitor DAHP (1 g/kg, i.p) exacerbated the adverse molecular and cardiovascular effects caused by ethanol. Our pharmacological studies support a protective role for the NOS co-factor BH4 against ethanol-evoked cardiac dysfunction and hypotension in female rats. •Ethanol reduced myocardial function and blood pressure along with increasing myocardial oxidative stress and NOS activity.•BH4 supplementation mitigated the cardiac dysfunction/hypotension and most of the adverse molecular effects of ethanol.•The BH4 inhibitor DAHP exacerbated the adverse molecular and cardiovascular effects of ethanol.