title: Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System.
abstract: Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R) injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR) model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg) group. Thirty min after drug infusion, ventricular fibrillation (8 min) and cardiopulmonary resuscitation (up to 30 min) was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II) and Ang (1-7) levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE), ACE2, Ang II type 1 receptor (AT1R), and the Ang (1-7) receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafil further boosted the upregulation of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) and inducible nitric oxide synthase(iNOS). Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation.
authors.affiliation: Department of Emergency Medicine, Beijing Chao-Yang Hospital, Capital Medical University, 8<sup>#</sup> Worker's Stadium South Road, Chao-Yang District, Beijing 100020, China. wangguoxing@ccmu.edu.cn.|Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, 95<sup>#</sup> Yong'an Road, Xicheng District, Beijing 100050, China. wangguoxing@ccmu.edu.cn.
authors.forename: Guoxing
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Emergency Medicine, Beijing Chao-Yang Hospital, Capital Medical University, 8<sup>#</sup> Worker's Stadium South Road, Chao-Yang District, Beijing 100020, China. zqian604@163.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Emergency Medicine, Beijing Chao-Yang Hospital, Capital Medical University, 8<sup>#</sup> Worker's Stadium South Road, Chao-Yang District, Beijing 100020, China. 2000ywei@sina.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Emergency Medicine, Beijing Chao-Yang Hospital, Capital Medical University, 8<sup>#</sup> Worker's Stadium South Road, Chao-Yang District, Beijing 100020, China. wu007838@sina.com.
authors.forename: Junyuan
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Emergency Medicine, Beijing Chao-Yang Hospital, Capital Medical University, 8<sup>#</sup> Worker's Stadium South Road, Chao-Yang District, Beijing 100020, China. lichunsheng@ccmu.edu.cn.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Li
mesh_terms: D000804:Angiotensin II / Q000097:blood / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016887:Cardiopulmonary Resuscitation; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006323:Heart Arrest / Q000150:complications / Q000401:mortality / Q000628:therapy; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D013552:Swine
chemical_list: D002316:Cardiotonic Agents; D058986:Phosphodiesterase 5 Inhibitors; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D007703:Peptidyl-Dipeptidase A; D006152:Cyclic GMP
keywords: Ang (1–7); myocardial ischemia; porcine model; renin-angiotensin system; sildenafil