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Diabetes abolishes sildenafil-induced cGMP-dependent protein kinase-I expression and cardioprotection. J Cardiovasc Pharmacol 2007 Dec;50(6):670-6

Date

12/20/2007

Pubmed ID

18091584

DOI

10.1097/FJC.0b013e318157fd5b

Abstract

The selective phosphodiesterase type 5 inhibitor sildenafil has been demonstrated to produce cardioprotection; however, diabetes is known to abolish cardioprotective signaling. We tested the hypothesis that sildenafil-induced cGMP-dependent protein kinase-I (PKG-I) expression and cardioprotection are attenuated by diabetes. Barbiturate-anesthetized dogs (n = 38) were instrumented for measurement of hemodynamics and subjected to 60-minute occlusion of the left anterior descending coronary artery and 3-hour reperfusion. Dogs were randomly assigned to receive 0.9% saline (control) or intravenous sildenafil (0.7 or 1.4 mg/kg) in the absence or presence of diabetes (3 weeks after administration of alloxan and streptozotocin). No differences in hemodynamics or coronary collateral blood flow (radioactive microspheres) were observed between groups before and during ischemia and reperfusion, except that infusion of sildenafil produced transient decreases in left ventricle systolic pressure. Sildenafil significantly (P < 0.05) reduced infarct size (16 +/- 2% of the left ventricular area at risk; triphenyltetrazolium staining) as compared to control (31 +/- 39%). Diabetes alone did not alter infarct size (31 +/- 2%) but abolished the protective effect of sildenafil (0.7 mg/kg: 26 +/- 3%; 1.4 mg/kg: 26 +/- 3%). Sildenafil increased PKG-I expression (immunohistochemistry and Western blotting) in the absence but not the presence of diabetes. The results indicate that diabetes abolishes cardioprotection by sildenafil and implicates PKG-I in the signal transduction pathway activated by this drug.

Author List

Jamnicki-Abegg M, Weihrauch D, Chiari PC, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR

Authors

Paul S. Pagel MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Alloxan
Animals
Blood Glucose
Blotting, Western
Cardiotonic Agents
Collateral Circulation
Coronary Circulation
Cyclic GMP-Dependent Protein Kinases
Diabetes Mellitus, Experimental
Dogs
Dose-Response Relationship, Drug
Hemodynamics
Immunochemistry
Injections, Intravenous
Microspheres
Myocardial Infarction
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Piperazines
Purines
Radioisotopes
Sildenafil Citrate
Streptozocin
Sulfones
Up-Regulation
jenkins-FCD Prod-387 b0ced2662056320369de4e5cd5f21c218c03feb3