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Diabetes Abolishes Sildenafil-Induced cGMP-Dependent Protein Kinase-I Expression and Cardioprotection.

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

From the Departments of *Anesthesiology; †Pharmacology and Toxicology; and ‡Medicine (Division of Cardiovascular Diseases), the Medical College of Wisconsin, Milwaukee, Wisconsin; §Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin; and ¶Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.

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.

Published 19 December 2007 in J Cardiovasc Pharmacol, 50(6): 670-676.
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