Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits.

Abstract

Sildenafil citrate (Viagra) is the most widely used pharmacological drug for treating erectile dysfunction in men. It has potent cardioprotective effects against ischemia-reperfusion injury via nitric oxide and opening of mitochondrial ATP-sensitive K(+) channels. We further investigated the role of protein kinase C (PKC)-dependent signaling pathway in sildenafil-induced cardioprotection. Rabbits were treated (orally) with sildenafil citrate (1.4 mg/kg) 30 min before index ischemia for 30 min and reperfusion for 3 h. The PKC inhibitor chelerythrine (5 mg/kg i.v.) was given 5 min before sildenafil. Infarct size (% of risk area) reduced from 33.65 +/- 2.17 in the vehicle (saline) group to 15.07 +/- 0.63 in sildenafil-treated groups, a 45% reduction compared with vehicle (mean +/- SE, P < 0.05). Chelerythrine abolished sildenafil-induced protection, as demonstrated by increase in infarct size to 31.14 +/- 2.4 (P < 0.05). Chelerythrine alone had an infarct size of 33.5 +/- 2.5, which was not significantly different compared with DMSO-treated group (36.8 +/- 1.7, P > 0.05). Western blot analysis demonstrated translocation of PKC-alpha, -, and -delta isoforms from cytosol to membrane after treatment with sildenafil. However, no change in the PKC-beta and -epsilon isoforms was observed. These data provide direct evidence of an essential role of PKC, and potentially PKC-alpha, -, and -delta, in sildenafil-induced cardioprotection in the rabbit heart.

• Authors: Anindita Das, Ramzi Ockaili, Fadi Salloum, Rakesh C Kukreja
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 286 Issue 4 Pg. H1455-60 (Apr 2004) ISSN: 0363-6135 [Print] United States
• PMID: 15020304 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkaloids
• Benzophenanthridines
• Enzyme Inhibitors
• Isoenzymes
• Phenanthridines
• Phosphodiesterase Inhibitors
• Piperazines
• Purines
• Sulfones
• Sildenafil Citrate
• chelerythrine
• Protein Kinase C

Topics

• Alkaloids
• Animals
• Benzophenanthridines
• Cytosol (drug effects, enzymology)
• Enzyme Inhibitors (pharmacology)
• Hemodynamics (drug effects)
• Isoenzymes (antagonists & inhibitors, physiology)
• Male
• Myocardial Infarction (enzymology, pathology, prevention & control)
• Phenanthridines (pharmacology)
• Phosphodiesterase Inhibitors (pharmacology)
• Piperazines (antagonists & inhibitors, pharmacology)
• Protein Kinase C (antagonists & inhibitors, physiology)
• Protein Transport (drug effects)
• Purines
• Rabbits
• Sildenafil Citrate
• Subcellular Fractions (drug effects, enzymology)
• Sulfones