Vardenafil protects isolated rat hearts at reperfusion dependent on GC and PKG

Br J Pharmacol. 2008 May;154(1):25-31. doi: 10.1038/bjp.2008.71. Epub 2008 Mar 10.


Background and purpose: The type-5 PDE inhibitor vardenafil reduces myocardial infarct size in situ, following ischemia/reperfusion, when applied at reperfusion in animal models. Little is known about the underlying protective signaling. Here, we test whether vardenafil is protective in rat isolated hearts and in a cell model of calcium stress.

Experimental approach: Infarct size in rat isolated hearts was measured after a 30 min regional ischemia and 120 min reperfusion. Vardenafil (1 nM-1 microM) was infused during reperfusion. HL-1 cardiomyocytes were loaded with tetramethylrhodamine ethyl ester (TMRE), a fluorescent marker of mitochondrial membrane potential (psi m).

Key results: Vardenafil at reperfusion reduced infarct size as percentage of the ischemic zone from 45.8+/-2.0% in control hearts to 26.2+/-2.7% (P<0.001) only at 10 nM, whereas higher or lower dosages failed to protect. This protective effect was blocked by co-administration of either the GC inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or the PKG inhibitor, KT-5823. HL-1 cardiomyocytes, loaded with TMRE, were treated for 80 min with the calcium ionophore, calcimycin, to induce calcium stress. This reduced the mean cell fluorescence to 63.3 +/- 3.8% of baseline values and vardenafil protected against this fall (78.6 +/- 3.6%, P<0.01). The vardenafil-induced protection of HL-1 cells was blocked by ODQ, KT-5823 or the PKG-inhibiting peptides DT-2 and DT-3, confirming a role for GC and PKG.

Conclusions and implications: These results further support the hypothesis that PDE-5 inhibitors are protective in ischemic hearts, in addition to their known clinical effects in the treatment of erectile dysfunction in men.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / pharmacology
  • Carbazoles / pharmacology
  • Cell Adhesion Molecules / physiology
  • Cell Death
  • Cell Line
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic GMP-Dependent Protein Kinases / physiology*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Guanylate Cyclase / antagonists & inhibitors
  • Guanylate Cyclase / physiology*
  • Imidazoles / therapeutic use*
  • In Vitro Techniques
  • Microfilament Proteins / physiology
  • Mitochondria, Heart / drug effects
  • Mitochondrial Membranes / drug effects
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / pathology
  • Oxadiazoles / pharmacology
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Phosphoproteins / physiology
  • Piperazines / therapeutic use*
  • Quinoxalines / pharmacology
  • Rats
  • Sulfones / therapeutic use
  • Triazines / therapeutic use
  • Vardenafil Dihydrochloride


  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • Carbazoles
  • Cell Adhesion Molecules
  • Enzyme Inhibitors
  • Imidazoles
  • Microfilament Proteins
  • Oxadiazoles
  • Phosphodiesterase Inhibitors
  • Phosphoproteins
  • Piperazines
  • Quinoxalines
  • Sulfones
  • Triazines
  • vasodilator-stimulated phosphoprotein
  • KT 5823
  • Vardenafil Dihydrochloride
  • Cyclic GMP-Dependent Protein Kinases
  • Guanylate Cyclase
  • Calcium