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The role of cGMP and PKG in cardioprotection

Interrupting blood flow to a heart (ischemia) for several minutes followed by several minutes of restored flow renders it very resistant to cell death from a subsequent much more prolonged ischemic episode. This phenomena, termed ischemic preconditioning, is the result of a complex signal transduction pathway which ultimately prevents formation of lethal mitochondrial permeability transition pores when blood flow is restored. In mapping this pathway we found that NOS was in the pathway [1] and proposed that it was involved in opening ATP-sensitive potassium channels (KATP) in the mitochondrial inner membrane. Those channels play a key role in preconditioning's mechanism. Incubating isolated heart mitochondria in cGMP + PKG + ATP opened the channel as indicated by mitochondrial swelling [2]. To test this hypothesis further the cGMP analog 8-CPT-cGMP (10 μM) was infused for 30 min starting 5 min prior to the end of 30 min of regional ischemia in an isolated rabbit heart [3]. It greatly attenuated the resulting infarction by an amount similar to that seen with preconditioning (infarct size approximately 50% of that in untreated hearts). 8-CPT's protection could be blocked by the KATP blocker 5 hydroxydecanoate confirming its position in the pathway. Because there is a medical need for an intervention that prevents myocardial infarction when given at reperfusion we looked for a method of raising cGMP that would be clinically feasible. We gave the direct guanylyl cyclase activator BAY 58-2667 (cinaciguat) to open-chest rabbits at 53 μg/kg bolus just prior to reperfusion followed by a 60 min 1.25 μg/min infusion. It reduced infarct size from 40.6% of the ischemic zone to only 16.0%. In another experiment we tested Vardenafil infusion of 140 μg/kg/h starting 5 min before coronary occlusion in the open-chest rabbit. It also greatly protected the hearts against infarction. Because it is controversial as to whether heart muscle expresses PDE 5, we transfected isolated rabbit ventricular myocytes with CNG channels selective for cGMP. In the resting cells cGMP as monitored with patch clamping was near zero and did not increase when they were exposed to 1 μM vardenafil. However, when cGMP was first increased with 1 μM BAY 58-2667 addition of vardenafil greatly increased the cGMP-dependent membrane current indicating that a vardenafil-sensitive PDE was present which is presumed to be PDE5. We conclude that raising cGMP in the reperfused heart is an effective anti-infarct strategy.


  1. Oldenburg O, Qin Q, Krieg T, Yang XM, Philipp S, Critz SD, Cohen MV, Downey JM: Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mitoKATP channel opening and leads to cardioprotection. Am J Physiol. 2004, 286: H468-H476.

    CAS  Google Scholar 

  2. Costa ADT, Garlid KD, West IC, Lincoln TM, Downey JM, Cohen MV, Critz SD: Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res. 2005, 97: 329-336. 10.1161/01.RES.0000178451.08719.5b.

    Article  CAS  PubMed  Google Scholar 

  3. Kuno A, Solenkova NV, Solodushko V, Dost T, Liu Y, Yang XM, Cohen MV, Downey JM: Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A2b agonists by protein kinase C. Am J Physiol Heart Circ Physiol. 2008, 295: H1288-H1295. 10.1152/ajpheart.00209.2008.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Correspondence to James M Downey.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Downey, J.M., Liu, Y. & Xin, W. The role of cGMP and PKG in cardioprotection. BMC Pharmacol 9 (Suppl 1), S9 (2009).

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