NO-independent activation of sGC by BAY 41-2272 at reperfusion limits infarct size

Bice, Justin S , Prof. Baxter, Gary F. Cardiff University Welsh School of Pharmacy, King Edward VII Avenue, Cardiff, CF10 3NB, Great Britain.

Background: The extent of myocardial reperfusion injury plays a critical role in the pathological outcome of acute myocardial infarction. Both endogenous and exogenous nitric oxide (NO) reduce this injury at reperfusion, signaling through soluble guanylyl cyclase (sGC), a heterodimeric haemprotein that catalyses the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). BAY 41-2272 is one of several NO-independent, haem-dependent activators of sGC which have been developed to facilitate the understanding of the NO-sGC-cGMP pathway. Previous studies have shown that the cGMP analogue 8Br-cGMP is cardioprotective at reperfusion (Burley et al. 2007). We therefore hypothesised that administration of BAY 41-2272 at reperfusion would be cardioprotective.

Methods: Hearts from male Sprague-Dawley rats (350-400g) were Langendorff perfused with modified Krebs-Henseleit buffer at constant pressure (74mmHg). After stabilisation hearts were subjected to 35min regional ischaemia by occluding the left descending coronary artery. At 30 min ischaemia BAY 41-2272 was perfused at either 3μM or 300nM for 15 min (10 min into reperfusion). Controls were perfused with the same buffer in the absence of the drug. Hearts were then sectioned and stained with triphenyltetrazolium chloride and infarct was expressed as a percentage of the risk zone.

Results: Administration of 3μM BAY 41-2272 at early reperfusion caused a concentration-dependent limitation of infarct size (control 30.9 ± 3.7 % vs. BAY 41-2272 3μM 17.0 ± 2.2 %, p< 0.05, n≥6 per group respectively). Coronary flow rate measurements suggest that BAY 41-2272 produced a concentration-dependent vasodilator effect when administered at reperfusion.

Conclusions: These data show that NO-independent activation of sGC at reperfusion is cardioprotective, with further experiments required to ascertain the exact mechanisms of action and the most efficacious dose of BAY 41-2272.

Burley D.S et al. Br J Pharmacol 2007; 152: 855-69.