CGX-1051, a peptide from Conus snail venom, attenuates infarction in rabbit hearts when administered at reperfusion

CGX-1051, isolated from the venom of the marine snail Conus purpurasens, was previously noted to interact with potassium channels. Since potassium channels play an important role in cardiac physiology, we assessed the effect of CGX-1051 on infarct size in a rabbit heart model of ischemia/reperfusion. A coronary branch was occluded for 30 minutes followed by 3 hours of reperfusion in in situ and 2 hours in in vitro preparations. Infarct size was measured with triphenyltetrazolium chloride staining and expressed as a percent of the risk zone. In in situ studies, a bolus intravenous injection of CGX-1051, either 10 or 100 microg/kg, administered 5 minutes before reperfusion, reduced infarct size from 40.4 +/- 2.8% of the risk zone in untreated animals to 19.8 +/- 3.8% and 15.0 +/- 1.9%, respectively. One microg/kg CGX-1051 was not protective. To see if the salvage was sustained, two groups of rabbits underwent 72 hours of reperfusion. The dose of 10 microg/kg infused 5 minutes before reperfusion reduced infarct size from 37.0 +/- 1.6% in untreated rabbits to 15.5 +/- 2.0%. When administered 10 minutes after reperfusion had begun, 100 microg/kg CGX-1051 had no effect. CGX-1051 also reduced infarct size in crystalloid-perfused, isolated rabbit hearts suggesting that protection did not depend on circulating leukocytes. The mitochondrial KATP inhibitors glibenclamide and 5-hydroxydecanoate and the MEK(1/2), ERK and hence, inhibitor PD 98059 aborted protection from CGX-1051. These data indicate that functionally active ERK and mitochondrial KATP channels are necessary for protection. CGX-1051 caused no hemodynamic alterations at any dose tested. We conclude that CGX-1051 has a powerful anti-infarct effect when given just before reperfusion.