VEGF IMPROVES MYOCARDIAL BLOOD-FLOW BUT PRODUCES EDRF-MEDIATED HYPOTENSION IN PORCINE HEARTS

Several recent studies have demonstrated the potential for improving m yocardial perfusion by the continuous administration of angiogenic gro wth factors. Studies in our laboratory have shown that a single intraa rterial or intravenous bolus of the endothelial cell specific mitogen vascular endothelial growth factor (VEGF) can significantly improve pe rfusion in a rabbit ischemic limb model. To test the efficacy of this therapeutic approach in chronic myocardial ischemia, 18 Yorkshire pigs underwent a left thoracotomy followed by placement of an ameroid cons trictor around the proximal circumflex coronary artery, Gradual occlus ion of the artery (26 +/- 4 days) was accompanied by identifiable hypo kinesis of the posterolateral wall of the left ventricle (2D echo). Th irty days postoperatively, rhVEGF(165) (2 mg; n = 8) or saline (n = 10 ) was administered directly into the left coronary ostium. Postadenosi ne myocardial perfusion studies using colored microspheres 30 days lat er demonstrated superior blood flow in the ischemic zone of the VEGF-t reated hearts (ischemic/normal ratio 1.09 vs 0.97, P < 0.05) compared with those receiving saline injection. Four of eight VEGF-treated anim als succumbed, however, to severe hypotension following VEGF administr ation. Therefore 500 mu g of VEGF were administered intracoronary to f ive normal pigs. A significant drop in mean arterial pressure (-44.4 /- 3.2%, P < 0.05 vs baseline) and peripheral resistance (-13.2 +/- 4. 5%, P < 0.05 vs baseline) was accompanied by increased heart rate. TV administration of N-omega-nitro-L-arginine (L-NNA), an EDRF inhibitor, restored blood pressure to baseline. We conclude that a single intrac oronary bolus of VEGF is capable of significantly augmenting flow to c ollateral-dependent ischemic myocardium. The associated hypotension ap pears to be EDRF-mediated. Further studies are needed to define the be st dose and route of administration of VEGF for the treatment of coron ary insufficiency. (C) 1996 Academic Press, Inc.