title: VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts.
abstract: Several recent studies have demonstrated the potential for improving myocardial perfusion by the continuous administration of angiogenic growth factors. Studies in our laboratory have shown that a single intraarterial or intravenous bolus of the endothelial cell specific mitogen vascular endothelial growth factor (VEGF) can significantly improve perfusion 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 constrictor around the proximal circumflex coronary artery. Gradual occlusion of the artery (26 +/- 4 days) was accompanied by identifiable hypokinesis of the posterolateral wall of the left ventricle (2D echo). Thirty days postoperatively, rhVEGF(165) (2 mg; n = 8) or saline (n = 10) was administered directly into the left coronary ostium. Postadenosine myocardial perfusion studies using colored microspheres 30 days later demonstrated superior blood flow in the ischemic zone of the VEGF-treated hearts (ischemic/normal ratio 1.09 vs 0.97, P < 0.05) compared with those receiving saline injection. Four of eight VEGF-treated animals succumbed, however, to severe hypotension following VEGF administration. Therefore 500 micrograms of VEGF were administered intracoronary to five 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. IV administration of N(omega)-nitro-L-arginine (L-NNA), an EDRF inhibitor, restored blood pressure to baseline. We conclude that a single intracoronary bolus of VEGF is capable of significantly augmenting flow to collateral-dependent ischemic myocardium. The associated hypotension appears to be EDRF-mediated. Further studies are needed to define the best dose and route of administration of VEGF for the treatment of coronary insufficiency.
authors.affiliation: Division of Cardiothoracic Surgery, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Hariawala
authors.forename: J R
authors.initials: JR
authors.lastname: Horowitz
authors.forename: D
authors.initials: D
authors.lastname: Esakof
authors.forename: D D
authors.initials: DD
authors.lastname: Sheriff
authors.forename: D H
authors.initials: DH
authors.lastname: Walter
authors.forename: B
authors.initials: B
authors.lastname: Keyt
authors.forename: J M
authors.initials: JM
authors.lastname: Isner
authors.forename: J F
authors.initials: JF
authors.lastname: Symes
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D004452:Echocardiography; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007022:Hypotension / Q000139:chemically induced*; D008222:Lymphokines / Q000494:pharmacology*; D008863:Microspheres; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000241:Adenosine