Vasopeptidase inhibition in a canine model of exercise-induced left ventricular dysfunction.
1. The present study compared the acute efficacies of vasopeptidase inhibition with omapatrilat, nitroglycerin and angiotensin-converting enzyme (ACE) inhibition in exercise-induced myocardial dysfunction. Omapatrilat, a vasopeptidase inhibitor, inhibits both neutral endopeptidase and ACE. Whereas vasopeptidase inhibitors have demonstrated clinical efficacy in hypertension and heart failure, their effects in myocardial ischaemia remain unclear. 2. Omapatrilat (0.3 mg/kg) was compared with vehicle (saline), an ACE inhibitor (fosinoprilat; 0.44 mg/kg) and nitroglycerin (8.0 microg/kg per min), in an established canine model of exercise-induced myocardial dysfunction induced by progressive closure of an ameroid constrictor placed about the proximal circumflex coronary artery. Maximal treadmill exercise tests, terminated when heart rate failed to increase with increasing workload or failure to continue exercise, were performed in chronically instrumented dogs. 3. During exercise, omapatrilat and nitroglycerin similarly increased ischaemic wall thickening (P< or = 0.0001, ANOVA, 12 d.f.), whereas fosinoprilat and vehicle were without effect. Ischaemic zone ST changes were decreased with nitroglycerin (P = 0.0006, ANOVA, 12 d.f.) and tended to decrease with omapatrilat (P = 0.07, ANOVA, 12 d.f.). Peak exercise capacity was increased with nitroglycerin (9.7 +/- 1.1 vs 11.2 +/- 1.0 kcal, control vs 4 h, respectively; n = 6) and omapatrilat (9.7 +/- 0.8 vs 11.4 +/- 0.6 kcal, control vs 4 h, respectively; n = 6) and was unchanged with ACE inhibition (9.0 +/- 1.2 vs 9.5 +/- 1.1 kcal, control vs 4 h, respectively; n = 7). Omapatrilat differentially increased double product during exercise (P = 0.001, ANOVA, 12 d.f.) compared with other treatments. 4. During exercise-induced myocardial dysfunction, acute ACE inhibition did not attenuate ischaemic changes and failed to improve exercise capacity. Increased exercise capacity with omapatrilat was accompanied by a differential increase in double product, consistent with increased oxygen supply and demand. Improvements in ischaemic function were comparable between omapatrilat and nitroglycerin, suggesting that omapatrilat may represent a novel therapy in demand-induced ischaemia.
Holzgrefe
Henry H
HH
08534Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey 08534, USA. holzgreh@bms.com
Arthur
Susan R
SR
Powell
James R
JR
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D005996:Nitroglycerin / Q000494:pharmacology / Q000627:therapeutic use; D010805:Physical Conditioning, Animal; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D013841:Thiazepines / Q000494:pharmacology / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology
D000806:Angiotensin-Converting Enzyme Inhibitors; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D015260:Neprilysin; D005996:Nitroglycerin