enalaprilat-anhydrous and fosinoprilat

To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril.. Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalaprilat; Female; Fosinopril; Heart Failure; Humans; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Time Factors

The interaction of angiotensin-converting enzyme (ACE) inhibitors and bradykinin was investigated in isolated bovine and human coronary arteries. Rings with and without endothelium were mounted in organ chambers for measurement of isometric force. The effects of the ACE inhibitors lisinopril, enalaprilat, fosinoprilat, ramiprilat, and captopril were determined during submaximal stimulation with bradykinin or other vasodilators. Lisinopril and captopril alone did not affect vascular tone; however, in rings with endothelium partially relaxed with bradykinin (> or = 10(-10) M), all ACE inhibitors caused further relaxations. Lisinopril did not affect bradykinin concentrations in the incubation medium. Mechanical removal of the endothelium or incubation with nitro-L-arginine or the bradykinin2-receptor antagonist Hoe 140 prevented the relaxations to bradykinin and lisinopril. Other vasodilators including acetylcholine, adenosine diphosphate, substance P, or SIN-1 did not prime the rings to respond to ACE inhibitors. Endothelium-dependent relaxations to lisinopril were also observed in human coronary arteries treated with bradykinin (> or = 10(-7) M). Thus, ACE inhibitors potentiate endothelium-dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries. This local mechanism occurs regardless of elevated bradykinin concentrations in the blood and reduced angiotensin II generation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Captopril; Cattle; Coronary Vessels; Dipeptides; Enalaprilat; Endothelium, Vascular; Fosinopril; Humans; In Vitro Techniques; Lisinopril; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroarginine; Ramipril; Receptors, Bradykinin; Receptors, Neurotransmitter; Vasodilation; Vasodilator Agents

We determined the relationship between cardiac angiotensin-converting enzyme (ACE) inhibition and anti-ischemic efficacy of several structurally different ACE inhibitors or their prodrug esters perfused through the isolated rat heart. Seven ACE inhibitors inhibited cardiac ACE to varying degrees due to differences in uptake during perfusion through nonischemic rat hearts. Zofenopril-sulfhydryl and fosinoprilic acid were the most effective of the free inhibitors. Among the prodrugs, zofenopril and S-benzoylcaptopril, hydrolyzed rapidly by cardiac esterase, were more effective than their component ACE-inhibitors, whereas fosinopril, ramipril and enalapril were poorly active. For studies in ischemic rat hearts, vehicle or drug treatment was initiated 10 min before a 25-min period of global ischemia and during a 30-min reperfusion period. Of five unesterified ACE inhibitors studied for anti-ischemic activity, only captopril and zofenopril-sulfhydryl were found to improve postischemic contractile function and reduce cell death in the isolated rat hearts. Fosinoprilic acid, ramiprilat and enalaprilat were not cardioprotective at high perfusion concentrations, despite the fact that nearly complete inhibition of cardiac ACE was achieved with all of the compounds studied. The S-benzoyl prodrugs of zofenopril-sulfhydryl and captopril were at least as potent as their component ACE inhibitors in reducing ischemic-reperfusion damage in the same model. Neither zofenopril nor captopril, however, had any effect on coronary flow before or after ischemia. Thus, it appears that the cardioprotective effects of zofenopril and captopril are independent of cardiac ACE inhibition or, at least, that ACE inhibition alone is not sufficient. Both captopril and zofenopril are sulfhydryl-containing compounds whereas the inactive compounds are not; and, thus, this group appears to be important in mediating their cardioprotective actions.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Coronary Disease; Drug Stability; Enalaprilat; Fosinopril; Heart; In Vitro Techniques; Male; Myocardium; Organophosphorus Compounds; Prodrugs; Proline; Pyrroles; Ramipril; Rats; Rats, Inbred Strains; Sulfhydryl Compounds

A rapid, sensitive assay for angiotensin-converting enzyme (ACE) inhibitors is described. Biological samples were diluted with methanol to precipitate endogenous ACE and centrifuged. Supernatants were further diluted with 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, pH 8. Diluted samples were incubated at 37 degrees C with the substrate [3H]hippurylglycylglycine and rabbit lung ACE for 45 min. Acid (1.0 N HCl) was then added, and the product, [3H]hippuric acid, was extracted into a water-immiscible scintillation cocktail. Drug standards were prepared in the biological matrix to correct for drug recovery. A computer program was used to convert radioactivity (dpm) to units of enzyme activity and then correlate enzyme activity with drug concentration. The ester prodrugs fosenopril and enalapril could be assayed down to 4 ng/ml in plasma after ester hydrolysis with NaOH. Drug disposition studies in rats, dogs, and monkeys have demonstrated that the method can be readily adapted to any ACE inhibitor and is suitable for determining drug bioavailability and pharmacokinetics.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biological Availability; Dogs; Enalapril; Enalaprilat; Fosinopril; Haplorhini; Hydrolysis; Male; Proline; Rats