enalaprilat-anhydrous and chymostatin

We sought to demonstrate non-angiotensin converting enzyme (ACE) dependent angiotensin II (AII) generating pathways in resistance arteries from patients with chronic heart failure (CHF).. Non-ACE dependent AII generation occurs in resistance arteries from normal volunteers. Inhibition of non-ACE dependent AII generation may have therapeutic potential in CHF.. Resistance arteries were dissected from gluteal biopsies from patients with coronary heart disease (CHD) and preserved left ventricular function and from patients with CHF. Using wire myography, concentration response curves to angiotensin I (AI) and AII were constructed in the presence of 1) vehicle, 2) chymostatin [an inhibitor of chymase], 3) enalaprilat, and 4) the combination of chymostatin and enalaprilat.. In resistance arteries from patients with CHD, the vasoconstrictor response to AI was not inhibited by either inhibitor alone (chymostatin [p > or = 0.05] or enalaprilat [p > or = 0.05]) but was significantly inhibited by the combination (p < 0.001). In arteries from patients with CHF, AI responses were inhibited by enalaprilat (p < 0.05) but not by chymostatin alone (p > 0.05). The combination ofchymostatin and enalaprilat markedly inhibited the response to AI (p < 0.001) to a greater degree than enalaprilat alone (p < or = 0.01).. Non-ACE dependent AII generating pathways exist in resistance arteries from patients with both CHF and CHD. In resistance arteries from patients with CHD, inhibition of either the ACE or chymase pathway alone has no effect on AII generation, and both pathways must be blocked before the vasoconstrictor action of AI is inhibited. In CHF, blockade of ACE results in marked inhibition of responses to AI, but this is enhanced by coinhibition of chymase. These studies suggest that full suppression of the renin-angiotensin system cannot be achieved by ACE inhibition alone and provide a rationale for developing future therapeutic strategies.

Topics: Acetylcholine; Aged; Angina Pectoris; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Arteries; Bradykinin; Chymases; Enalaprilat; Female; Heart Failure; Humans; In Vitro Techniques; Losartan; Male; Middle Aged; Oligopeptides; Peptidyl-Dipeptidase A; Serine Endopeptidases; Vascular Resistance; Vasoconstriction

In vitro studies of myocardial tissue suggest that angiotensin II (Ang II) may be generated by both ACE and chymase. A similar dual pathway may exist in the vasculature. We studied the effects of ACE and chymase inhibitors on the contractile response to angiotensin I (Ang I) in human resistance arteries to investigate ACE-independent generation of Ang II.. Subcutaneous resistance arteries (250 to 350 microm) were obtained from gluteal biopsies from volunteers and New Zealand White rabbits and mounted on a wire myograph. Contractile ability was tested with high-potassium depolarization and norepinephrine 10 micromol/L and endothelial integrity by relaxation to acetylcholine 3 micromol/L. Cumulative concentration-response curves were constructed for Ang I in the presence of enalaprilat 1 micromol/L, chymostatin 10 micromol/L, or both inhibitors together. In the rabbit, enalaprilat completely inhibited the Ang I response. In human vessels, enalaprilat or chymostatin alone had no effect, but the combination of enalaprilat and chymostatin almost completely inhibited the response to Ang I.. A dual pathway for Ang II generation exists in human resistance arteries, mediated by ACE and a chymostatin-sensitive enzyme, probably chymase. We confirm that a marked species difference exists in the mechanism of Ang II generation between the human and the rabbit. More efficacious suppression of the renin-angiotensin system may require development of novel enzyme inhibitors or combinations of currently available drugs.

Topics: Acetylcholine; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteries; Bradykinin; Drug Combinations; Enalaprilat; Endothelium, Vascular; Humans; Male; Norepinephrine; Oligopeptides; Peptidyl-Dipeptidase A; Potassium; Rabbits; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents