angiotensin-i and Angina-Pectoris

Topics: Angina Pectoris; Angiotensin I; Captopril; Clinical Trials as Topic; Coronary Circulation; Myocardial Infarction

[Pro(11)(D)-Ala(12)] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II-generating pathway exists in human dorsal hand veins.. Using a modified Aellig technique, we studied the response to Ang I and [Pro(11)(D)-Ala(12)] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean+/-SEM venoconstrictor response of 45+/-11%, 40+/-10%, 55+/-8%, and 4+/-4% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril (P=0.002). [Pro(11)(D)-Ala(12)] Ang I induced a mean venoconstrictor response of 42+/-9%, 49+/-9%, 48+/-10%, and 54+/-11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro(11)(D)-Ala(12)] Ang I.. We have demonstrated that [Pro(11)(D)-Ala(12)] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.

Topics: Administration, Oral; Angina Pectoris; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Captopril; Chronic Disease; Chymases; Dose-Response Relationship, Drug; Double-Blind Method; Hand; Humans; Infusions, Intravenous; Irbesartan; Middle Aged; Peptidyl-Dipeptidase A; Reproducibility of Results; Serine Endopeptidases; Substrate Specificity; Tetrazoles; Vasoconstriction; Veins

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