title: Effects of enalapril on vasoactive intestinal peptide metabolism and tissue levels.
abstract: Angiotensin converting enzyme inhibitor therapy results in an increase in cardiac output without an increase in heart rate suggesting a positive inotropic effect. This cannot be explained by changes in angiotensin II and bradykinin concentrations. Angiotensin converting enzyme may also metabolise vasoactive intestinal peptide (VIP), a vasodilator and positive inotrope whose concentration in the heart declines in heart failure. We sought to determine whether changes in plasma VIP or its metabolism might explain the positive inotropic effect of angiotensin converting enzyme inhibitors. We also measured VIP in the heart to determine whether a local increase in VIP might explain this effect. Male Sprague-Dawley rats were randomised to control and enalapril groups (2 mg kg(-1) day(-1)). After 7 days, rats were anaesthetised and underwent metabolic clearance studies for VIP or had hearts, lungs and kidneys removed and snap frozen. VIP concentrations in plasma, infusate and tissue extracts were measured by radioimmunoassay. Plasma concentrations of VIP were unchanged by treatment with enalapril (control: 7.7 +/- 0.8 pmol l(-1); enalapril: 7.9 +/- 0.8 pmol l(-1) ), while the metabolic clearance rate of) VIP increased significantly (control: 10.4 +/- 1.4 ml min(-1) 100 g(-1); enalapril: 17.3 +/- 1.6 ml min(-1) 100 g(-1); p < 0.005). Secretion rate) also increased in enalapril treated rats (139.1 +/- 25.0 pmol min(-1) 100 g(-1) compared with controls (96.3 +/- 13.4 pmol min (-1) 100 g(-1); P< 0.01). VIP in the heart increased after enalapril (control: 208.4 +/- 39.0 pmol g (-1); enalapril: 928.9 +/- 123.6 fmol g(-1); P < 0.0005). Angiotensin converting enzyme inhibition increases the metabolism of VIP. However, the significant increase in the myocardial concentration of VIP may contribute to the beneficial haemodynamic inotrope effects of angiotensin converting enzyme inhibitors.
authors.affiliation: Hypertension Laboratory, The Liverpool Hospital, Sydney, Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Duggan
authors.forename: V Z
authors.initials: VZ
authors.lastname: Ye
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004656:Enalapril / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014660:Vasoactive Intestinal Peptide / Q000097:blood / Q000187:drug effects* / Q000493:pharmacokinetics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D014660:Vasoactive Intestinal Peptide; D004656:Enalapril