Sodium depletion with diuretics augments the efficacy of angiotensin-converting enzyme-inhibitor therapy for hypertension and renal dysfunction, and possibly for left ventricular dysfunction after myocardial infarction. Underlying mechanisms may involve altered angiotensin-converting enzyme-inhibitor pharmacokinetics. We hypothesized that the diuretic hydrochlorothiazide causes increased steady-state levels of the angiotensin-converting enzyme-inhibitors lisinopril and zofenopril in rats with myocardial infarction. Rats were subjected to coronary ligation to induce myocardial infarction. After 1 week, rats were randomized to 50 mg/kg/day hydrochlorothiazide or control treatment for 3 weeks. The last week, rats received lisinopril or zofenopril in equipotentent dosages (3.3 and 10 mg/kg/day, respectively). Rats were sacrificed at Tmax after the last dose of angiotensin-converting enzyme-inhibitor, and tissues were collected for analysis of drug concentrations. Lisinopril concentrations in plasma were significantly increased by hydrochlorothiazide, at unchanged tissue concentrations. This increase could be fully explained by decreased renal function, as evidenced by increased plasma creatinine levels (lisinopril + hydrochlorothiazide 82+/-5 microM versus lisinopril 61+/-5 microM, P < 0.001). In contrast, zofenoprilat levels in kidney and non-infarcted left ventricle were markedly increased by hydrochlorothiazide, whereas plasma concentrations were unchanged. Although hydrochlorothiazide tended to increase plasma creatinine in zofenopril-treated rats as well, this increase was less pronounced (zofenopril + hydrochlorothiazide 61+/-3 microM versus zofenopril 54+/-2 microM, P = 0.15). Hydrochlorothiazide increases steady-state angiotensin-converting enzyme-inhibitor drug levels, most likely by affecting their renal clearance. Notably, the lipophilic angiotensin-converting enzyme-inhibitor zofenopril accumulated in tissue, whereas the hydrophilic lisinopril increased in plasma. Whether combining different angiotensin-converting enzyme-inhibitors with hydrochlorothiazide translates into distinct clinical profiles requires further study.