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To investigate whether dopamine plays a role in the regulation of aldosterone secretion during long-term blockade of the renin-angiotensin system, we studied the effect of metoclopramide, a competitive antagonist of dopamine, in 6 patients with essential hypertension chronically treated with the angiotensin converting enzyme inhibitor enalapril. All but one of these patients received a diuretic in addition to enalapril. Six hours after the daily morning dose of enalapril (10-40 mg p.o.) a 10 mg bolus dose of metoclopramide was injected intravenously. In one patient a hypotensive episode developed following metoclopramide administration. In the 5 other patients plasma aldosterone significantly rose within 30 min after metoclopramide from 51 +/- 8.7 to 128.2 +/- 29.2 pg/ml. This metoclopramide-induced release of aldosterone occurred in the absence of concomitant changes in circulating angiotensin 11, potassium and ACTH levels. Metoclopramide given during chronic blockade of the renin-angiotensin system caused anxiety and agitation in 2 patients. The increase in plasma aldosterone following competitive dopamine blockade in the face of chronic angiotensin converting enzyme inhibition, unchanged plasma potassium and ACTH levels strongly suggests that in hypertensive patients, dopamine exerts a direct inhibitory effect on aldosterone secretion.

A reproducible model of platelet rich thrombi was produced in canine arteries by a previously described technique of intravascular insertion of metal tubing. The effect of platelet suppressants including sulfinpyrazone and ticrynafen, a clofibrate analog, on the rate and nature of thrombus formation was studied. ADP and epinephrine induced platelet aggregation of the animal's platelet rich plasma was monitored during the experiment. Platelet aggregation was impaired after the intravenous administration of either sulfinpyrazone (30 mg/kg body weight) or ticrynafen (100 mg/kg body weight). The rate of thrombus formation was not significantly altered by sulfinpyrazone when compared to the control, but histochemically, the thrombus studied showed a greatly diminished platelet content. In contrast, ticrynafen was able to prevent a complete occlusion of the involved vascular segment and a weak thrombus composed mostly of fibrin was produced instead. This effect of ticrynafen was dose related with minimal changes observed at a dose of 75 mg/kg. The results suggest that this arterial thrombosis model is of value in evaluating antithrombotic agents. They also indicate a potential value of ticrynafen as a therapeutic agent which should be further studied.

Thrombocytopenia complicating heparin therapy is always alarming since the bleeding risk is greatly increased. The observations of Bell et al (Ann Int Med. 85:155, 1976) of a 30% incidence of thrombocytopenia in patients receiving bovine lung heparin was not supported by later reports from Powers et al (JAMA 241:2396, 1979) of only 3.4%. However, the latter study involved the use of heparin prepared from porcine gut mucosal. A prospective randomized study of these two respective heparin preparations was carried out at the VA Lakeside Medical Center on 98 patients to whom heparin therapy was given for the treatment of various forms of thromboembolism. All received a heparin dose that prolonged the activated partial thromboplastin time to l1/2-21/2 times the control level for at least 5 days. 86 patients had heparin for 7 or more days. The observation of platelet counts was carried out for 7 days. 10 patients (10.2%) had a fall in their platelet counts to less than 150×l06/dl during therapy with one of the ten having a platelet count of 95×l06/dl on the 4th day of therapy. All but one of the thrombocytopenias were transient, lasting 1-6 days despite continuation of heparin therapy. Of 49 patients who received porcine heparin, 4 (8.2%) had thrombocytopenia while the incidence was 6 out of 49 (12.2%)in those who received bovine heparin. These results suggest that complications of severe thrombocytopenia are uncommon with heparin derived from both sources.

The pharmacokinetics of the converting enzyme inhibitor, enalapril, were studied in an open, randomized, balanced crossover design in 12 hospitalized patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril maleate 10 mg orally, enalapril maleate 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72 h period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of enalaprilat, before and after sample hydrolysis. Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first-pass effect 10%. The results were compared with available data in normal subjects. After oral administration of 10 mg enalapril maleate, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normals with differences less than 10%. The rate of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF and maximal concentrations were reached at 6 h in CHF as compared to 4 h in normal subjects. We conclude that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.