Comparison of monotherapy with enalapril and atenolol in mild to moderate hypertension. The Canadian Enalapril Study Group.

Therapy with 10 to 40 mg once daily of enalapril, a new angiotensin converting enzyme inhibitor, was compared with therapy with 50 to 100 mg once daily of atenolol in a double-blind randomized multicentre trial in 180 patients with a diastolic blood pressure (determined with the patient seated) of 95 to 115 mm Hg between March 1984 and April 1986. A total of 86 patients (61 men and 25 women with a mean age of 49.4 years and a mean blood pressure [and standard deviation] at entry into the trial of 155.5 [15.7]/101.0 [6.3] mm Hg) received enalapril, and 94 patients (63 men and 31 women with a mean age of 50.9 years and a mean blood pressure at entry of 156.6 [16.6]/101.2 [5.7] mm Hg) received atenolol. After a placebo run-in period the patients received increasing dosages of medication every 2 weeks until the target diastolic blood pressure of 90 mm Hg or less was achieved on two consecutive visits, the maximum dosage was reached, or the patient withdrew because of adverse effects. At 14 weeks the mean blood pressure was 141.6 (18.0)/90.1 (9.5) mm Hg in the enalapril group (61 patients) and 140.0 (17.1)/88.4 (8.7) mm Hg in the atenolol group (54 patients). The target diastolic blood pressure was achieved on completion of therapy (between weeks 10 and 14) in 67 (77%) of the patients receiving enalapril and 75 (79%) of the patients receiving atenolol. Compliance was similar in the two groups. Seven patients withdrew because of adverse effects, three in the enalapril group and four in the atenolol group. The results suggest that once-daily monotherapy with enalapril, 10 to 40 mg, is effective in the treatment of mild to moderate hypertension and is as effective as and tolerated as well as once-daily therapy with atenolol, 50 to 100 mg.     

Gastric effects and side effects of synthetic secretin in man

The gastric effects of synthetic secretin given in a depot reparation as subcutaneous injection or in different doses as intravenous infusion were studied in 10 healthy volunteers. Peptone-stimulated gastric acid secretion and serum gastrin were significantly suppressed with a clear dose-response inhibition of acid output. There was a significant correlation between percentage inhibition of acid secretion and plasma secretin concentrations which were greatly above those seen physiologically. Serum lipase and trypsin increased significantly. Most subjects lost fluid from diuresis and diarrhoea, so that serum sodium and total protein concentrations also increased significantly. These side effects cast doubt on the clinical value of prolonged infusions of pharmacological doses of synthetic secretion in critically ill patients.     

Regional differences of cardiovascular effects of diltiazem in the rat

The dose-response relations of the central and peripheral effects of diltiazem were studied in 26 anaesthetized rats. Measured were the heart rate (HR), atrioventricular conduction time (PR), mean arterial blood pressure (BP), carotid and renal blood flow (Fc, Fr) and the corresponding relative regional resistance (RRc, RRr). The effects were evaluated by their maxima regularly reached 15-20 s after the i.v. bolus administration. The minimum dose which produced a significant HR decrease and PR prolongation were 0.4 and 2.0 mg/kg, respectively. In the mg/kg dose range a transient second degree AV block was regularly recorded. The lethal dose (cardiac arrest) was 20 mg/kg. BP significantly already decreased after 4 micrograms/kg. The dose-dependent decrease of Fr matched the hypotensive effect in the whole range due to unchanged RRr. In contrast Fc invariably increased at lower doses reflecting the RRc decay. Only in the mg/kg dose range Fc decreased in accord with BP since RRc dropped to a constant value (50% of control) with each administration. The peripheral reactions were significantly augmented in rats with renovascular hypertension. It is concluded that, in this model, the peripheral effects of diltiazem evidently surpass the central ones. The regional difference between the inert renal and responsive carotid vasculature might be due to a different mode of regulation of the respective vascular tone, hypothetically reflecting different density of membrane, potential-dependent Ca2+ channels.     

Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy.

OBJECTIVE--To assess whether angiotensin converting enzyme inhibition reduces proteinuria in diabetic nephropathy more than blood pressure reduction with other antihypertensive treatment. DESIGN--Prospective, open randomised study lasting eight weeks in patients with diabetic nephropathy. SETTING--Outpatient nephrology clinics. PATIENTS--40 Patients with type I diabetes and diabetic nephropathy with reduced renal function. INTERVENTION--Antihypertensive treatment with enalapril or metoprolol, usually combined with frusemide. MAIN OUTCOME MEASURES--Arterial blood pressure and urinary excretion of albumin and protein. RESULTS--Arterial blood pressure after eight weeks was 135/82 (SD 13/7) mm Hg in the group given enalapril and 136/86 (16/12) mm Hg in the group given metoprolol. Proteinuria and albuminuria were similar in both groups before randomisation. After eight weeks'' treatment, the geometric mean albumin excretion was 0.7 (95% confidence interval 0.5 to 1.2) g/24 h in the patients given enalapril and 1.6 (1.1 to 2.5) g/24 h in the patients given metoprolol (p less than 0.02). The proteinuria was 1.1 (0.7 to 1.7) and 2.4 (1.6 to 3.6) g/24 h respectively (p less than 0.02). CONCLUSIONS--Antihypertensive treatment with enalapril reduced proteinuria in patients with diabetic nephropathy more than an equally effective antihypertensive treatment with metoprolol. This points to a specific antiproteinuric effect of the angiotensin converting enzyme inhibitor independent of the effect on systemic blood pressure.     

Amphotericin B: side effects and toxicity

Amphotericin B (AmB) is a crucial agent in the management of serious systemic fungal infections. In spite of its proven track record, its well-known side effects and toxicity will sometimes require discontinuation of therapy despite a life-threatening systemic fungal infection. The mechanism of action of AmB is based on the binding of the AmB molecule to the fungal cell membrane ergosterol, producing an aggregate that creates a transmembrane channel, allowing the cytoplasmic contents to leak out, leading to cell death. Most of the efforts at improving AmB have been focused on the preparation of AmB with a lipid conjugate.AmB administration is limited by infusion-related toxicity, an effect postulated to result from proinflammatory cytokine production. The principal acute toxicity of AmB deoxycholate includes nausea, vomiting, rigors, fever, hypertension or hypotension, and hypoxia.Its principal chronic adverse effect is nephrotoxicity. AmB probably produces renal injury by a variety of mechanisms. Risk factors for AmB nephrotoxicity include male gender, higher average daily dose of AmB (≥35 mg/day), diuretic use, body weight ≥90 kg, concomitant use of nephrotoxic drugs, and abnormal baseline renal function. Clinical manifestations of AmB nephrotoxicity include renal insufficiency, hypokalemia, hypomagnesemia, metabolic academia, and polyuria due to nephrogenic diabetes insipidus. Human studies show convincingly that sodium loading in excess of the usual dietary intake notably reduces the incidence and severity of AmB-induced nephrotoxicity.     

Different potentiating effects of imidapril and enalapril on kaolin-induced writhing reaction in mice

Effects of the angiotensin-converting enzyme (ACE) inhibitors, imidapril and enalapril, on kaolin-induced writhing reaction, which is believed to be caused by bradykinin (BK), were examined in mice. The number of writhes was increased significantly by 200 microg/kg of imidapril and by 100 and 200 microg/kg of enalapril. The intensity of writhing reaction was significantly suppressed by 1,000 nmol/kg of icatibant, a selective bradykinin B2 receptor antagonist, in the imidapril-, but not in the enalapril-treated groups. These results suggest that the potentiating effect of enalapril on kaolin-induced writhing reaction is greater than that of imidapril. This might depend on the difference of their inhibitory effects on BK degradation.     

Beneficial effects of enalapril on chlorhexidine digluconate-induced liver peritoneal fibrosis in rats

Peritoneal fibrosis (PF) is a recognized complication of long-term peritoneal dialysis (PD) and can lead to ultrafiltration failure. The present study was designed to investigate the protective effects of enalapril on chlorhexidine digluconate-induced liver PF by decreasing transforming growth factor-β1 (TGF-β1) production in rats. PF was induced in Sprague-Dawley rats by daily administration of 0.5 ml 0.1% chlorhexidine digluconate in normal saline via PD tube for one week. Rats received daily intravenous injections of low dose enalapril (1 mg/kg), or high dose enalapril (2.5 mg/kg), for one week. After 7 days, conventional 4.25% Dianeal (30 ml) was administered via a PD catheter with a dwell time of 4 h and assessment of peritoneal function. At the end of dialysis, the rats were sacrificed and liver peritoneum was harvested for microscopic examination and immunohistochemistry. There was no significant difference in mean arterial pressure and heart rate between groups. After 4 h of PD, the D?/P?(urea) level was reduced, the D?/D? glucose level, serum and the dialysate TGF-β1 level was increased, the liver peritoneum was markedly thicker, and the expression of TGF-β1, alpha-smooth muscle actin (α-SMA), fibronectin, collagen and vascular endothelial growth factor (VEGF) were elevated in the PF group compared with the vehicle group. High dose of enalapril decreased the serum and dialysate TGF-β1 levels, decreased the thickness of the liver peritoneum, and decreased the expression of TGF-β1, α-SMA, fibronectin, collagen and VEGF-positive cells in the liver peritoneum. Low dose of enalapril did not protect against chlorhexidine digluconate-induced PF in the rat. Enalapril protected against chlorhexidine digluconate-induced PF in rats by decreasing TGF-β1 production.