Superficial and deep juxtaglomerular apparatus renin activity of the rat kidney. Effect of surgical preparation and NaCl intake.

The intrarenal gradient of renin activity was determined in rats by using superficial (S) and deep (D) cortical juxtaglomerular apparatuses (JGA's), identified and microdissected after silicone-rubber compound injection. Angiotensin generated from single JGA's using partially purified sheep renin substrate was quantified by rat bioassay. When, in rats on a normal NaCl diet, silicone-rubber was injected into a carotid artery, alone or with abdominal aorta catheterization, S:D renin activity ratios were 1.18+/-0.08 (SEM) and 1.21+/-0.12, respectively. The S:D renin activity ratios obtained when silicone-rubber was injected into the abdominal aorta (2.52+/-0.09) or a chronic carotid artery catheter (3.44+/-0.40) were significantly higher (P < 0.001). The lower S:D renin activity ratios after carotid artery manipulation were due to significantly higher D-JGA renin activities. This increased D-JGA renin activity and the lack of a renin gradient appear to be related to acute carotid artery manipulation. Alterations in JGA renin activity were examined relative to NaCl intake. 2 wk after high-NaCl diet the absolute net renin activity decreased (P < 0.001) more in S (5.84+/-0.11 ng AI.JGA(-1).h(-1)) than D (1.73+/-0.06 ng AI.JGA(-1).h(-1)) JGA's, and the intrarenal renin gradient was lost (S:D-JGA renin activity, 1.00+/-0.07), as compared to the regular NaCl diet. 2 wk of a low-NaCl diet resulted in a greater (P < 0.01) increase in S (14.28+/-1.47 ng AI.JGA(-1).h(-1)) than D (9.62+/-1.19 ng AI.JGA(-1).h(-1)) JGA renin activity and a renin gradient (S:D-JGA renin activity) of 1.75+/-0.12. These results demonstrate that NaCl intake clearly influences total JGA renin content and may also affect the relative intrarenal distribution of renin activity.

Micropuncture studies of proximal tubule albumin concentrations in normal and nephrotic rats.

The concentration of serum albumin in proximal tubule fluid of normal rats and animals with aminonucleoside nephrosis was studied using renal micropuncture techniques. Albumin was quantitated by an ultramicrodisc electrophoresis method capable of measuring 3 chi 10(-11) g of albumin, in 10 nl volumes. With this sensitivity, only small samples of tubule fluid were required for analysis. Collection times could be kept short, therefore decreasing the opportunity for sample contamination with extraneous serum albumin. The measured mean concentration of albumin in proximal tubule fluid (1 mg/100 ml in females and 0.7 mg/100 ml in males) was somewhat lower than values reported by others, but even these values are apt to have been artifactually high as a result of animal preparation and trace contamination of samples during micropuncture. Rats injected with aminonucleoside of puromycin 4 days earlier, showed a significant increase in tubule-fluid albumin concentration coincident with a fall in serum albumin concentration and a 43-fold increase in urine albumin concentration. Tubular absorption of albumin was small relative to that of water. Although albumin filtration was significantly increased over that in normal animals, the glomerular basement membrane still served as a highly efficient barrier to albumin transfer.

Effect of acute and chronic calcium administration on plasma renin.

To evaluate the effect of Ca(++) on renin release, plasma renin activity (PRA) was measured after acute and chronic Ca(++) administration. 1% CaCl(2) was infused into one renal artery of 10 anesthetized dogs (0.3 mg/kg/min). The excreted fraction of filtered calcium (EF(ca++)) and EF(Na+) from the infused kidney were elevated (P < 0.04) during three successive 15-min infusion periods. Serum calcium concentration was significantly elevated (P < 0.001). Creatinine clearance, systemic arterial pressure, and renal blood flow did not change (P > 0.10). Compared to control (45 ng/ml/h+/-5.2 SE), renal venous PRA was suppressed (P < 0.0001) after infusion of Ca(++) for 15, 30, and 45 min (20 ng/ml/h+/-4.6, 16 ng/ml/h+/-4.0, and 13 ng/ml/h+/-2.7, respectively). 15 and 30-min after infusion, PRA did not differ from control (P > 0.20). Chronic Ca(++) loading was achieved in Sprague-Dawley rats by replacing drinking water with 1% CaCl(2) for 17 days. At sacrifice, serum Ca(++), Na(+), and K(+) of controls (n = 12) did not differ (P > 0.60) from Ca(++)-loaded rats (n = 12). Ca(++) excretion (467 mueq/24 h+/-51) was elevated (P < 0.001) compared to controls (85 mueq/24 h+/-12). PRA (8.6 ng/ml/h+/-1.4) and renal renin content of Ca(++)-loaded rats did not differ from controls (P > 0.80). However, after 8 days of sodium deprivation, both PRA and renal renin content of calcium-loaded animals were significantly lower than the respective values in pair-fed controls (P < 0.005). During the period of sodium deprivation, calcium-drinking animals were in greater negative sodium balance than controls (P < 0.005). The data are consistent with the hypothesis that acute and chronic calcium administration inhibit renin secretion.

Propranolol in hypertensive dialysis patients: efficacy and compliance.

The effect of propranolol therapy on plasma renin activity and blood pressure control was evaluated in 35 uremic patients receiving intermittent center-based outpatient hemodialysis. Patients were determined to be either compliant or noncompliant with therapy based on the steady-state predialysis plasma propranolol concentration. Noncompliance occurred with remarkable frequency and was associated with persistent hyperreninemia and poorly controlled hypertension. Blood pressure control was significantly better in compliant patients, in whom plasma renin activity was generally, but not universally, suppressed. Propranolol can be effectively used in the management of hypertensive dialysis patients, but steady-state plasma propranolol levels should be measured to assess compliance in patients apparently refractory to treatment.

Dose ranging efficacy and safety of subcutaneous sumatriptan in the acute treatment of migraine. US Sumatriptan Research Group.

Sumatriptan, a specific serotonin1-like receptor agonist, was studied in the acute treatment of migraine. Two hundred forty-two adult migraineurs participated in a randomized, double-blind study in which one dose of 1, 2, 3, 4, 6, or 8 mg of subcutaneous sumatriptan succinate was evaluated in sequential ascending fashion. At each dose level, a placebo group was included. Efficacy was defined as reduction of moderate or severe pain to mild or no pain, without the use of rescue medication. Headache relief rates showed an approximate dose-response relationship and at 1 hour were as follows: placebo, 24%; 1 mg, 43%; 2 mg, 57%; 3 mg, 57%; 4 mg, 50%; 6 mg, 73%; and 8 mg, 80%. Relief of nausea and improvement in clinical disability were also approximately dose related. Adverse events were dose related; the most common types were injection site reactions and tingling. The 6-mg dose was as effective as the 8-mg dose but was associated with fewer adverse effects and so is optimal.

Obesity and hypertension. Demonstration of a "floor effect".

Weight loss has a role in the treatment of essential hypertension. With the use of a medically supervised protein-sparing supplemented fast and a behavioral program, the changes in blood pressure as a result of weight loss in 135 obese hypertensive subjects were examined. Subjects' weight, blood pressure, and antihypertensive medication intake were recorded at baseline, at conclusion of supplemented fast, and at follow-up. Significant weight loss accompanied by decrements in blood pressure occurred in all subjects. Reductions in the number of antihypertensive medications also occurred. Although the correlations between changes in weight and blood pressure were significant, their moderate size suggests the amount of weight loss accounted for a relatively small part of the blood pressure reduction. Given the large weight losses in the majority of subjects, there appears to be a degree of weight loss beyond which further decrements in blood pressure will not occur ("floor effect"). Maintenance of blood pressure reductions at realimentation/follow-up suggests that weight loss, and not the supplemented fast, results in decreased blood pressure and medication level.

Renal artery dysplasia in a patient with membranoproliferative glomerulonephritis.

A 27 year old man with nephrotic syndrome due to membranoproliferative glomerulonephritis had multifocal stenoses of the renal and intestinal arteries. The arterial lesions demonstrated by angiograhy closely resembled those of medial fibromuscular dysplasia. The dysplasia progressed over a five year period to involve both renal arteries from their extrarenal segments through their interlobar branches. Low serum levels of complement components C3 and C4, focal reduplication of the glomerular basement membrane on light microscopy, and the patterns of glomerular localization of IgG and C3 by immunofluorescence were characteristic of type I membranoproliferative glomerulonephritis. The development of the arterial dysplasia in a patient with chronic glomerulonephritis suggests a common immunologic pathogenesis of both disorders.

Intravenous labetalol in the treatment of severe hypertension and hypertensive emergencies.

The antihypertensive effects of intravenous labetalol were evaluated in 59 patients with hypertensive crises or severe hypertension in need of rapid lowering of blood pressure in a multicenter study. Patients appearing with a supine diastolic blood pressure 125 mm Hg or greater, or a supine systolic blood pressure of more than 200 mm Hg received an initial mini-bolus injection (20 mg) of labetalol. This was followed by repeated incremental doses of 20 to 80 mg given at 10 minute intervals to achieve a supine diastolic blood pressure of less than 95 mm Hg or decrease 30 mm Hg or greater, or a satisfactory decrease in systolic blood pressure. Patients were stratified into those who had taken antihypertensive medication within 24 hours and those who had not. The initial mini-bolus injection caused rapid but not abrupt reduction in blood pressure; the baseline mean blood pressure decreased 23/14 mm Hg. Further injections were needed in the majority of patients (mean: 197 mg). The blood pressure reduction after the last dose of labetalol was 55/33 mm Hg. In pretreated patients and in those who had no medication for 24 hours prior to the intravenous labetalol, the response was similar. Heart rate decreased 10 beats per minute in the total population. In patients pretreated with beta-adrenergic blockers, blood pressure response was similar to that in the total group (59/35 versus 55/33 mm Hg), but heart rate remained essentially unchanged. The dose required to achieve the therapeutic effect was less in pretreated patients than in untreated patients, but the duration of action was shorter. No serious adverse effects were encountered even in patients with concomitant diagnoses of acute left ventricular failure, myocardial infarction, stable congestive heart failure, atrial fibrillation, angina pectoris, acute stroke, transient ischemic attack or encephalopathy. Labetalol is a safe and effective treatment for a rapid blood pressure reduction in hypertensive emergencies.

Diuretic use in the elderly: potential for diuretic-induced hypokalemia.

The more potent "loop" diuretics are being used with increasing frequency. The elderly constitute a growing portion of the population undergoing treatment with diuretics. The alterations in renal function and pharmacokinetics in the elderly (over 60 years of age) may result in the development of certain adverse effects. In patients over 70 years old, there is a progressive decline in overall renal function, resulting in a more than 50% decrease in glomerular filtration rate. Most of the pharmacokinetic changes in the elderly consist of alterations resulting in enhanced plasma levels of any given drug; diminished hepatic drug extraction, detoxification/metabolism or prodrug conversion; decreased renal excretion of drug; and diminished volume of distribution of drug. Adverse reactions to diuretics may be grouped into metabolic changes (e.g., hypokalemia), physiologic alteration (e.g., volume contraction), toxic manifestation (e.g., interstitial nephritis) and allergic or idiosyncratic phenomena (e.g., rash or thrombocytopenia). There is general agreement that significant hypokalemia, particularly among elderly patients receiving digitalis glycosides, is significant and requires therapy. Diuretic-associated hypokalemia reflects the potency and duration of action of a diuretic, factors modulating potassium balance including dietary intake and concurrent medical processes. The short duration of action and greater natriuresis relative to kaliuresis characteristic of loop diuretics may result in a lesser degree of hypokalemia than that seen with traditional thiazide diuretics.

Hypertension, changes in high-density lipoproteins and antihypertensive therapy.

The risk for development of coronary heart disease (CHD) is related to a number of factors. Among these, both hypertension and various lipid abnormalities have been shown to play an important role. A clear inverse relation between high-density lipoprotein (HDL) cholesterol and CHD has been observed in numerous observational and short studies. Pharmacologic treatment of hypertension has been shown to reduce dramatically some of the sequelae of high blood pressure--renal failure, cerebrovascular accidents and congestive heart failure. However, a consistent reduction in associated CHD has not been demonstrated, and the dissociation between reducing blood pressure and reduction in CHD has not been definitively explained. One of the suggested explanations relates to alterations in blood lipid levels that may be induced by certain antihypertensive agents. Changes in HDL cholesterol levels or other lipid alterations due to antihypertensive therapy could modify the beneficial effects achieved by the direct reduction of blood pressure. If so, antihypertensive agents could be subclassified as atherogenic or antiatherogenic depending on the associated changes in lipid levels. Therefore, the antihypertensive agents of choice for patients whose cholesterol levels are a concern would be those that reduce the CHD risk factor of hypertension without compromising the risk factor associated with a patient's lipid profile.

Celiprolol in systemic hypertension.

The safety and efficacy of orally administered celiprolol, a new beta 1-selective adrenergic blocking drug with peripheral beta 2-agonist properties, were assessed in 91 patients with mild to moderate systemic hypertension (supine diastolic blood pressure [BP] 95 to 114 mm Hg without medication) using a placebo-controlled, double-blind, randomized, titration-to-effect study design. All patients received placebo for 4 weeks and were then randomized to receive placebo (n = 46) or once-daily celiprolol (n = 45), which was titrated every 2 weeks (200, 400, 600 mg/day) over a 6-week period to achieve a reduction in supine diastolic BP to less than or equal to 90 mm Hg. Plasma lipids and lipoproteins were also assessed at baseline, during placebo and after randomization to active therapy in a subgroup of patients. Compared with placebo, celiprolol reduced supine and standing BP (reduction of supine BP -0.4/-2.1 mm Hg with placebo, -5.7/-6.4 with celiprolol, p less than 0.05; reduction of standing BP -1.7/-1.0 with placebo, -7.2/-4.9 with celiprolol, p less than 0.05). Supine heart rate was reduced by 6.8 beats/min with celiprolol compared with 2.0 beats/min with placebo (p less than 0.05). No differences were seen when the effects of placebo and celiprolol on plasma lipoproteins were compared. Celiprolol is a safe, effective and well tolerated once-daily antihypertensive drug and has no detrimental effects on plasma lipids.

Beta-blockers and hypertension.

While there is general agreement on the natural history, pathology, and pathophysiology of hypertension, there continues to be controversy over the selection of specific antihypertensive agents. All antihypertensive agents will, by definition, lower blood pressure, and factors beyond side effects and other difficulties associated with therapy form the basis of selecting specific agents. One of these factors is the effect of a given drug on core organ function. Propranolol was the first beta-adrenoceptor-blocking agent introduced for the treatment of hypertension. Initiation of therapy with propranolol may result in a decline in blood pressure more at the expense of cardiac function due to a concomitant rise in total peripheral resistance. Furthermore, propranolol may result in a decline in both glomerular filtration rate (GFR) and renal blood flow (RBF). In contrast, cardioselective beta-blockers or those with intrinsic sympathomimetic activity may not adversely affect renal function. It had been predicted that nadolol, a noncardioselective beta-blocker without intrinsic sympathomimetic activity, should result in decreased renal function. In contrast, observations demonstrated a preservation or improvement in both RBF and GFR, suggesting the presence of an alternative effective mechanism. Recent additions to the beta-adrenolytic group of antihypertensive agents include drugs with concurrent beta-blockade and vasodilation. This vasodilatation may be achieved through agonist properties resulting in lesser increases in vasomotor tone and smaller, if any, decreases in cardiac output. Alternatively, vasodilation may be achieved by concomitant alpha-adrenoceptor blockade, such as with labetalol. This agent preserves GFR and RBF during therapy of hypertension, in patients with normal as well as diminished renal function and hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Bumetanide-induced diuresis and natriuresis: effect of prostaglandin synthetase inhibition.

The effects on the renal actions of bumetanide of two inhibitors of prostaglandin synthetase, acetylsalicylic acid (ASA) and indomethacin, were studied in eight normal adults. Indomethacin alone resulted in a significant decrease in FENa compared to the control period. Bumetanide alone resulted in increases in urine volume, FENa, and plasma renin activity. Both ASA and indomethacin blunted the increases in urine volume and sodium excretion, although the inhibition by indomethacin was greater than that of ASA. In addition, indomethacin completely inhibited the bumetanide-induced increase in plasma renin activity. No consistent relationship between these effects and urinary prostaglandin E2 or F excretion was noted. These studies indicate that prostaglandin synthetase inhibitors may interfere with the effects of bumetanide.

Epoprostenol (PGI2, prostacyclin) during high-risk hemodialysis: preventing further bleeding complications.

The frequency of hemodialysis-associated hemorrhage was studied prospectively in two successive, parallel, heparin-controlled studies using epoprostenol (PGI2; average dose, 4.1 ng/kg.min) as the sole antithrombotic agent. Sixty-three patients with active or recently active bleeding underwent 163 hemodialysis treatments in each of which prospective bleeding risk was assessed. PGI2 was associated with up to 50% overall reduction in the frequency of bleeding, particularly in the highest risk circumstances. PGI2 also allowed successful completion of the full, prospectively prescribed hemodialysis time in the most treatments (82% versus 93% with heparin). Furthermore, the efficiency of hemodialysis using PGI2, as indicated by the reduction in concentration of blood urea nitrogen and serum creatinine, was equal to that using heparin, even though there was a tendency toward modest reduction in residual volume of the hollow fiber dialyzer and slightly more frequent early termination of treatment from dialyzer clotting with PGI2. No severe vasodilatory side effects of PGI2 were observed during these studies. Hypotension was equally frequent during hemodialysis with heparin as with PGI2. The current results suggest that PGI2 should be considered as a substitute for heparin during high-risk hemodialysis because PGI2 may reduce the incidence of dialysis-associated bleeding without severe adverse side effects.

Pharmacokinetic interactions of moricizine and diltiazem in healthy volunteers.

Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.

Effect of lovastatin on serum lipids in patients with nonfamilial primary hypercholesterolemia.

The effect of lovastatin on serum lipids and its tolerability in patients with non-familial primary hypercholesterolemia (type II-A and type II-B) during a six-month period were evaluated in this open-label study. Thirty-eight patients were enrolled in the study; tolerability was assessed in all 38 patients. Thirty patients completed the study, and the effect of lovastatin on serum lipids in these patients was assessed. Some patients had been treated for hypercholesterolemia with long-term dietary and other non-pharmacologic means before entry into the study. All patients were unresponsive to a six-week program of intensive dietary therapy and other nonpharmacologic treatment to lower their blood cholesterol levels before receiving lovastatin. While maintaining intensive dietary therapy, administration of lovastatin was instituted at a dosage of 20 mg/day, which was increased by 20-mg increments monthly, as necessary, to a maximum of 80 mg/day. In an effort to achieve goal levels of low-density lipoprotein cholesterol (LDL-C), ten patients received a daily dosage of 20 mg, 12 patients received 40 mg, seven patients 60 mg, and one patient 80 mg. Twenty-nine of the 30 patients achieved significant lowering of serum levels of total cholesterol (TC), LDL-C, and apolipoprotein (apo) B-I; this was demonstrated after the first month of therapy with lovastatin and was maintained throughout the six-month treatment period. One patient failed to demonstrate lowering of these serum lipids, despite receiving the maximum recommended dosage of lovastatin of 80 mg/day. Comparative measurements of serum lipids during dietary therapy alone and after six months of diet plus lovastatin therapy were as follows: TC, 289 +/- 5 versus 216 +/- 9 mg/dl (P less than 0.0005); LDL-C, 206 +/- 4 versus 141 +/- 5 mg/dl (P less than 0.0005); and apo B-I, 112 +/- 3 versus 89 +/- 2 mg/dl (P less than 0.0005). Serum levels of very-low-density lipoprotein cholesterol (VLDL-C) and triglycerides decreased slightly during lovastatin therapy, but the changes were not statistically significant. There were slight but statistically insignificant increases in serum levels of high-density lipoprotein cholesterol (HDL-C), apo A-I, and apo A-II.(ABSTRACT TRUNCATED AT 400 WORDS)

Natriuretic and phosphaturic response to diuretics after parathyroidectomy in dogs.

Intact and acutely parathyroidectomized (TPTX) dogs were studied during hydropenia, volume expansion (VE), volume expansion plus ethacrynic acid (EA), and volume expansion plus acetazolamide (AZ). In intact dogs, VE produced marked increases in both Na+ and phosphate (Pi) excretion; in TPTX dogs, Na+ excretion increased but phosphaturia was minimal. Addition of EA increased Na+ but not Pi excretion in both groups. Discontinuing EA and substituting AZ in intact dogs produced a marked increase in Pi excretion compared to both VE and VE + EA. In TPTX dogs, AZ failed to increase Pi excretion compared to VE alone. The results suggest that increased distal Pi absorption in acutely TPTX dogs is not associated with NaCl reabsorption in the thick ascending loop of Henle or may occur at an alternative nephron site. Furthermore, the increased distal Pi reabsorptive capacity revealed by TPTX can overcome the increased distal Pi delivery produced by the superimposition of AZ on VE.

Pharmacology, therapeutic efficacy, and adverse effects of bumetanide, a new "loop" diuretic.

Bumetanide is a recently developed natriuretic and diuretic agent, belonging to the "loop" class of diuretics. Since it is rapidly and almost completely absorbed after oral administration, oral and parenteral formulations have a similar pharmacokinetic profile. Peak plasma levels are achieved approximately 30 min after oral administration. The apparent half-life is 1.2-1.5 hr, and the volume of distribution is about 25 liters. Plasma clearance is 228-255 ml/min. Bumetanide is promptly and almost completely eliminated by metabolism of the butyl side chain and urinary excretion of the parent drug and its metabolites. The principle renal site of action is the ascending limb of the loop of Henle, with a minor effect on the proximal tubule. The drug causes decreases in both free water clearance (during water diuresis) and solute free water reabsorption (during hydropenia), increased fractional delivery of sodium chloride to the distal tubule and a natriuresis approaching 20% of the filtered load of sodium, calciuria, phosphaturia, and minimal bicarbonaturia. Extensive clinical studies have been conducted with both oral and parenteral bumetanide in patients with a variety of edematous conditions. The agent has been clearly demonstrated to be an effective diuretic in the treatment of edema due to cardiac disease (congestive heart failure) and edema, with or without ascites, due to hepatic disease. Bumetanide has also been shown effective in treating edema due to renal disease, even when modest to severe renal insufficiency is present, and it may be useful in the treatment of edema refractory to other loop diuretics. As would be predicted for any potent diuretic, bumetanide administration has been associated with hypokalemia, hypochloremia, metabolic aklalosis, hyperuricemia, and prerenal azotemia. Alterations in glucose metabolism are an inconsistent finding. Transient thrombocytopenia and granulocytopenia have been noted, but no consistent or important alterations in biochemical parameters have been observed. In some patients, especially those with renal failure receiving high doses, myalgias and muscle tenderness have been described. To date only a very limited potential for ototoxicity has been observed. Bumetanide has been administered without difficulty to patients having side effects from other loop diuretics.

Comparison of the efficacy and tolerability of an angiotensin converting enzyme inhibitor (lisinopril) versus a calcium channel antagonist (diltiazem SR) in the treatment of moderate to severe hypertension.

One hundred and ten patients (mean age 50.6 years) with moderate to severe essential hypertension (DBP between 105 and 116 mmHg) were randomised to eight weeks of double-blind treatment with lisinopril (n = 56) or diltiazem SR (n = 54). Fourteen patients withdrew from therapy; six patients withdrew because of adverse events (lisinopril, n = 3; diltiazem SR, n = 1) and lack of BP control (lisinopril, n = 1; diltiazem SR, n = 1). Both monotherapies were titrated upward (lisinopril 20-40 mg daily, diltiazem SR 120-180 mg twice daily) to achieve an office DBP < 90 mmHg. Hydrochlorothiazide (HCTZ; 25 mg daily) was added to monotherapy after week 4 if patients did not reach the BP goal (i.e. non-responders). After four weeks of therapy, 72% of patients (74 of 103) were nonresponders. At eight weeks of therapy, 66 patients (lisinopril, n = 32; diltiazem SR, n = 34) had received HCTZ. At week 8, 53% of lisinopril and 36% of diltiazem SR patients met the response criteria. Mean office DBP decreased from baseline -18.1 +/- 8.6 mmHg for lisinopril patients and -15.9 +/- 10.1 mmHg for diltiazem SR patients at week 8. Lisinopril was as effective as diltiazem in reducing systolic and diastolic office BP at week 4 (p > 0.1). Likewise, at weeks 4 and 8, no statistically significant differences were detected between treatments (p > 0.05) for systolic and diastolic ambulatory BP averaged over 24 hours. Both treatments were well tolerated and showed important antihypertensive efficacy in patients with moderate to severe BP elevation.

Lower dose diuretic therapy in the treatment of patients with mild to moderate hypertension.

Indapamide (Lozol), an indoline antihypertensive drug with diuretic and vasodilating activities, was evaluated in 195 patients with mild to moderate essential hypertension (sitting DBP between 95 and 110 mmHg) in a multicentre, randomised, double-blind, parallel-group design trial. A four week single-blind placebo wash-out period was followed by an eight week double-blind period. Patients were randomised to indapamide 1.25 mg/day or to placebo. The primary efficacy endpoint was the mean change in sitting DBP from baseline to week 8. Ninety patients in the placebo group (93%) and 82 patients (84%) in the indapamide group completed the eight weeks of double-blind therapy. Indapamide produced a mean (SE) decrease in sitting DBP of 7.4 (0.63) mmHg (from 100.1 to 92.8 mmHg) compared with a decrease of 3.6 (0.75) mmHg (from 99.6 to 95.8 mmHg) produced by placebo (p < 0.0001). Indapamide and placebo also produced mean decreases in standing DBP of 6.8 (0.75) and 2.8 (0.77) mmHg, respectively (p = 0.0002), in sitting SBP of 11.1 (1.18) and 3.2 (1.35) mmHg, respectively (p = 0.0001) and in standing SBP of 11.4 (1.29) and 4.0 (1.43) mmHg, respectively (P = 0.0002). Reduction in BP of > or = 10 mmHg or to a DBP of < or = 90 mmHg was more frequent (P = 0.0005) among indapamide (46.6%) compared with placebo (23.7%) treated patients. During the eight week double-blind treatment period, incidence rates for all adverse experiences and for drug-related adverse experiences were similar between the two treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)