The effects of benazepril, a new angiotensin-converting enzyme inhibitor, in mild to moderate essential hypertension: a multicenter study.

Benazepril hydrochloride is a new angiotensin-converting enzyme inhibitor. In a multicenter study, 206 patients with mild to moderate hypertension were randomized to receive benazepril at a dose of 2, 5, 10, or 20 mg, hydrochlorothiazide, 25 mg, or placebo once daily for 4 weeks. The 20 mg dosage of benazepril lowered blood pressure to a degree equal to that of 25 mg hydrochlorothiazide: -12.2/7.7 mm Hg and -13.4/-7.5 mm Hg, respectively. Hydrochlorothiazide proved to be more effective in black subjects. At lower dosage levels of benazepril (2, 5, and 10 mg), blood pressure reduction was not significantly different from that with placebo. In those patients who failed to achieve goal diastolic blood pressure of less than 90 mm Hg with monotherapy after 4 weeks, the addition of open-label hydrochlorothiazide (25 mg/day) to benazepril, hydrochlorothiazide, or placebo produced a substantial additional decrease in blood pressure over a 2-week period. No definite adverse effects on hematologic measurements, serum biochemistry test results, or urinalyses were noted. Subjective adverse experiences were common in all groups but except in three or possibly four instances were not considered causally related to the study drug.

Thiazide treatment of systemic hypertension: effects on serum magnesium and ventricular ectopic activity.

Clinical and investigational evidence has proved an association between thiazide-induced electrolyte imbalances and ventricular arrhythmias. It is hypothesized that this increases the potential for sudden unexplained death. Elderly hypertensive patients are at particular risk because of their tendency to have significantly depressed serum magnesium levels, which decrease even further when treated with thiazide diuretics. Potassium supplementation does not effectively restore electrolyte balance unless accompanied by magnesium. Therefore, concomitant administration of potassium and magnesium supplementation appears to be an approach to reducing the risk of arrhythmias and death in thiazide-treated hypertensive patients.

Electrolyte disarray and cardiovascular disease.

Thiazide diuretics have frequently been recommended as initial therapy in patients with mild to moderate hypertension. However, their undesirable metabolic consequences have been suspected of contributing to increases in cardiovascular morbidity and mortality. Even at low doses, there is a definite decrease in both potassium and magnesium levels. The degree of decrease in potassium and magnesium levels has been shown to be directly related to the hydrochlorothiazide dosage. Many investigators have now reported an increase in ventricular ectopy associated with diuretic-induced hypokalemia. Whereas there is no single study that conclusively proves that thiazide therapy results in malignant arrhythmias and an increased risk of sudden death, the circumstantial evidence is strong. Although sodium restriction is critical to potassium restoration, it rarely works alone. Potassium chloride supplementation can be effective in restoring potassium but not magnesium. Potassium-sparing diuretic combinations can both prevent and treat hypokalemia and hypomagnesemia, possibly reducing the risk of potentially lethal arrhythmias and sudden death.

Comparison of equal-weight oral dosages of verapamil hydrochloride and diltiazem hydrochloride in patients with mild to moderate hypertension.

The clinical efficacy, safety, and tolerability of oral verapamil and diltiazem, at total daily dosages of equal weight, were evaluated in a placebo-controlled, double-blind crossover study. Thirty-six ambulatory patients with chronic, stable, mild to moderate hypertension (supine diastolic blood pressure of 94-116 mm Hg) received a dosage of either verapamil or diltiazem 80 mg t.i.d. as the hydrochloride salt for one week after an antihypertensive-drug washout period. Each then received 120 mg of the same drug t.i.d. for one week. After another two-week washout period, the patients were crossed over to the other drug. Each patient had a 12-lead electrocardiogram and measurement of supine and standing blood pressure weekly. In the 32 patients completing the study, low-dose verapamil reduced supine diastolic blood pressure (DBP) from a mean of 101.5 +/- 5.2 to 95.3 +/- 9.5 mm Hg; high dose verapamil reduced DBP to 90.9 +/- 7.4 mm Hg. Standing DBP was reduced to a similar degree. Diltiazem showed an almost identical effect: Supine DBP was reduced from a mean of 101.7 +/- 5.3 to 94.0 +/- 10.1 mm Hg with the low dose and to 91.0 +/- 8.6 mm Hg with the high dose, with similar effects on standing DBP. The high dose of both drugs significantly increased the QTc interval, and both doses of diltiazem significantly increased the PR interval compared with baseline. Both drugs exhibited consistent efficacy with minimal adverse effects. The electrophysiologic safety profile of verapamil was superior to that of diltiazem.

Serum magnesium and potassium levels in hypertensive patients after a therapeutic switch from hydrochlorothiazide plus a potassium supplement to maxzide.

Determinations of serum magnesium and potassium levels and blood pressure were made in 40 hypertensive patients in whom daily therapy with 50 mg of hydrochlorothiazide plus potassium supplements was switched to a once-daily regimen of 50 mg of hydrochlorothiazide plus 75 mg of triamterene (Maxzide). Patients showed no clinically significant changes in blood pressure or in serum magnesium or serum potassium values following the switch. It is concluded that therapy in patients receiving hydrochlorothiazide and up to 60 meq of potassium can be safely switched to Maxzide without adversely affecting serum magnesium levels, serum potassium levels, or blood pressure control.

Magnesium depletion, diuretics, and arrhythmias.

Increasing information on the potentially serious risks of potassium and magnesium depletion associated with diuretic therapy demands a clinical focus on understanding the factors involved and on methods for preventing these electrolyte deficiencies. Data suggest that serum potassium and magnesium levels may be normal in the presence of tissue depletion, but decreases in serum levels are almost always associated with tissue and whole-body depletion of these electrolytes in patients in whom such depletion cannot be risked. Ventricular ectopy has also been associated with depletion of potassium and magnesium, which may explain the increased risk of sudden unexpected death in hypertensive patients. Any clinician who treats hypertension or congestive heart failure must consider whether to replete potassium and magnesium in patients already receiving diuretic therapy, or, better still, consider how to prevent depletion of these electrolytes in patients in whom such depletion cannot be risked. If prevention is selected, the clinician must then evaluate the data on available diuretic combinations for efficacy in electrolyte conservation, bioavailability, and dosage convenience. The combination of triamterene and hydrochlorothiazide (Maxzide, 75 mg triamterene/50 mg hydrochlorothiazide) has demonstrated electrolyte conservation, with bioavailability and dosage convenience.

Thiazide treatment of hypertension. Effects of thiazide diuretics on serum potassium, magnesium, and ventricular ectopy.

Thiazide diuretics are considered to be the cornerstone of contemporary antihypertensive therapy and are generally recommended as the initial treatment for patients with mild to moderate, uncomplicated hypertension. Hypokalemia and hypomagnesemia are two metabolic alterations that are associated with long-term thiazide therapy. Thirty-five patients (20 with low renin status and 15 with normal renin status) with mild to moderate essential hypertension were treated with hydrochlorothiazide in a dose-titration experiment after a four-week lead-in period. The initial daily dose was 12.5 mg; this was increased at four-week intervals to 25 mg, 37.5 mg, and 50 mg daily. The endpoint dose of this titration was that dose at which the patient's blood pressure normalized, or the dose of 50 mg, if that dose was reached. Patients were maintained on their endpoint dose of hydrochlorothiazide for 24 weeks of continuous thiazide monotherapy beyond the dose titration. The serum potassium and serum magnesium levels during the control period were 4.4 +/- 0.2 mmol/liter and 2.30 +/- 0.08 mg/dl, respectively. During dose titration, each incremental increase of hydrochlorothiazide produced a decrease in blood pressure and a stepwise decrease in serum potassium and magnesium levels. A previously reported study involving 38 patients with mild to moderate hypertension (22 with low renin status and 16 with normal renin status) used similar methods to study higher-dose thiazide therapy. An initial dose of 50 mg daily of hydrochlorothiazide was administered; this was increased at four-week intervals to 100 mg, 150 mg, and 200 mg. The serum potassium and serum magnesium levels during the control period were 4.5 +/- 0.2 mmol/liter and 2.1 +/- 0.18 mg/dl, respectively. In the hypertensive patients with normal renin status, doses of hydrochlorothiazide greater than 50 mg did not result in further blood pressure lowering effects; however, the undesirable effects of hypokalemia and hypomagnesemia continued to be manifested and increased at higher doses of hydrochlorothiazide. Thirty-eight patients who had previously experienced hypokalemia, palpitations, or cardiac arrhythmia were placed on hydroclorothiazide therapy for one to three months and were monitored for arrhythmias after treadmill exercise. The occurrence of premature ventricular contractions correlated significantly with the decrease in serum potassium (r = 0.73, p less than 0.001) and serum magnesium (r = 0.68, p less than 0.001) levels during hydrochlorothiazide therapy and with the product of the change of the two cations (r = 0.81, p less than 0.001).

Primary aldosteronism: computerized tomography in preoperative evaluation.

We reviewed the value of computerized tomography (CT) in the preoperative evaluation of 34 patients with primary aldosteronism. All 34 patients entered a standard protocol including saline suppression testing, abdominal CT scanning, and adrenal venous sampling. Surgical pathologic findings, biochemical determinations, and clinical response to adrenalectomy were the criteria used to evaluate 68 adrenals in 34 patients. Of 36 diseased glands 17 were correctly identified by CT (48%). Of the 32 normal glands, 29 were identified correctly by CT (91%). Thus, CT is not sensitive (0.48), but very specific (0.91) in Conn's syndrome. Our patients were divided into two groups: group 1 were those scanned between 1977 and 1980, group 2 were those scanned from 1981 to 1983 with a high-resolution GE-8800 scanner. CT results in group 2 showed no significant improvement in specificity (0.92), but improvement in sensitivity (0.58) over group 1 (specificity 0.90, sensitivity 0.42). Furthermore, CT is less sensitive in patients with smaller tumors than in those with larger tumors.

The prediction of anatomical morphology of primary aldosteronism using serum 18-hydroxycorticosterone levels.

Serum 18-hydroxycorticosterone, aldosterone, and potassium were measured under basal conditions in 34 patients with documented primary aldosteronism, 10 patients with essential hypertension, and 9 normal subjects. The results revealed that 22 of 23 patients with aldosterone-producing adenomas had 18-hydroxycorticosterone levels greater than 100 ng/dl, and all 9 patients with idiopathic adrenal hyperplasia had plasma levels less than 100 ng/dl. Two patients with unusual macromicronodular hyperplasia of the adrenal glands had levels greater than 100 ng/dl. We found a significant relationship between serum potassium and the ratio of 18-hydroxycorticosterone to aldosterone in patients with idiopathic adrenal hyperplasia, but not in those with an aldosterone-producing adenoma. We conclude that measurement of serum 18-hydroxycorticosterone is a useful predictor of the etiology of primary aldosteronism.

Potassium and magnesium abnormalities: diuretics and arrhythmias in hypertension.

Thiazide diuretics are widely accepted as the cornerstone of antihypertensive treatment programs. Hypokalemia is a commonly encountered metabolic consequence of long-term thiazide therapy but the effect of thiazide on serum magnesium is less well known. Thirty-eight patients (22 low renin, 16 normal renin) with moderate diastolic hypertension were treated with hydrochlorothiazide administered twice a day. The initial daily dose was 50 mg; this was increased at four week intervals to 50 mg, 100 mg, 150 mg, and 200 mg. Dose escalation was discontinued when either normalization blood pressure was attained or the 200 mg dose level was reached. Patients were then maintained with their hydrochlorothiazide dose for 24 weeks of continuous thiazide monotherapy. The serum potassium during the control period was 4.5 +/- 0.2 mmol/liter. During dose escalation and long-term maintenance therapy, the serum potassium and magnesium levels fell in a step wise, dose-dependent fashion. In another 38-patient study, the effects of hydrochlorothiazide therapy (100 mg daily) on the occurrence of premature ventricular contractions were observed during rest as well as during static and dynamic exercise. During rest 0.6 +/- 0.08 premature ventricular contractions per minute (mean +/- SEM) were observed, and during dynamic exercise 0.8 +/- 0.15 premature ventricular contractions per minute. During hydrochlorothiazide therapy (50 or 100 mg per day) premature ventricular contractions per minute were 1.4 and 5.7, respectively. The occurrence of premature ventricular contractions correlated significantly with the decrease observed in serum potassium (r = 0.71, p less than 0.001) and in serum magnesium (r = 0.68, p less than 0.001). Thiazide therapy appears to cause both potassium and magnesium depletion, and decreases in both correlate well with the appearance of ventricular ectopic depolarizations.

Operative management of renovascular hypertension. Results after a follow-up of fifteen to twenty-three years.

From March 1960 through January 1968, 71 patients underwent operations for renovascular hypertension at our center. There were three operative deaths in 94 procedures. Primary nephrectomy was performed in 26 patients. Attempted revascularization of 62 kidneys was successful in 46 (74%). In 13 (87%) of the 15 cases considered operative failures, the patients underwent either secondary nephrectomy (11) or repeat revascularization (two). Based on the results of the final operation, initial blood pressure response (1 to 6 months postoperatively) in the surviving patients indicated 44% cured (30 patients), 40% improved (27), and 16% unchanged (11). The sequential clinical, functional, and anatomic follow-up evaluations to time of death or to date are available in 66 of the 68 patients (97%) who survived operation and form the basis of this report. Fifteen- to 20-year arteriographic follow-up in 16 patients revealed one late neointimal anastomotic stenosis and an additional three aortic suture line false aneurysms in Dacron aortorenal grafts. During this 15- to 23-year follow-up, 71% of atherosclerotic (AS) patients and 23% of fibromuscular dysplasia (FMD) patients died. Cardiovascular (CV) morbid events occurred in 77% of AS patients and in 19% of FMD patients. The cumulative incidence of death and CV morbid events during follow-up is examined by Kaplan-Meier life tables and Cox's proportional hazards regression analysis in these respective groups to identify preoperative markers predictive of longer event-free survival in relation to blood pressure benefit by operation (for example, focal vs. diffuse AS, presence of cerebrovascular disease, ischemic heart disease, left ventricular hypertrophy seen by electrocardiography, azotemia, smoking, diabetes, and hyperlipidemia).(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of digital venous angiography for the diagnosis of renovascular hypertension.

Thirty-two patients being evaluated for hypertension by angiography were also studied by digital video subtraction angiography (DVSA). Twenty-three of the 76 renal arteries were found by conventional angiography to have significant lesions. Two experienced angiographers evaluated the DVSA studies without knowledge of the angiographic results. The accuracy of DVSA for evaluation of renal arteries was 87% for Observer I and 80% for Observer II. Sensitivities were 87% and 83% and specificities 87% and 79% for the two observers. Of the 13 patients with significant lesions, Observer I identified at lest one lesion in all 13 while Observer II identified a lesion in 12 of the 13. The high false-positive rate (26% for Observer I and 37% for Observer II) was thought to be caused by subtraction artifacts, quantum noise, relatively low spatial resolution, and the Mach effect.

Renovascular hypertension: anatomic and renal function changes during drug therapy.

Serial renal function studies were performed on 41 patients wtih renovascular hypertension (RVH) secondary to atherosclerotic renal artery disease who had been randomly selected for nonoperative management. In 19 patients, serum creatinine levels increased between 25% and 120%. The glomerular filtration rates dropped between 25% and 50% in 12 patients. Fourteen patients (37%) lost more than 10% of renal length. In four patients (12%), a significant stenosis progressed to total occlusion. Seventeen patients (41%) had deterioration of renal function or loss of renal size that led to operation. One patient required removal of a previously reconstructible kidney. Of the 17 patients with deterioration, 15 had acceptable blood pressure (BP) control during the period of nonoperative observation. Progressive deterioration of renal function in nonoperatively treated patients with atherosclerotic renal artery stenosis and RVH is common, and occurs even in the presence of BP control with drugs.

Papilledema in two patients with acromegaly and intrasellar pituitary tumors.

Two patients had bilateral papilledema complicating acromegaly. Both patients had enlarged blind spots, but otherwise visual fields were normal. Suprasellar extension of the pituitary tumors was diligently sought with the use of visual field examination, pneumoencephalography, internal carotid arteriography, and computed axial tomography, and tumor extension did not exist. Transphenoidal and transethmoidal routes were used to perform partial hypophysectomies in these patients. The procedure was completely successful in one patient and partially successful in the other patient. After hypophysectomy, papilledema resolved in both patients. This beneficial effect may be the result of anatomical changes, the reduction in growth hormone levels, or both. These observations suggest that the acromegaly may be different from papilledema that occurs secondary to suprasellar expansion of pituitary tumors.

Progression of renal artery fibromuscular dysplasia in 42 patients as seen on angiography.

Forty-two hypertensive patients with fibromuscular dysplasia who had angiographic evidence of the development of new disease or of the progression of existing disease were studied. Renal arterial disease was classified as medial fibroplasia with aneurysms (12 patients), subadventitial fibroplasia (24 patients), or intimal fibroplasia (6 patients). Progression of the disease was shown in all 42 patients during the follow-up period (from 1 month to 11 years and 4 months). The results indicate that all forms of fibromuscular dysplasia are progressive and have variable rates of progression.

Thiazide diuretics, hypokalemia and cardiac arrhythmias.

Thiazide diuretics are widely accepted as the cornerstone of antihypertensive treatment programs. Hypokalemia is a commonly encountered metabolic consequence of chronic thiazide therapy. We treated 38 patients (22 low renin, 16 normal renin) with moderate diastolic hypertension with hydrochlorothiazide (HCTC) administered on a twice daily schedule. Initial dose was 50 mg and the dose was increased at monthly intervals to 100 mg, 150 mg and 200 mg daily until blood pressure normalized. The serum K during the control period was 4.5 +/- 0.2 mEq/l an on 50, 100, 150 and 200 mg HCTZ daily 3.9 +/- 0.3, 3.4 +/- 0.2, 2.9 +/- 0.2, and 2.4 +/- 0.3 mEq/l, respectively. Corresponding figures for whole body K were 4107 +/- 208, 3722 +/- 319, 3628 +/- 257, 3551 +/- 336, and 3269 +/- 380 mEq, respectively. In 13 patients we observed the effects of HCTZ therapy (100 mg daily) on the occurrence of PVC's during rest as well as during static and dynamic exercise. During rest we observed 0.6 +/- 0.08 PVC beats/min +/- SEM and during static and dynamic exercise 0.6 +/- 0.06 and 0.8 +/- 0.15, respectively. Corresponding figures during HCTZ therapy 100 mg daily were 1.4 +/- 0.1, 3.6 +/- 0.7 and 5.7 4/- 0.8, respectively. The occurrence of PVC's correlated significantly with the fall in serum K+ observed r = 0.72, p less than 0.001. In conclusion we found that thiazide diuretics cause hypokalemia and depletion of body potassium. The more profound hypokalemia, the greater the propensity for the occurrence of PVC's.

Radionuclide evaluation of renal artery dilatation.

Radionuclide studies were sued in three patients to evaluate renal perfusion and function within 24 hours following transluminal dilatation. In one patient, technetium-99 m pertechnetate showed good renal perfusion one and 12 hours after a post-dilatation arteriogram had shown a renal artery intimal defect. Improved clearance of iodine-131 ortho-iodohippurate from the blood demonstrated an increase in renal function 18 hours following dilatation of a stenosis at a renal allograft anastomosis in the second patient, while technetium-99 m-labeled DTPA showed an improved total glomerular filtration rate 24-hours after dilatation of a saphenous vein bypass graft in the third patient. It was concluded that renal radionuclide studies are of benefit in evaluating patients in the immediate post-dilatation period.

[Surgical treatment of renovascular hypertension: results of operation in 400 patients with renal artery stenosis (author's transl)]. / Hinweise zur chirurgischen Behandlung der renovaskulären Hypertonie: Erfahrung an 400 operierten Nierenarterienstenosepatienten.

A report is given on patients treated surgically for renal artery stenosis (RAS) and renovascular hypertension. High-quality arteriograms, as well as renal vein (RVR) determination and split-function studies (SFS) are the most important preoperative diagnostic procedures. Since only 40% of the patients with renal artery stenosis have renovascular hypertension, the value of RVR and SFS for diagnosis, indication and prognosis in surgical cases is stressed. Unilateral RAS patients show a 50% cure rate with regard to arteriosclerosis (AS) and 74% in fibromuscular displasia (FD). Improvement following surgery was recorded in 92% and 96% of cases, respectively. Bilateral reconstructions are preferably done as staged procedures. Simultaneous repair results in a higher postoperative thrombosis rate, as well as being a significant risk to both kidneys; only 50% of patients really do need surgical treatment of the contralateral kidney. Patients older than 50 years became normotensive in 36% of cases, 86% showed improvement and 13% no benefit from operation; the mortality rate was 1.3% in patients over 50. Cases with a severe reduction in kidney function (less than 30 ml/min/kidney creatinine clearance) showed a significant increase in creatinine clearance with a 90% improvement in and 36% cure of hypertension, after reconstruction. 50% of totally occluded renal arteries could be revascularized via an appropriate distal vessel; the cure rate in this group was 55%. A higher incidence of renovascular hypertension is seen in patients under the age of 20. 68% of this group became normotensive, whilst only 8% did not show any benefit from surgery. Combined diagnostic procedures to evaluate morphology and functional status of the kidney, as well as the indications for and prognosis of surgery are emphasized; a more refined technical approach to RAS revascularisation is described.