Efficacy, safety and tolerability of valsartan 80 mg compared to irbesartan 150 mg in hypertensive patients on long-term hemodialysis (VALID study).

BACKGROUND: End stage renal disease (ESRD) patients mainly die of cardiovascular disease, and hypertension is regarded as the major risk factor. Valsartan is an angiotensin receptor blocker (ARB) with a well-established efficacy and safety profile in hypertensive patients, but with relatively few data in patients on hemodialysis (HD). The aim of this 2 A 5-week, open-label, multicenter, randomized cross-over study was to investigate whether valsartan (Val) 80 mg is as effective, safe and well-tolerated as irbesartan (Irb) 150 mg in patients with arterial hypertension on long-term hemodialysis. METHODS: After a wash-out of previous ARBs for 1 week, 67 patients (ITT) on long-term hemodialysis, between 18 and 80 years, with mean supine systolic blood pressure (MSupSBP) >or= 140 mmHg and < 180 mmHg were randomized to either Val 40 or Irb 75 for 1 week with forced titration to Val 80 or Irb 150 for another 4 weeks. After a second wash-out period of 1 week, patients were switched from Val to Irb or vice versa for another 5 weeks (1 week low-dose, 4 weeks target dose). The primary objective was non-inferiority of Val versus Irb on predialytic MSupSBP. Secondary objectives were predialytic MSupDBP, adverse events (AEs), laboratory abnormalities, hypotension during and after dialysis and quality of life. BP values are given as mean A+/- SD. RESULTS: Baseline BP values were 158 A+/- 11 / 78 A+/- 13 mmHg (Val) and 161 A+/- 13 / 83 A+/- 10 mmHg (Irb). The predialytic MSupSBP and MSupDBP after 4 weeks of treatment were similar in both treatment groups (Val 150 A+/- 19 / 79 A+/- 13 mmHg; Irb 151 A+/- 16 / 78 A+/- 14 mmHg). Most of the reported AEs were mild to moderate. The percentage of AEs considered by the investigator to be possibly drug-related was similar between both groups: 15.4% in the valsartan group and 20.4% in the irbesartan group. The most common AEs were nausea, muscle spasms and nasopharyngitis. Eight SAEs occurred, four in each treatment group (all not drug-related), including one death (cardiovascular insufficiency) in the Irb group. Laboratory changes were similar in both groups and not clinically relevant. The number of patients with symptomatic hypotension was similar during (9% each) as well as after dialysis (1.3% each). The quality of life data (SF-36) were comparable for each category. CONCLUSIONS: Valsartan 80 mg is as effective, safe and well tolerated as irbesartan 150 mg in hypertensive patients on chronic hemodialysis.

Protein A-immunoadsorption in chemotherapy associated hemolytic-uremic syndrome.

Circulating IgG-immune complexes (IgG-IC) play a role in the complex etiology of C-HUS. In an ongoing open clinical study protein A immunoadsorption treatment is carried out for patients who developed severe forms of the syndrome after mitomycin-C chemotherapy. So far, successful treatment of 14 out of 19 evaluable patients was possible. A protein A immunoadsorption system was used, allowing processing of large plasma volumes to eliminate IgG and IgG-IC from the patient's plasma.

[Treatment of the hypertensive crisis in general practice and the clinic]. / Behandlung der Hochdruckkrise in Praxis und Klinik.

Patients with a hypertensive crisis should, if possible be treated in hospital. Although such drugs as sodium nitroprusside, diazoxide, dihydralazine, and clonidine have been very useful and effective in the past in the treatment of severe arterial hypertension, they are now being replaced by drugs as nifedipine, urapidil, captopril, and co-dergocrine mesylate, which maintain cerebral and coronary blood flow while effective by lowering blood pressure. Practical recommendations are given for the emergency out-of-hospital treatment of hypertensive crises.

Contrasting renal effects of different antihypertensive agents in hypertensive rats with bilaterally constricted renal arteries.

Systemic and renal effects of the vasodilators dihydralazine and minoxidil were compared with those of the converting-enzyme inhibitor captopril (SQ 14225) and the AII antagonist sarisoleucin (Sar1Ile8-AII) in chronically sodium-depleted, two-kidney, two-clip hypertensive rats. Arterial blood pressure normalized in all experimental groups within 24 hours and remained normal until the end of the experiment. By day 4, plasma concentrations of creatinine and urea in animals treated by captopril or sarisoleucin were significantly higher than those measured after the administration of dihydralazine or minoxidil. Renal tubular lesions were also more frequently observed after the renin-angiotensin system (RAS) was blocked than they were after vasodilatation was induced by direct smooth muscle relaxation. Captopril and sarisoleucin stimulated the RAS more extensively than dihydralazine and minoxidil did. The results indicate that, in the presence of bilateral renal artery stenosis and sodium deprivation, systemic blood pressure normalization after the blockade of the RAS may be accompanied by acute renal failure. This may be explained partially by poststenotic renal hypotension, but it may also reflect a reduction of the GFR because of the blockade of intrarenal actions of AII.

Effects of the converting enzyme inhibitor captopril on blood coagulation and fibrinolysis in man.

Systematic blood coagulation analyses were conducted in 32 severely hypertensive patients treated with the angiotensin converting enzyme inhibitor captopril. Two hours after the first captopril dose, fibrin monomer complexes had already increased. This rise was even more distinct after 26 h and 1 week. Tests after 6 and 12 months of therapy showed a regression of fibrin monomer complexes to pretreatment values. In several patients with a marked increase in fibrin monomer complexes, the partial thromboplastin time (PTT) became shorter and antiplasmin activity increased. The most pronounced increase in fibrin monomer complexes was seen in patients with a rapid and excessive blood pressure reduction. The concentration of fibrin monomer complexes also rose in 15 healthy normotensive subjects, after a single oral dose of captopril (25 mg). Additionally, the PTT was shortened and antiplasmin significantly rose. An inhibition of fibrinolysis by captopril could be demonstrated by the effect on fibrin plates and thrombus weight after streptokinase. Out of 58 patients with severe hypertension and atherosclerosis treated with captopril, 7 patients suffered vascular complications during antihypertensive therapy: myocardial infarction (n = 2), coronary insufficiency (1), cerebral ischemia (1), renal insufficiency (3). These ischemic lesions may be partly explained by the alterations of coagulation and fibrinolysis under captopril therapy.

The role of plasma and renal renin in the rise in blood pressure following unilateral renal artery constriction.

Constriction of the artery to the remaining kidney of control rats uninephrectomized 24 h previously induced a sixfold rise in plasma renin level from 11 +/- 1 to 60 +/- 11 ng AI ml-1 h-1, a 43% decrease of renal cortical renin level, and a 21% rise of mean arterial pressure from 119 +/- 2 to 144 +/- 3 mm Hg. Constriction of the artery to a renin-depleted kidney (with a renin level which was 5% of normal) was not followed by any significant increase in plasma renin level or mean blood pressure. Renin-depleted kidneys were produced by removing the clipped kidney from two-kidney one-clip hypertensive rats, 24 h before the experiment. Such a maneuver induces renin depletion but does not completely normalize blood pressure. When a large dose of frusemide (50 mg/kg i.p.) was injected immediately following removal of the clipped kidney, mean arterial pressure (117 +/- 7 mm Hg) returned to control values 24 h later but again constriction of the remaining renal artery failed to induce a rise in plasma renin level or mean arterial pressure. By 7 days after removal of the clipped kidney, plasma renin level and mean arterial pressure were normal and clipping of the remaining kidney (in spite of the fact that kidney renin level was still low) now produced a wave of renin release and an increase in mean arterial pressure. These results suggest that the initial, rapid increase in mean arterial pressure following unilateral renal artery constriction is dependent on an increase in plasma renin level. Our results from animals with kidneys of varying renin levels suggest the existence of a cortical renin content of about 20% of normal below which the kidney is incapable of responding to renal artery constriction with significant renal release. Complete recovery of the renin (and blood pressure) response to clipping occurred when the renin content had reached about 75% of normal.

The renal effects of clonidine in unanesthetized rats.

Clonidine s.c. (0.01-0.3 mg/kg), in unanesthetized rats, caused an initial rise (+20 mm Hg), followed by a continuous fall of BP and a dose-dependent natriuresis and diuresis for up to 2 h. Glomerular filtration rate (GFR) (CIn) increased during the first 20 min, while effective renal plasma flow (ERPF) (CPAH) remained normal. Subsequently, between 20 and 60 min after injection, ERPF (CPAH) decreased considerably while GFR had reverted to its normal value. In saline-infused rats clonidine diuresis was accompanied by an "inappropriate" positive free water clearance. Pentobarbital anesthesia suppressed the initial BP peak and the diuresis. Phenoxybenzamine (1 mg/kg i.v.) was antinatriuretic in saline diuresis; the effect of phenoxybenzamine + clonidine on diuresis and salt excretion represented the sum of the effects of both drugs, but phenoxybenzamine enhanced the clonidine-induced increase of GFR. Neither haloperidol (1 mg/kg i.v.) nor bulbocapnine (3 mg/kg i.v.) interfered with the renal effects of clonidine. Clonidine s.c. caused hyperglycemia and glucosuria which did not account for the natriuresis. Clonidine thus appears to increase the GFR and "filtration fraction" (FF) by a phenoxybenzamine-insensitive rise of glomerular ultrafiltration, to depress ERPF by alpha-adrenergic afferent vasoconstriction, to induce natriuresis by a tubular action not blocked by phenoxybenzamine and to exert an antivasopressin effect, either by depressing pituitary vasopressin secretion or the renal response to vasopressin.

Effect of chronic clonidine treatment and its abrupt cessation on mean blood pressure of rats with a normal or an elevated blood pressure.

1. Clonidine (6 mg of base/l of water) was given as drinking fluid to normotensive rats or rats with established or early hypertension. 2. Spontaneous hypertensive rats (6 months old: average dose of clonidine, 0.6 mg 24 h-1 kg-1) showed a sustained fall in blood pressure over 3 weeks. 3. The same clonidine solution given for 6 weeks to two-kidney Goldblatt rats with early-stage hypertension (average dose of clonidine: 1 mg 24 h-1 kg-1) or spontaneously hypertensive rats (clonidine dose: 1 mg) induced a fall in mean blood pressure, but no change in normotensive rats. 4. Replacement of clonidine by water induced hypertension and lability which led to death in hypertensive but not in normotensive rats.

Mechanism of blood pressure reduction by teprotide (SQ 20881) in rats.

The mechanism by which the angiotensin converting enzyme inhibitor, teprotide (SQ 20881), lowers blood pressure was assessed in anesthetized normotensive and spontaneously hypertensive (SHR) rats. Teprotide always was administered at a maximally effective dose of 1 mg/kg. In six normal Wistar rats, teprotide lowered blood pressure only after sodium depletion, an effect which was abolished by bilateral nephrectomy. Saralasin infusion (5 microgram/kg/min) into salt-depleted normal rats induced a blood pressure effect similar to that of teprotide. When administered in addition to saralasin infusion, teprotide did not reduce blood pressure further in normal rats or in SHR. When blood pressure of normal rats was raised by angiotensin II infusion (200 ng/kg/min), teprotide did not affect the induced blood pressure increase. In contrast, the pressure rise induced by angiotensin I infusion (230 ng/kg/min) was reversed by saralasin, but again concomitant administration of teprotide did not induce further blood pressure reduction. Thus, under the particular conditions of the present study, teprotide did not appear to exert its hypotensive effect by any mechanism other than inhibition of the renin-angiotensin system. Furthermore, given at a maximally effective dose to the rat, it produced no greater vasodepressor effect than did saralasin.

Renal hypotension in sodium and fluid deprivation: experimental findings in renin-depleted rats.

Arterial hypotension of renal origin occurred as consequence of low plasma renin activity in the presence of sodium and extracellular fluid volume depletion. Secretory insufficiency of the renin-producing juxtaglomerular cells and sodium and volume deprivation, simultaneously, were achieved by removing the "clamped" kidneys in renal hypertensive, sodium- and volume-depleted rats leaving in situ the contralateral kidneys deprived of renin during the preceding period of hypertension. It is suggested that renal hypotension after acute losses of sodium and extracellular fluid may also develop in patients with chronically depressed renin-angiotensin system.

[Protection against acute renal insufficiency by means of forced diuresis in an ischemic rat model]. / Protection contre l'insuffisance rénale aiguë par une diurèse forcée dans un modèle ischémique chez le rat.

Renal ischemia of 90 min duration provokes initial oliguria and hyperazotemia; however, in rats with high diuresis, with or without renal renin depletion, protection against acute renal failure is observed in this model. The protection is directly proportional to the diuresis.