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The hemodynamic effects of prostacyclin (PGI2) were studied in seven patients with severe or malignant hypertension. Blood pressure, cardiac output (Cardio-Green dilution method) and total blood volume (131I- Albumin dilution method) were measured before and during a PGI2 infusion, the effective dose ranging from 10 to 20 ng/kg/min. Cardiac index (CI) rose from 2.8 to 3.9 l/min/m2 and heart rate (HR) from 75 to 94 beats/min (P < 0.01). Mean blood pressure decreased from 154 to 120 mm Hg (P < 0.001) and total peripheral resistance from 4650 to 2540 dynes s cm−5 (P < 0.001). The ratio: central blood volume/total blood volume increased from 0.21 to 0.26 (P < 0.001). The decrease in blood pressure was related to the dose of prostacyclin (P < 0.001), but the vasodilatation was dose-dependent only from 5 to 12–5 ng/kg/min; for a higher dose, the decrease in blood pressure was related to the decrease in cardiac output as the heart rate was reduced.The results confirmed that PGI2 produces a potent vasodilatation of the arterial system; the decrease in blood pressure was limited by an increase in cardiac index mainly related to the tachycardia induced by prostacyclin; significant central translocation of blood suggested that PGI2 did not produce dilatation of the capacitance vessels. At low doses, the sympathetic nervous system was greatly stimulated by PGI2; at a higher dose, the vagal stimulation was predominant, inducing bradycardia and a fall in blood pressure. [ABSTRACT FROM PUBLISHER]

Background & Aims: In Crohn's disease, cases of interstitial nephritis with renal failure have been reported in connection with the use of mesalamine., Methods: We observed 4 patients with severe interstitial nephritis proven by examination of kidney biopsy specimens. Renal failure was discovered before or simultaneously with the diagnosis of Crohn's disease, and patients were not treated with mesalamine. Impairment of renal function progressed to end-stage renal failure in 3 of the 4 patients., Results: Our results show that the kidney can be an extraintestinal target of Crohn's disease., Conclusions: Several unanswered questions remain concerning the frequency of interstitial nephritis in patients with Crohn's disease, as well as the exact role of mesalamine in the development of chronic interstitial nephritis.

Renal failure secondary to CDDP is due to acute tubular necrosis and is usually reversible. We report 4 cases of definitive renal failure secondary to administration of cisplatin (CDDP). Three women and one man, mean age 40 +/- 8 years (24 to 64 years), at onset of dialysis are reported. They had received 1 to 4 courses of CDDP for an endometrial carcinoma (n = 2), a breast carcinoma or a thymoma. The mean total dose of CDDP was 447 +/- 169 mg (160 to 900 mg). There was no additional nephrotoxic drug. Before treatment serum creatinine concentration was normal (77 +/- 7 mumol per liter) in all patients. In 2 cases dehydration (due to vomiting and use of mannitol) occurred during CDDP treatment. One patient was treated 30 days after a nephrectomy. At the onset of dialysis, renal ultrasound was normal. In 3 cases dialysis was necessary within 15 days following chemotherapy. In one case renal function deteriorated progressively to end stage renal failure 12 months after CDDP treatment. Dialysis was performed in 3 cases by hemodialysis and in one patient by peritoneal dialysis. All patients remained more than 6 months on dialysis. Three patients died from their cancer. One patient, being considered cured from his thymoma, is currently being evaluated for a kidney transplantation. Our observations outline the potential severity of CDDP nephrotoxicity. Systemic hydration with serial serum creatinine measurements are mandatory during and after CDDP administration these patients.

The acute renal effects of intravenous tertatolol were studied in eight patients with moderate essential hypertension: the study included a 100 mmol/day sodium intake during 3 days. Then, tertatolol was infused after a water load during 2 consecutive periods of 30 min (priming dose followed by constant infusion) in order to obtain plasma concentrations of tertatolol at 2 different levels: 10 ng/ml, then 40 ng/ml successively; the measurements were obtained at 15, 30, 45 and 60 min. The renal plasma flow (RPF) and the glomerular filtration rate (GFR) were calculated from the 131I-Hippuran clearance and the 125I-Iothalamate clearance respectively; a bladder catheter allowed a precise urine collection. The results indicate that intravenous tertatolol, at low dose, induced a marked and early renal vasodilatation; higher dose of tertatolol attenuated the vasodilator response, probably because of a decrease in cardiac output (suggested by the decrease in heart rate); thus, the systemic effects would hide the direct renal hemodynamic effects of tertatolol. Natriuresis and kaliuresis were unchanged by intravenous tertatolol.

Fifty hypertensive patients were given a beta-blocker, acebutolol, alone or in association with other hypotensive drugs, in an open therapeutic trial lasting for a year. The results of treatment were considered to be good or moderate in 74 p.cent of the patients. Treatment failures were recorded in 26 p.cent. The mean dosage of acebutolol was 10 mg/kg (maximum 22 mg/kg) and the drug was very well tolerated. Hypertension with an increased cardiac index and reno-vascular hypertension with increased plasma renin activity are good indications for acebutolol.

140 cases of malignant hypertension were diagnosed in our clinic from January 1966 to December 1982. On admission the mean blood pressure was 183 +/- 17 mm Hg, and all patients had grade III to IV retinopathy according to the Keith and Wagener classification; 84% of the patients had renal failure (10% of acute origin). 43% of the patients presented with clinical signs of left heart failure. Hypertension was associated with various renal diseases in 48%, was essential in 41%, and renovascular lesions were found in 9% of the cases. Headaches, asthenia and visual disorders were the 3 main symptoms of malignant hypertension, as classically described. Severe cerebral damage (including all the neurological manifestations present on admission) was found in 27% of the patients. Among the 122 patients available to follow-up, half died during the study period. The survival rate, calculated on a 5-year basis, has doubled compared with a similar patient population 17 years ago, increasing from 35% (period 1966 to 1970) to 72% (period 1977-1982). This remarkable achievement in survival rate is due to more intensive research and therapeutic progress (including, more recently, extrarenal epuration) reaching an increasingly large hypertensive population.

The pharmacokinetics of prazosin were studied in 10 patients (7 male and 3 female, Group I) with permanent hypertension and chronic renal failure (serum creatinine 40,5 +/- 5,9 mg/l) and in 10 normal subjects (10 male, Group II). Each patient received a single oral dose of 2 mg of prazosin; serum levels were studied at regular intervals over a ten hour period by spectrofluorometry Clinostatic blood pressure was measured with a mercury manometer in the patients in Group I. The rate of absorption of prazosin was identical in the two groups (t max: I,3 +/- 0,2 h and I,6 +/- 0,4 h). Maximal serum concentrations were significantly higher in Group I (33,5 +/- 3,7 microgram/1 compared to 22,0 +/- 2.5 microgram/l, p less than 0,02) as was the surface under the serum concentration curve plotted against time (206,I +/- 31.I microgram.h.l-1 compared to 99,9 +/- 12,3 microgram.h.l-1, p less than 0,01). Prazosin induced a significant fall in systolic and diastolic blood pressure (-19% and -23% respectively, p less than 0.001) in Group I, 90 minutes after administration, associated with a moderate rise in heart rate (+16%, p less than 0.01). The variation of blood pressure induced by prazosin correlated closely with its serum concentration (p less than 0.001). These results suggest that the bioavailability of prazosin is significantly higher in chronic renal failure and that a reduction of the daily dose should be envisaged in these patients on long-term therapy.

A controlled multicentre trial was organised to compare the effects of 20 mg Nifedipine tablets (N) and 2,5 mg Indapamide tablets (I) during a 4 months' treatment period after a placebo period, in 59 patients with moderate essential hypertension (n = 59). The results of blood pressure measurements of 18 patients treated by nifedipine (1 tablet twice daily) and 22 patients treated by indapamide (1 tablet every morning) were compared. The systolic blood pressure, after 10 minutes recumbency, fell from 165 +/- 10 mmHg to 148 +/- 13 mmHg (p less than 0.01), and the diastolic pressure from 104 +/- 6 mmHg to 86 +/- 7 mmHg (p less than 0.01) in the patients treated with nifedipine. In the indapamide group, the SBP fell from 164 +/- 13 mmHg to 152 +/- 15 mmHg (p less than 0.01) and the DBP from 100 +/- 4 mmHg to 87 +/- 6 mmHg (p less than 0.01). There were no significant changes of heart rate with either drug; plasma creatinine, potassium and uric acid concentrations were also unchanged. There was a higher incidence of headaches and tiredness in the nifedipine group, whilst patients treated with indapamide complained more often of muscular cramps. Flushing was observed in nearly a quarter of the patients in both groups. These results confirm that both nifedipine and indapamide induce significant and persistant falls in systolic and diastolic blood pressure. Although the fall was greater with nifedipine than with indapamide, the difference was not statistically significant. The tolerance was satisfactory in both groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal hemodynamics and natriuresis were studied in 10 hypertensive patients without renal failure, 2 and 4 h after oral intake of 30 mg nicardipine; then, nicardipine was given at a dose of 30 mg three times a day and the hemodynamic study was repeated on the 6th day (2 h after the morning dose). The first dose of nicardipine produced an increase in renal blood flow (from 888 +/- 45 to 999 +/- 59 ml/min 1.73 m2, p less than 0.01) and a decrease in renal vascular resistances (from 0.16 +/- 0.01 to 0.12 +/- 0.01 arbitrary unit, p less than 0.05). Glomerular filtration rate did not change and the decrease in filtration fraction was not significant. Sodium excretion increased markedly during the first 2 h (from 0.17 +/- 0.04 to 0.29 +/- 0.06 mmol/min, p less than 0.05). On the 6th day renal vascular resistances and filtration fraction remained lowered whereas glomerular filtration rate was unchanged. Nicardipine did not produce any significant alteration in plasma renin activity and plasma aldosterone after acute or chronic administration. These results confirm the potent renal vasodilatory effect of nicardipine; glomerular filtration rate was not significantly altered whereas renal blood flow and filtration fraction returned to normal levels. An early and transient natriuretic effect was observed after the first dose of nicardipine, and body weight showed a significant decrease during the study indicating that no sodium retention was induced by nicardipine.

Hemodialysis has been reported to produce a decrease in cardiac output partially related to a peripheral relocation of blood volume. In order to further evaluate this hypothesis, the hemodynamic effects of dihydroergotamine (DHE), a veino-constrictor drug, were investigated in 5 patients undergoing hemodialysis. Body weight, total blood volume, arterial blood pressure, cardiac output and heart rate were obtained before (period A) and immediately after hemodialysis: before (period B) and after an acute infusion of DHE (period C); studies were performed in supine then in tilted position. During period B, cardiac index decreased by 27% (p less than 0.05) and stroke index by 35% (p less than 0.02). Acute infusion of DHE produced a significant increase in cardiac index (+ 18%, p less than 0.05), stroke index (+ 28%, p less than 0.05) and blood pressure (+ 20%, p less than 0.05). These results indicate that the hemodynamic alterations induced by hemodialysis may be partially reversed by contraction of the capacitance system following DHE infusion.

Renal haemodynamics and natriuresis were studied before and 6 h after oral intake of perindopril (8 mg) in eight hypertensive patients without renal failure. The patients were then treated with perindopril (8 mg per day) and renal haemodynamics were measured on the fifth day, 6 h after the morning intake. Sodium intake was controlled during the study (100 mmol sodium per day). Renal blood flow and the glomerular filtration rate were measured by the clearance method using 131I-hippuran and 125I-iothalamate, respectively. Mean blood pressure decreased from 135 to 110 after 6 h, and was 118 mmHg on the fifth day (P less than 0.001, respectively). Renal vascular resistance decreased significantly after acute drug intake from 0.19 to 0.15 arbitrary units (P less than 0.001) and on the fifth day to 0.16 arbitrary units (P less than 0.001). Renal blood flow rose from 708 to 723 after 6 h, and to 750 ml/min per 1.73 m2 on the fifth day but the change was no significant. There was no alteration in the glomerular filtration rate so that the filtration fraction decreased from 0.27 to 0.26 (after 6 h), and to 0.25 on the fifth day (P less than 0.02). Natriuresis increased after the first intake between the first and tenth hours. On the fifth day, maximum natriuresis was observed between the fourth and sixth hours. Perindopril caused strong renal vasodilation after the first intake and during the following days, with no change in the glomerular filtration rate. There was a significant decrease in the filtration fraction, indicating efferent, as well as afferent, arteriolar vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficiency and the variety of drugs used in the treatment of arterial hypertension demand that the various disorders responsible for the blood pressure increase be well individualized. The study of the haemodynamic and hormonal factors and of their interelations in the patients provides interesting informations which make it possible to classify the hypertensive subjects according to physiopathological criteria. Starting from these data, it is possible to consider a rational treatment by selecting the drugs acting specifically on the anomalies to be corrected.

Beta blockade was instituted in 10 patients with renovascular hypertension due to renal artery stenosis or thrombosis. The treatment was very effective in unilateral stenosis with a normal contralateral kidney (2 kidney Goldblatt) and in fibromuscular dystrophy of the renal artery. On the other hand many failures were observed in hypertension with a single kidney (1 kidney Goldblatt) and in renovascular hypertension with complex lesions or associated renal failure. Although a clear relationship was often observed between the increased plasma renin activity and the antihypertensive effect of beta blockade, this association was sometimes completely erroneous. Beta blockade, which is easy to perform, should be tried out systematically in renovascular hypertension, but, when no result is observed, this therapeutic test should not exclude surgical management thereafter.

A 42 year woman presented with malignant hypertension, anuria and hemolytic anemia with schistocytosis. The diagnosis of thrombotic microangiopathy was confirmed by early renal biopsy. Purely symptomatic treatment (peritoneal dialysis and hypotensive drugs) was supplemented by administration of heparin and Dipyridamole. Gastro-intestinal bleeding prevented early thrombolytic therapy. Microangiopathic anemia rapidly disappeared but anuria persisted. Three months later a second renal biopsy showed persistence of active lesions and absence of irreversible parenchymal damage. Streptokinase treatment was then instituted and followed by a rapid return of urinary output. Hemodialysis was stopped and renal function continued to improve over the following months. Two years later the patient remains well despite persistence of hypertension difficult to control. Creatinine clearance is stable at 20 ml/min. This observation suggests that late thrombolytic therapy may be effective in patients with thrombotic microangiopathy when histological findings do not indicate extensive irreversible lesions.

In a controlled double-blind study the effect of muzolimine (20 mg o.d.) and acebutolol (400 mg o.d.) were investigated in outpatients suffering from moderate essential hypertension. After a three week placebo run-in period, 49 patients were recruited and followed by a cooperative group of general practitioners over a period of 3 months. Blood pressure decreased to the same extent in both groups. With regard to clinical and biological tolerance, no differences appeared between the two drugs.

Two patients developed anuria associated with tight stenosis, though not complete obstruction, of the renal arteries. This rare and little known accident is found in atheromatous patients with severe arterial hypertension of renovascular origin. It usually occurs when blood pressure falls under the influence of a precipitating factor. Diagnosis rests on angiography. Diuresis is resumed immediately after surgical revascularization. The operation must be performed in every case, even after a long delay, since the kidneys remain viable for a long time due to the development of an extensive collateral circulation. Such anurias are particularly severe in patients with poor underlying condition and when vascular lesions are diffuse.

Renal hemodynamics and natriuresis were studied in 9 hypertensive patients without renal failure, 2 hours and 4 hours after oral intake of Nicardipine 30 mg; sodium intake was kept constant during the study (100 mmol per day). Then, Nicardipine was given at a dose of 30 mg three times a day and the hemodynamic study was repeated on the 6th day (2 hours after the morning dose). Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by the clearance methods using 131I-hippuran and 125I-iothalamate respectively. Results are as follows: (Table: see text). These results confirm the potent renal vasodilatory effect of Nicardipine; GFR was not significantly altered while RBF and FF returned to normal levels. An early and transient natriuretic effect was observed after the first dose of Nicardipine and body weight showed a significant decrease during the study indicating that no sodium retention was induced by Nicardipine.

The authors describe a simple method of fluorimetric estimation of atenolol, applicable to blood and urine, sufficiently sensitive to permit a pharmacokinetic study. After administration of a dose of 200 mg by the oral route to hypertensive subjects, one may observe a maximal plasma concentration 3 hours after the dose average value 3.91 +/- 0.71 mumol/l (1.04 +/- 0.19 mg/l). The apparent half life of elimination of phase beta is 14.1 +/- 4.9 h, values comparable with those calculated from urinary data 14.6 +/- 2.0 h. The renal clearance was 140 +/- 32 ml/min; 54 +/- 14% of the administered dose are excreted in the urine. After administration by the venous route, urinary excretion represents 96% of the dose administered.

The orally active angiotensin converting enzyme inhibitor SQ 14225 (captopril) was administered to 14 hypertensive patients resistant to conventional therapy. A marked antihypertensive effect was observed; all the patients were responders and blood pressure decreased by more than 20% in 13 out of them. Subjective tolerance was very good. Untoward effects of an immuno-allergic type have been noticed in 30% of these cases but disappeared in all instances when daily doses of the drug had been reduced, allowing maintenance of the treatment. Plasma renin activity increased during captopril administration but no relationship appeared between pretreatment plasma renin activity and the extent of blood pressure response to the drug. The use of captopril must be considered in severe and resistant hypertension but careful monitoring of this treatment is needed.

Numerous studies have recently been devoted to the effects of prostaglandins on blood vessels. Prostacyclin (PGI2) produces relaxation of vascular smooth muscles, thereby contributing, with other vasoactive substances, to the regulation of general and local haemodynamics. Moreover, it would appear that the effects of some risk factors in atherosclerosis are mediated, at least partly, by changes in prostaglandin production. The potent vasodilator action of prostacyclin has been confirmed in man and has been investigated in some pathological conditions, such as lower limb arteriopathy, malignant arterial hypertension and coronary artery disease. The vascular effects of many therapeutic drugs are now known to be associated with their action on the biosynthesis of prostaglandins. Further studies are required to determine the role of prostaglandins, especially prostacyclin, in the pathophysiology, prevention and treatment of vascular diseases.

The beta-adrenergic stimulation test with nitroglycerin, described by Fitzgerald, was used to monitor antihypertensive treatment with the beta-blocker acebutolol in 30 hypertensive patients. The nitroglycerin-induced tachycardia was reduced by acebutolol and this allowed the degree of beta-blockage to be estimated. It would also be possible, by tests performed before treatment, to select hypotensive patients who could be highly responsive to beta-adrenergic blockers, for whom there are the best prospects of success.

The acute effects of Metoprolol on blood pressure and heart rate were studied with reference to the plasma level of the betablocker in 10 patients (6 male and 4 female) with permanent moderate uncomplicated hypertension. Each patient was given a single oral dose of 200 mg Metoprolol: blood samples were taken over a 12 hour period at given times for Metoprolol estimation. The blood pressure was measured with a mercury manometer; heart rate was measured lying and during a stress test (glyceryl trinitrate). The antihypertensive effect of Metoprolol was significant from the 4th hour; at the 8th hour the systolic pressure was reduced by 15% and the diastolic pressure by 17% (p less than 0.001). The blood pressure then rose progressively. The heart rate in the recumbent position fell 10 to 15% during the study. The heart rate during the trinitrin test varied linearly with time (r = 0.991, p less than 0.001). The variation in systolic and diastolic blood pressure did not correlate with the plasma Metoprolol level (r = 0.03, and 0.19); no correlation was found between the fall in lying heart rate and the plasma betablocker level. On the other hand, the trinitrin heart rate (at the end of the test) correlated negatively with the logarithm of the plasma Metoprolol (n = 56, r = 0.688, p less than 0.001). These results confirm that the antihypertensive effect of Metoprolol is not directly related to the plasma level of the betablocker. On the other hand, the betablocker effect assessed by the trinitrin test, correlated with the plasma Metoprolol level. This relationship is similar to those previously observed with other betablockers; atenolol and oxprenolol.

In a 66-year-old female patient with a past history of tuberculosis, prolonged fever at 38 degrees C accompanied by a strong increase in ESR ultimately led to the diagnosis of renal cyst. Biopsies of renal tissue and of lymph nodes taken during surgery showed renal granulomatosis without caseum. Despite negative bacterial findings and anergy to tuberculin, an anti-tuberculous treatment was administered and the patient recovered.