Effects of residual renal function in haemodialysis patients.

Thirty-six haemodialysis patients on treatment for more than six months were studied for residual renal function (RRF). Twenty patients were anuric. The remaining 16 patients with RRF excreted 35-1600 ml urine/day with creatinine clearance ranging 0.17-6.95 ml/min. Patients with RRF were on dialysis therapy for shorter periods than those with anuria (25.5 +/- 18.5 vs. 101.7 +/- 14.2 months, p = 0.001). Twelve out of 20 anuric patients had had previous renal transplantation, whereas none of those with RRF had been transplanted (p = 0.0006). Interdialytic weight gain, serum potassium and phosphate were lower in patients with RRF. Serum phosphate and uric acid were correlated with their respective urinary excretion rates (p = 0.013 and 0.005, respectively), but interdialytic weight gain could not be correlated with urinary output. Creatinine clearance significantly correlated with urinary excretion of potassium, sodium, phosphate and uric acid. In this series of patients a previous unsuccessful renal transplantation was an important factor in the loss of RRF. The presence of RRF contributed to the regulation of the blood levels of phosphate and the excretion rate of potassium, sodium and uric acid.

Causes of death in patients with end-stage renal disease treated by dialysis in a center in Israel.

The causes of death in 84 end-stage renal failure patients, treated with dialysis, who died during a 66-month period were reviewed retrospectively. Cardiac and infectious diseases were the main cause of death (27% each). These two constituted 44% of causes of death in hemodialysis and 75% in continuous ambulatory peritoneal dialysis patients. Malignant disease (7%) and hyperkalemia (5%) were responsible for death only in hemodialysis patients. Patients who died following hyperkalemia were younger than 50 years old. Patients who died from malignant disease were dialyzed for more than 3 years. In summary, the mode of dialysis therapy, age at start of therapy, time on dialysis, and previous cardiac disease may play a role in determining the causes of death in dialysis patients.

Overdiagnosis of hypertension in the elderly.

Seventeen untreated and 36 treated hypertensives aged 65 years or more were referred to our clinic because of repeated values of systolic blood pressure > or = 160 mmHg and diastolic blood pressure > or = 95 mmHg. All 53 patients underwent 24h blood pressure monitoring during their customary daily activities. Eleven (65%) untreated and 23 (64%) treated patients were normotensive during their daily activities. Thus, ambulatory BP monitoring appears to be useful in the elderly hypertensive patients in detecting those whose BP is elevated only in the clinic. Ambulatory BP obtained outside the clinic may be useful in diagnostic and therapeutic decision-making in the elderly population.

Evaluation of clinic blood pressure measurements: assessment by daytime ambulatory blood pressure monitoring.

The clinical value of a set of three clinical blood pressure measurements as a predictor of daytime ambulatory hypertension was assessed by performing a set of clinical blood pressure measurements in 171 borderline hypertensives, and calculating their diagnostic accuracy, sensitivity, specificity and predictive value compared to the daytime average of ambulatory blood pressure monitoring. Diagnostic accuracy was 0.63, sensitivity was 81% and specificity was 47%. Positive and negative predictive values were 0.60 and 0.74, respectively. The set of clinical measurements detected 81% of hypertensives, but 36% of the population screened was mislabelled--48 patients (28%) as hypertensive and 15 (8%) as normotensive. A single set of clinic blood pressure measurements is quite sensitive for diagnosing daytime hypertension, although its accuracy, specificity and predictive value are low. The subpopulation incorrectly labelled as normotensive may have a different prognosis and merits further prospective study.

Cyclosporin A treatment enhances angiotensin converting enzyme activity in lung and serum of rats.

Nephrotoxicity and arterial hypertension are the most common side effects of treatment with cyclosporin A (CSA). Its effects on angiotensin converting enzyme (ACE) activity in the renal cortex, lung and serum of nephrotoxic rats have been investigated. Wistar rats were treated with CSA (20 mg kg-1 day-1 i.p.) or vehicle (olive oil containing 10% ethanol) for 14 days. On day 15, the rats were killed and ACE activity determined by radiometric assay using [3H]hippuryl-glycyl-glycine as substrate. CSA treatment resulted in a decrease in creatinine clearance, urine flow and body weight and a significant increase in serum and lung ACE activities (436 +/- 9 vs 391 +/- 7 nmol mL-1 min-1, P less than 0.001; 184 +/- 8 vs 142 +/- 10 nmol mg-1 min-1 P less than 0.01, respectively). In contrast, renal cortex ACE activity was reduced in the CSA-treated rats (0.35 +/- 0.02 vs 0.51 +/- 0.02 nmol mg-1 min-1, P less than 0.01). ACE activities in the renal cortex and serum were not affected by treatment with gentamicin (80 mg kg-1 day-1) for 11 days. In rats treated simultaneously with CSA and captopril (50 mg kg-1 day-1) ACE activity in the serum, lung and renal cortex was inhibited by 95, 93 and 92%, respectively. These changes in ACE activity were associated with a decreased systolic blood pressure in the rats receiving CSA and captopril. Therefore, ACE activity in the serum and lung of CSA-treated rats was increased, while its activity in the renal cortex was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy and tolerability of nifedipine (NIF) and nisoldipine (NIS) both alone and combined with a beta-blocker in patients with essential hypertension: a multicenter, parallel-group study.

We have assessed the efficacy and tolerance of Nifedipine twice daily and Nisoldipine once daily, both alone and in combination with a beta-blocker in 171 essential hypertensives in a randomized parallel comparison fashion. Both drugs were equally effective in lowering blood pressure: 72.6% of the subjects on Nisoldipine and 80.5% of those on Nifedipine reached a supine diastolic blood pressure less than or equal to 90 mmHg. Spontaneously reported side effects were frequent but no biochemical, hematological or electrocardiographic abnormalities were detected.

The renin-angiotensin system, the kidney, and hypertension.

The most important component of the renal-body fluid feedback is renal pressure natriuresis which through sodium and water excretion stabilizes arterial pressure. The chronic effects of angiotensin II in regulating the pressure natriuresis was studied in dogs by the Guyton school. Renal perfusion was either permitted to increase or was maintained constant with a servo-controlled occluder placed on the abdominal aorta just above the kidneys. When the renal pressure was allowed to increase, sodium excretion was reduced for a day and after 4-5 days there was little net change in sodium balance and arterial pressure stabilized at about 30 mm Hg above control. In the servo-controlled renal perfusion, escape from sodium retention did not occur, arterial pressure continued to rise, and pulmonary edema developed. Angiotensin II, by its hemodynamic and tubular effects, modulates renal sodium and water excretion and has an important role in blood pressure regulation. Antibodies to renin and converting enzyme inhibitors showed a causal relationship between the stimulated renin-angiotensin system and the antihypertensive effect of these agents. Chronic effects are observed in hypertensive patients with normal or even low plasma renin activity. This suggests that local angiotensin concentrations in the vascular and renin tissues may be more important in determining sodium and water excretion. Our knowledge of the renin-angiotensin system in regulating blood pressure made the usage of converting enzyme inhibitors a logical and efficacious modality in the therapy of hypertension. In a multicenter study of 202 hypertensive patients, the efficacy and safety of ramipril and enalapril was studied.(ABSTRACT TRUNCATED AT 250 WORDS)

A multi-centre comparative study between ramipril and enalapril in patients with mild to moderate essential hypertension.

A multi-centre, randomized, double-blind, parallel group study was undertaken in order to assess efficacy and tolerability of ramipril as compared to enalapril in mild to moderate hypertension. A 4-week placebo run-in period was followed by 4 weeks of treatment with active medication (5 mg ramipril or 10 mg enalapril in a single morning dose). In patients not responding to this dosage regimen at the end of a 4-week treatment period, the dose was doubled. After 8 weeks of active medication, 3 mg daily of the diuretic piretanide was added to the treatment of patients not responding to the doubled dose. A total of 202 patients was admitted in the placebo phase from which 174 patients who had evaluable data at the end of the study were included in the efficacy analysis. Based on the definition of a 'responder' as a patient who achieved a supine diastolic blood pressure of 90 mmHg or less, 40% of those on 5 mg ramipril achieved this level within 4 weeks; in the enalapril group, the corresponding figure was 36.6%. By the end of 12 weeks of active treatment, a total of 55% of the ramipril group had responded to a daily dose of 5 to 10 mg ramipril. An additional 18% responded when 3 mg piretanide was added to the regimen. In the enalapril group, 59% responded to 10 to 20 mg enalapril. A further 17% responded to addition of piretanide to 20 mg enalapril. A total of 19 patients developed 29 adverse drug events while receiving ramipril, alone and in combination with piretanide. In the enalapril group, 24 patients developed 36 adverse events during enalapril monotherapy and combination treatment. It is concluded that ramipril and enalapril in a ratio of 1:2 have comparable antihypertensive efficacy in mild to moderate hypertension but the number of adverse reactions was slightly higher with enalapril in this study.

Effects of beta-adrenergic blockade on the arterial vasculature in essential hypertension.

The effect of beta-blockade was studied in 3 different kinds of human hypertension: borderline, sustained and isolated systolic hypertension. Young patients with borderline hypertension had a similar decrease in cardiac output with both nonselective and selective beta-blockade. Only nonselective beta-blockade decreased brachial artery blood flow and increased forearm vascular resistance. In patients with sustained essential hypertension, chronic administration of 2 nonselective beta-blockers, propranolol and pindolol, caused a similar significant decrease in blood pressure with different effects on forearm circulation. Pindolol produced a significant vasodilation of both large and small arteries of the forearm while propranolol did not. In patients with isolated systolic hypertension, short-term beta-adrenergic blockade with propranolol had different effects according to age. In younger patients, propranolol significantly decreased systolic pressure with a concomitant increase in rapid ventricular ejection. In older patients, a lack of systolic pressure reduction was observed with an increase in total peripheral resistance and a decrease in systemic arterial compliance. The results suggested that beta-adrenergic blockade in hypertension may affect blood vessels with different effects, according to age, to the characteristics of hypertension and to the specific properties of the beta-blocking agent. The vascular effects involve not only resistive vessels but also large arteries.

Ketanserin and alpha 1-adrenergic antagonism in humans.

Ketanserin has been shown to antagonise both alpha 1-adrenergic (alpha 1) and 5-HT2-serotonergic (5-HT2) receptors in animal experiments but the findings in humans have been conflicting. Its mode of action in reducing blood pressure is unclear. We have studied, therefore, the effects of ketanserin 40 mg b.i.d. given orally for 4 days to seven normal volunteers on blood pressure, heart rate, and tests of baroreflex function, including infusion of the alpha 1-adrenergic agonist, phenylephrine. Ketanserin caused a small reduction in both lying and standing blood pressure after 4 days but with no change in heart rate; no subject had a severe fall in pressure after the first dose. The 30:15 and Valsalva manoeuvre ratios were decreased slightly. The dose-response curve of blood pressure against rate of phenylephrine infusion was shifted to the right in keeping with alpha 1-adrenergic antagonism; the degree of shift was small compared with that after prazosin. The relationship between change in blood pressure and heart rate during phenylephrine infusion was not affected by ketanserin. Ketanserin may act as an alpha 1-adrenergic antagonist. The development of more selective agents to antagonise 5-HT2-serotonergic receptors should clarify the role of this aspect of the drug's action in reducing blood pressure.

Pressor effects of brief and prolonged infusions of epinephrine in the conscious rat.

Plasma epinephrine may be increased in some patients with essential hypertension, and prolonged infusion of this catecholamine has been claimed to raise blood pressure. The objectives of our experiments were to determine whether continuous intravenous infusion of epinephrine raised blood pressure in a rat preparation known to respond in this way to angiotensin II in low dose and, if so, the plasma concentration of epinephrine required to raise pressure in comparison to the physiological range of plasma catecholamine concentration in the rat. Intravenous infusion of epinephrine at a rate of 400 ng X kg-1. min-1 or less for 30 min into Wistar rats did not increase mean arterial pressure (MAP); pressure did rise when the rate was increased to 800 ng X kg-1. min-1. However, when rats were given epinephrine at 400 ng X kg-1. min-1 for 4 days with continuous blood pressure recording, average MAP showed a progressive rise on successive days of infusion, reaching a maximum increase of 12 mmHg on the 4th and final day of infusion (P less than 0.02). Blood pressure did not change significantly during epinephrine infusion at 10 and 70 ng X kg-1. min-1. Plasma epinephrine was raised more than 13 times basal at the highest rate of infusion. In comparison, blood pressure and catecholamine concentrations increased only slightly although significantly during a period of restraint. We confirm the existence of a slowly developing pressor effect of epinephrine, but it is small and requires a large sustained increase of plasma epinephrine for its development.

Enalapril (MK421) and its lysine analogue (MK521): a comparison of acute and chronic effects on blood pressure, renin-angiotensin system and sodium excretion in normal man.

The immediate and long-term effects of enalapril (MK421) and its lysine analogue (MK521) in once-daily dosage, were compared in a study of 12 normal subjects. Both compounds lowered blood pressure equally throughout 24 h without causing tachycardia. The biochemical changes with MK521 were more sustained than with MK421, but this did not affect the magnitude of blood pressure reduction. Twenty-four hours after the previous dose, with both active drugs, plasma renin concentration was significantly higher on day 8 than on day 1, though angiotensin I did not increase in proportion; this probably reflects a fall in renin-substrate with prolonged converting enzyme inhibition. There was an early natriuresis with each compound but this effect was no longer apparent after 8 days of continuous therapy. Both MK421 and MK521 were well tolerated with no serious side effects.

Effect of the 5-hydroxytryptamine type 2 receptor antagonist, ketanserin, on blood pressure, the renin-angiotensin system and sympatho-adrenal function in patients with essential hypertension.

Ketanserin, a 5-HT type 2 receptor antagonist, was administered intravenously to nine patients with essential hypertension in a double-blind placebo controlled study to investigate the drug's effects on blood pressure, heart rate, the renin-angiotensin system and sympatho-adrenal function. Average blood-pressure for the group prior to injection of the drug was 150 +/- 7/94 +/- 4 (s.e. mean) mm Hg and decreased significantly (P less than 0.01) to 137 +/- 8/88 +/- 5 mm Hg during the 2 h after injection; heart rate increased immediately after injection of ketanserin, reaching a maximum of 81 +/- 4 beats/min. After drug administration systolic and diastolic blood pressure decreased on tilting, but the heart rate response was not different from that with placebo. Ketanserin did not affect the blood pressure response to graded infusion of the alpha 1-adrenoceptor agonist phenylephrine. Plasma active renin, angiotensin II and aldosterone concentrations increased slightly but not significantly after the drug; plasma noradrenaline increased transiently. 5-HT may be important in the maintenance of blood pressure but alternative mechanisms for the action of ketanserin in reducing blood pressure require investigation.

The effect of a 5-HT antagonist, ketanserin, on blood pressure, the renin-angiotensin system and sympathoadrenal function in normal man.

The role of endogenous 5-hydroxytryptamine (5-HT) in the control of blood pressure, the renin-angiotensin system and sympatho-adrenal function was investigated in normal man. Ketanserin (a specific 5-HT2 antagonist) administered intravenously caused a small decrease in blood pressure in salt-depleted recumbent subjects. A more marked postural fall in pressure occurred in both sodium-depleted and repleted normal subjects. Plasma active renin concentration and angiotensin II increased after administration of ketanserin, but plasma aldosterone, cortisol and noradrenaline were unchanged. 5-HT may be important in the control of blood pressure in man and specific 5-HT2 receptor antagonists could be a useful new class of antihypertensive agents.