Cyclosporine A-related proximal tubular dysfunction: impaired handling of uric acid.
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Azathioprine↗
Biomedical subjects
G J Wenting
Publications and source records attributed to G J Wenting.
Impaired fractional excretion of lithium: a very early marker of cyclosporine nephrotoxicity.
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Cyclosporins↗
Alterations in lipid and carbohydrate metabolism attributable to cyclosporin A in renal transplant recipients.
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Carbohydrate Metabolism↗
Mononuclear subsets during cytomegalovirus disease in renal transplant recipients treated with cyclosporine and rabbit antithymocyte globulin.
The effect of cytomegalovirus (CMV) disease on mononuclear subpopulations of 49 renal transplant recipients treated with cyclosporine and prednisone are reported. Clinical overt CMV infection developed in 8/21 patients treated for rejection with rabbit antithymocyte globulin. They all showed true inversions of the T helper/T suppressor-cytotoxic (Th/Ts-c) ratio. A reduction of T helper cells and increase in T suppressor-cytotoxic cells preceded clinical symptoms of CMV disease by one week. None of the 26 patients without RATG anti-rejection treatment developed CMV disease and in only three of them an inversion of Th/Ts-c ratio was found.
Antilymphocyte Serum↗
Impairment of the immune response to influenza vaccination in renal transplant recipients by cyclosporine, but not azathioprine.
Influenza vaccination has been strongly recommended for immunosuppressed renal transplant recipients. However, immunosuppression may lead to impaired antibody responses. We studied the antibody response to an inactivated trivalent influenza vaccine in 59 renal transplant recipients with life-sustaining kidney function: 21 were on cyclosporine and prednisone, 38 on azathioprine and prednisone. Healthy volunteers (n = 29) and patients on hemodialysis (n = 28) served as controls. Despite comparable renal allograft function, cyclosporine-treated patients had a significantly lower immune response against influenza A viruses than azathioprine-treated patients, whether mean antibody levels, fourfold titer rise, or seroconversion to protective titers was analyzed. No significant differences in antibody responses were found between healthy controls and patients on azathioprine. The patients on hemodialysis showed an impaired response to vaccination. However, in contrast to the cyclosporine-treated patients, booster immunization proved valuable in this group.
Adult↗
Chronic effect of ketanserin in mild to moderate essential hypertension.
Ketanserin, an antagonist highly selective for 5-hydroxytryptamine (serotonin) type 2 (S2) receptors, was given as monotherapy in a dose of 40 mg b.i.d. to 24 subjects with mild to moderate essential hypertension. Its effects were evaluated in a placebo-controlled double-blind crossover study. The effect on blood pressure in 18 subjects was monitored by 24-hour ambulatory intra-arterial measurements. Systolic and diastolic intra-arterial pressures were significantly lowered by ketanserin both during the day and at night, whereas heart rate was unchanged. Cuff pressure readings (triplicate measurements) with the London School of Hygiene sphygmomanometer and an automatic device (12 measurements in 1 hour) in the outpatient clinic also showed a significant effect on both supine and standing pressures. No postural hypotension was noted. Ketanserin had no effect on endogenous creatinine clearance, serum cholesterol levels, and the plasma levels of norepinephrine, renin, and aldosterone. The only side effect that was significantly more common with ketanserin than with placebo treatment was an increase in body weight. Ketanserin may have a place in the treatment of mild to moderate essential hypertension.
Adult↗
Ketanserin: haemodynamic effects and mechanism of action.
The haemodynamic effects of ketanserin, a compound with S2-serotonergic receptor and alpha 1-adrenoceptor blocking properties, are reviewed in patients with essential hypertension. The drug has a definite antihypertensive action, both acutely and chronically, and its haemodynamic profile is similar to that of a vasodilator acting on both arterioles and veins but with its main action on arterioles. Its vasodilator action is associated with little reflex cardiostimulation. Pressor responses to i.v. phenylephrine are not altered by therapeutic i.v. doses of ketanserin but pressor responses to methoxamine, a compound that is more specific for vascular alpha 1-receptors than phenylephrine, have been reported to be reduced after chronic oral treatment with ketanserin. However, chronic ketanserin, unlike the alpha 1-adrenoceptor antagonist, prazosin in therapeutic doses, caused no parallel shift of the dose-pressor response curve of methoxamine and the shift was very small compared with prazosin. Studies in patients with autonomic failure and virtually no endogenous alpha 1-adrenergic tone have substantiated that ketanserin is capable of lowering blood pressure independently of alpha 1-adrenoceptor blockade.
Adrenergic beta-Antagonists↗
The second Sir George Pickering memorial lecture. What regulates whole body autoregulation? Clinical observations.
The autoregulation theory of essential hypertension states that the characteristic haemodynamic derangement of this disease, i.e. increased vascular resistance, is a homeostatic response to abnormal sodium retention by the kidneys. The postulated relationship between arterial pressure and urinary sodium excretion is disturbed in such a way that a higher than normal pressure is required for sodium excretion to keep up with intake. This will initially expand plasma volume and raise cardiac output. However, hyperperfusion of the tissues will ultimately induce vasoconstriction, presumably by greater than normal wash-out of vasodilator metabolic products. Thus, cardiac output will be restored. Some elements of this theory are not supported by current evidence, but the key element, i.e. the assumption that increased vascular resistance is somehow dependent on abnormal renal sodium handling, is consistent with the following clinical observations: Arterial pressure and urinary sodium excretion are directly correlated over a wide range of pressures in patients with autonomic failure, both acutely during titling and chronically with changes in posture during a 24-h period. The failure to demonstrate pressure-natriuresis in normal subjects may therefore be related to the amplifying effect of the sympathetic nervous system on this mechanism, so that small changes in pressure are capable of inducing large changes in sodium excretion. The pressure-natriuresis curve in patients with autonomic failure is shifted to higher pressures by administration of aldosterone, which is consistent with an important role of renal sodium retention in mineralocorticoid hypertension. Measurements of total extracellular fluid volume, plasma volume/interstitial fluid volume ratio, transcapillary escape rate of serum albumin, cardiac output and arterial pressure at timed intervals during the development of hypertension, in patients exposed to mineralocorticoid excess, or during the reversal of hypertension in nephrectomized patients treated with ultrafiltration haemodialysis, revealed an association of increased total peripheral resistance with a reduced plasma volume/interstitial fluid volume ratio and an increased transcapillary escape rate of serum albumin. This association has also been observed in cross-sectional studies of patients with essential hypertension and suggests that part of the increase in resistance is located at a post-capillary level. It may be related to compression of collapsible venules and veins due to abnormally increased interstitial fluid pressure, not only in sodium-dependent secondary forms of hypertension but also in essential hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Ketanserin: a possible tool for studying the role of serotonin in hypertension.
Ketanserin is a serotonin antagonist with high affinity for S2-serotonergic receptors, which mediate the vasoconstrictor effects of serotonin. It does not block the vasodilator effects of this monoamine, and it is devoid of agonist activity and serious central side effects. Ketanserin, however, also binds to alpha 1-adrenoceptors. The compound (10 mg i.v.) was given to 30 patients with essential hypertension and four normotensive patients with chronic autonomic failure, owing to an efferent sympathetic lesion. Ketanserin lowered systolic and diastolic arterial pressure by about 20%. The effects on cardiac output, cardiac filling pressures, forearm blood flow, renal blood flow, and glomerular filtration rate revealed a hemodynamic pattern compatible with dilatation of both resistance and capacitance vessels. These vasodilator effects were accompanied by moderate reflex stimulation of the heart. The drug did not alter the pressor effect of bolus injections of the alpha 1-adrenoceptor agonist phenylephrine, which contrasted with the competitive antagonism exerted by the alpha 1-adrenoceptor antagonist prazosin. Baroreflex-mediated bradycardia after phenylephrine also was not affected by ketanserin. The drug had a distinct hypotensive effect in patients with autonomic failure, despite the fact that these patients did not respond to the nonselective alpha-adrenoceptor antagonist phentolamine, 20 mg i.v. Thus, ketanserin is capable of lowering arterial pressure independently of alpha 1-adrenoceptor blockade. The results are therefore indirect evidence supporting a role of serotonin in hypertension.
Aldosterone↗
Use of captopril in the diagnostic work-up of renovascular hypertension.
A total of 179 patients were selected for a diagnostic work-up of renovascular hypertension from a consecutive series of hypertensive patients referred to a single outpatient clinic between January 1978 and January 1985. Selection criteria were: (1) diagnostic blood pressure > 120 mmHg in patients of 40 years or younger, irrespective of whether they were on treatment or not, and/or (2) diastolic blood pressure > 100 mmHg despite combination therapy with at least three drugs. All patients underwent renal angiography. The diagnostic value of the responses of blood pressure and plasma renin 1 h after 50 mg captopril was assessed while the patients were untreated for at least 2 weeks. The captopril test had a predictive value of 0.92 using a concentration of enzymatically active renin in plasma > 200 microU/ml as criterion for a positive test. The predictive value of a negative test was 0.81. Predictive values were not improved by combining blood pressure response with renin level after captopril. The prevalence of renal artery stenosis was 50% (unilateral stenosis 34%). In a hypertension clinic where patients with severe or therapy-resistant hypertension and a high prevalence of renal artery stenosis are seen, the captopril test proves to be useful for selecting cases for renal angiography.
Adult↗
Cyclic blood pressure changes in a patient with a phaeochromocytoma: role of a central oscillator?
During continuous intra-arterial pressure monitoring in an 18-year-old man with severe hypertension and a phaeochromocytoma we registered marked oscillations in blood pressure with a cycle length of 3 min (range 2-4 min) and amplitude of 40 mmHg (range 12-80 mmHg). Changes in heart rate were opposite to changes in pressure. The pressure waves almost invariably appeared at rest and were most prominent during sleep. Plasma levels of noradrenaline were between 180-240 nmol/l but failed to show cyclic fluctuations. Plasma adrenaline and dopamine were normal. The waves disappeared during blockade of ganglionic nerve transmission (trimetaphan) and finally after surgical removal of the tumour. A cerebral ischaemic pressor response related to local vasoconstriction and leading to baroreflex mediated feedback oscillation of sympathetic neuron activity might be responsible for these pressure waves. A central oscillator mechanism somehow amplified by high circulating noradrenaline is another possibility.
Adolescent↗
Splint renal function after captopril in unilateral renal artery stenosis.
The renal extraction ratios of 131I-sodium iodohippurate (131I-Hippuran) and 125I-thalamate were greatly reduced on the affected side by 50 mg captopril in seven out of 14 patients with unilateral renal artery stenosis. With long term captopril 150 mg daily the uptake of 99mTc-diethylenetriaminepenta-acetic acid by the affected kidney, which was determined by scintillation camera renography, became almost zero in these seven patients, indicating severe reduction of the glomerular filtration rate. Function of the affected kidney returned on discontinuing treatment. The reduced extraction of sodium iodohippurate probably reflected a shortened plasma transit time through the kidney due to intrarenal vasodilatation. The reduced extraction of thalamate reflected a low filtration fraction, suggesting that the vasodilatation was, at least in part, at the level of the postglomerular arterioles. Captopril had little effect on the contralateral kidney and on the kidneys of 17 patients with essential hypertension, and serum creatinine concentrations showed minor changes. Radioisotope renography should be performed after beginning captopril treatment in patients with renal artery stenosis. This is also recommended for patients given captopril as a third line drug when renal artery stenosis has not been excluded. Hypertension is these patients is often severe and difficult to control. Renal artery disease is not rare in this difficult group and finding seriously impaired renal function on one side during captopril treatment may be diagnostic.
Adult↗
Angiotensin converting enzyme inhibition in renovascular hypertension: failure of the stenotic kidney.
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Acute Kidney Injury↗
Distribution of extracellular fluid over the intra- and extravascular space in hypertensive patients.
The time course of hemodynamic responses to long-standing sodium overload was studied in humans. The study involved six patients who became hypertensive on exposure to excessive mineralocorticoid activity. Arterial pressure, cardiac output, and body fluid volumes were measured with noninvasive methods at weekly intervals for at least 6 weeks and at longer intervals for periods up to 2 years. Extracellular fluid volume was expanded by approximately 20%, and arterial blood pressure rose by 20-40%. Initially, cardiac output was the dominant factor for the pressure rise. But in a later stage the pressure remained high or rose even further, although cardiac output and body fluid volumes fell toward normal. In some cases, particularly in young subjects, it took weeks or months before the total peripheral resistance began to rise, and there was no quantitative relationship between the initial rise in cardiac output and the subsequent rise in resistance. These findings argue against a direct cause-and-effect relation between flow and resistance changes. Preferential expansion of the intravascular compartment was associated with high cardiac output, whereas preferential expansion of the interstitial fluid compartment was associated with high resistance. Thus, the hemodynamic pattern of sodium-induced hypertension seems somehow related to the distribution of extracellular fluid over the intra- and extravascular compartments.
Adenoma↗
Direct 24-hour haemodynamic monitoring after starting beta-blocker therapy: studies with pindolol in hypertension.
The acute haemodynamic effects of the non-selective beta-adrenoceptor antiagonist pindolol which has considerable intrinsic sympathomimetic activity (ISA), were studied in 10 patients with essential hypertension for 24 h. One hour after oral dosing (10 mg), the drug reduced supine arterial pressure significantly. The maximum antihypertensive effect was observed after 3-4 h (-15 +/- 3%, P less than 0.001). The fall in arterial pressure was associated with a 25% reduction of systemic vascular resistance (P less than 0.001) after 24 h. By that time cardiac output was increased by 16 +/- 5% (P less than 0.05). Cardiac filling pressures and pulmonary artery pressure did not change. The vasodilator effect of pindolol cannot easily be explained by suppression of plasma renin activity since changes in arterial pressure and plasma renin were inversely correlated (r = -0.58, P less than 0.001). Despite the antihypertensive and vasodilator effect of pendolol, plasma noradrenaline did not rise. The rapid fall in arterial pressure and systemic vascular resistance may be explained by the absence of an initial reflex vasoconstriction which normally follows blockade of cardiac beta-receptors. This may be related to ISA on cardiac and vascular postsynaptic beta-receptors. Concomitant blockade of central and/or peripheral presynaptic beta-receptors is suggested by the absence of a rise in plasma noradrenaline and may contribute to the vasodilator action of pindolol.
Adolescent↗
Mechanism of antihypertensive action of ketanserin in man.
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Antihypertensive Agents↗
Cardioprotection by blockade of beta 2-adrenoceptors.
The effects of different beta-adrenoceptor agonists and antagonists on plasma noradrenaline and potassium concentrations were studied in patients with borderline hypertension. Heart rate, arterial pressure and the heart rate corrected duration of total electromechanical systole (QS2I) were also measured. Infusion of the beta-adrenoceptor agonists isoprenaline (non-selective) and salbutamol (beta 2-selective), but not prenalterol (beta 1-selective) caused dose-dependent increments in plasma noradrenaline. Isoprenaline and salbutamol decreased plasma potassium dose-dependently. For a given effect on heart rate and QS2I the fall in potassium was less pronounced after prenalterol. The effects of isoprenaline were also studied after the beta-adrenoceptor antagonists propranolol, 320 mg day-1 for 1 week (non-selective) and atenolol, 100 mg day-1 for 1 week (beta1-selective). The effects of isoprenaline, when infused in equipotent chronotropic doses, on noradrenaline and potassium were not affected by atenolol, whereas they were completely abolished by propranolol. The rise in noradrenaline during beta-adrenoceptor stimulation could be explained by presynaptic facilitation of noradrenaline release. The fall in potassium probably reflects stimulation of Na-K-ATPase dependent transport of potassium into the cell. Both effects were seen after beta 2- but not after beta 1-adrenoceptor stimulation. Hypokalaemia and raised levels of noradrenaline are also known to occur under such stressful conditions as acute myocardial infarction, when circulating levels of the endogenous beta 2-adrenoceptor agonist adrenaline are high. Blockade of these effects by beta-adrenoceptor antagonists may contribute to the cardioprotective effect of these drugs. This warrants further consideration of the clinical significance of beta-blocker selectivity.
Adrenergic beta-Agonists↗
Effects of captopril in acute and chronic heart failure. Correlations with plasma levels of noradrenaline, renin, and aldosterone.
The angiotensin-converting enzyme inhibitor, captopril, was given to 19 patients with severe heart failure. Seven patients had acute myocardial infarction and the remainder had chronic myocardial damage caused by ischaemia or valvular disease. Cardiac filling pressures were raised in all, the pulmonary capillary "wedge" pressure being 17 mmHg or more. Captopril, 50 mg orally, raised stroke volume and cardiac output, and reduced heart rate, cardiac filling pressures, systemic arterial pressure, and the plasma concentrations of aldosterone and noradrenaline. These changes were attended by clinical improvement. Decrements in cardiac filling pressures, systemic arterial pressure, and total peripheral resistance were positively correlated with pretreatment plasma renin. Long-term treatment with captopril was offered to 14 patients. Four patients with severe coronary disease died suddenly after initial clinical improvement. In nine patients haemodynamic measurements were repeated after three months. The results showed sustained effects on cardiac output and filling pressures but there was no loss of body weight. The haemodynamic effects were at least as good as with previous vasodilators. The fall in systemic arterial pressure, however, was greater with captopril. Captopril may become a valuable adjunct to the treatment of acute and chronic heart failure, but more information about its effect on coronary blood flow is required.
Aged↗