A. J. Man In 'T Veld

The effect of balloon angioplasty on hypertension in atherosclerotic renal artery stenosis

BACKGROUND Patients with hypertension and renal-artery stenosis are often treated with percutaneous transluminal renal angioplasty. However, the long-term effects of this procedure on blood pressure are not well understood. METHODS We randomly assigned 106 patients with hypertension who had atherosclerotic renal-artery stenosis (defined as a decrease in luminal diameter of 50 percent or more) and a serum creatinine concentration of 2.3 mg per deciliter (200 micromol per liter) or less to undergo percutaneous transluminal renal angioplasty or to receive drug therapy. To be included, patients also had to have a diastolic blood pressure of 95 mm Hg or higher despite treatment with two antihypertensive drugs or an increase of at least 0.2 mg per deciliter (20 micromol per liter) in the serum creatinine concentration during treatment with an angiotensin-converting-enzyme inhibitor. Blood pressure, doses of antihypertensive drugs, and renal function were assessed at 3 and 12 months, and patency of the renal artery was assessed at 12 months. RESULTS At base line, the mean (+/-SD) systolic and diastolic blood pressures were 179+/-25 and 104+/-10 mm Hg, respectively, in the angioplasty group and 180+/-23 and 103+/-8 mm Hg, respectively, in the drug-therapy group. At three months, the blood pressures were similar in the two groups (169+/-28 and 99+/-12 mm Hg, respectively, in the 56 patients in the angioplasty group and 176+/-31 and 101+/-14 mm Hg, respectively, in the 50 patients in the drug-therapy group; P=0.25 for the comparison of systolic pressure and P=0.36 for the comparison of diastolic pressure between the two groups); at the time, patients in the angioplasty group were taking 2.1+/-1.3 defined daily doses of medication and those in the drug-therapy group were taking 3.2+/-1.5 daily doses (P<0.001). In the drug-therapy group, 22 patients underwent balloon angioplasty after three months because of persistent hypertension despite treatment with three or more drugs or because of a deterioration in renal function. According to intention-to-treat analysis, at 12 months, there were no significant differences between the angioplasty and drug-therapy groups in systolic and diastolic blood pressures, daily drug doses, or renal function. CONCLUSIONS In the treatment of patients with hypertension and renal-artery stenosis, angioplasty has little advantage over antihypertensive-drug therapy.

Determination of catecholamines in human plasma by high-performance liquid chromatography: comparison between a new method with fluorescence detection and an established method with electrochemical detection.

We report a sensitive fluorimetric method, in which catecholamines are concentrated from plasma by liquid-liquid extraction and derivatized with the selective fluorescent agent 1,2-diphenylethyl-enediamine prior to chromatography. Optimal conditions for extraction, derivatization and chromatography were investigated. With alpha-methylnorepinephrine as internal standard, the chromatographic separations are complete within 6 min. Limits of detection are 0.3 pg for norepinephrine and epinephrine and 0.5 pg for dopamine. Coefficients of variation are low (3-7%). Comparison of plasma catecholamine values determined with this method and with an established method with electrochemical detection (n = 135) shows good correlation (r = 0.94-1.00), and regression lines are close to lines of identity.

CONGENITAL DOPAMINE-BETA-HYDROXYLASE DEFICIENCY: A Novel Orthostatic Syndrome

A woman was referred with severe orthostatic hypotension at the age of 21. Ptosis, skeletal muscle hypotonia, and recurrent hypoglycaemia had been noticed in early childhood. There was noradrenergic denervation and adrenomedullary failure but baroreflex afferents, cholinergic innervation, and adrenocortical function were intact. Noradrenaline and adrenaline were undetectable in plasma, urine, and cerebrospinal fluid (CSF), but dopamine was 7-fold to 12-fold normal in plasma, 4-fold normal in urine, and 20-fold normal in CSF. Measurements of catecholamine metabolites showed further evidence for impairment of noradrenaline and adrenaline biosynthesis due to deficient dopamine-beta-hydroxylation. Dopamine-beta-hydroxylase was undetectable in plasma and CSF. Physiological and pharmacological stimuli of sympathetic neurotransmitter release caused increases in plasma dopamine rather than plasma noradrenaline.

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.

INACTIVE RENIN IN HUMAN PLASMA

Human plasma contains renin, which is enzymatically active at neutral pH (active renin), and a non-dialysable factor, which has renin-like activity after treatment at low pH (inactive renin). In vitro activated plasma-renin and purified human renal renin showed identical enzyme-kinetic properties. Quantitative estimations of inactive renin in renal venous plasma from 5 patients with renal-artery stenosis demonstrated its release by the kidney. Acute stimulation of renin release by isoprenaline, tilting, or diazoxide in 13 normotensive individuals and in 9 patients with essential hypertension increased active plasma-renin and reduced inactive plasma-renin. Inactive plasma-renin was increased and active plasma-renin decreased during suppression of renin release by propranolol in 12 patients with essential hypertension. In 55 patients with various disorders, inactive and active plasma-renin were directly correlated. However, the concentration of inactive renin, for a given value of active renin, varied widely from patient to patient. These results indicate that so-called inactive renin is indeed physiologically related to active renin. They also suggest that inactive renin can be activated not only in vitro, but also in vivo. Different renin assays measure different relative amounts of active and inactive renin. This may call for reinterpretation of results obtained by various methods, especially in situations where changes in plasma concentrations of the two forms of renin are in opposite directions.

Asynchronous changes in prorenin and renin secretion after captopril in patients with renal artery stenosis.

An assay of plasma prorenin was developed in which the conversion to renin occurred under apparently optimal conditions. Some characteristics of the assay were 1) prorenin was activated by Sepharose-bound trypsin at 4 degrees C; 2) the concentration of activator was not critical provided that incubation was prolonged until renin activity had reached a plateau; and 3) this plateau was stable and had the same height as after maximal activation with acid, pepsin, plasmin or urokinase. Maximal activity with Sepharose-bound trypsin at 4 degrees C was higher than with cryoactivation, and optimal conditions were more readily reproduced than with trypsin at 37 degrees C or with acid-activation. The assay was used for measurements in peripheral and renal vein plasma after captopril in hypertensive patients with unilateral renal artery stenosis. Peripheral renin rose within 30 minutes after a first dose of captopril, 50 mg orally, and it remained high with chronic treatment. In contrast, peripheral prorenin fell initially and rose after 4 hours. These changes in peripheral plasma were related to changes in the secretion rates of the two forms of renin from the affected kidney. Thus chronic, but not acute, stimulation of renin release was associated with an increased secretion rate of prorenin. The late rise in prorenin is probably an indication of enhanced synthesis in the kidney, so that more prorenin is available for conversion. The data suggest that prorenin is indeed a biosynthetic precursor of renin and that, at least under certain circumstances, a major proportion of circulating prorenin originates from the kidney.

Haemodynamic and neurohumoral effects of xenon anaesthesia A comparison with nitrous oxide

Thirty‐two patients were randomly allocated to be anaesthetised either with nitrous oxide or xenon. Those who received nitrous oxide required significantly more fentanyl peroperatively. Arterial blood pressure and heart rate were adequately controlled during surgery in both groups. Plasma noradrenaline and prolactin increased peroperatively in both groups, but plasma adrenaline and cortisol, which increased in the nitrous oxide group, did not change in the xenon group. Growth hormone was below control in those given xenon, but not in the nitrous oxide group, while dopamine remained unchanged in both groups. Postoperative plasma concentrations of noradrenaline, adrenaline, cortisol and prolactin (in both groups) and dopamine (in the nitrous oxide group) were elevated, and slowly returned to control. No differences were seen between the two gases in effects on plasma sodium and potassium. Xenon, because of its favourable haemodynamic, neurohumoral and antinociceptive properties, deserves a more prominent place in anaesthetic practice than it has so far occupied.

Circulating semicarbazide-sensitive amine oxidase is raised both in Type I (insulin-dependent), in Type II (non-insulin-dependent) diabetes mellitus and even in childhood Type I diabetes at first clinical diagnosis

Summary Plasma semicarbazide-sensitive amine oxidase is raised in patients with Type I (insulin-dependent) diabetes mellitus. It has been suggested that this enzyme is involved in the development of microvascular damage through its ability to convert amines (e. g. methylamine and aminoacetone) into aldehydes, hydrogen peroxide and ammonia. Plasma semicarbazide-sensitive amine oxidase was found to be equally raised both in patients with Type I diabetes (n = 73) and Type II (non-insulin-dependent) diabetes mellitus (n = 88) compared with control subjects (621 ± 209 and 619 ± 202 vs 352 ± 102 mU/l, p < 0.0001) and to correlate in multiple regression analysis with HbA1 c. Since the enzyme could protect the islets from the inhibitory effects of methylamine on insulin secretion, we also tested sera of 100 children, collected consecutively at first diagnosis of Type I diabetes, for semicarbazide-sensitive amine oxidase. The activity was greatly increased compared with serum values of 76 control (siblings) children (757 ± 300 vs 455 ± 138 mU/l, p < 0.0001), but not associated with HbA1 c. Our study confirms the increase of plasma semicarbazide-sensitive amine oxidase in Type I diabetes and extends this finding to Type II diabetes as well as to childhood Type I at first clinical diagnosis. In the last case increased enzyme activities could serve to protect the islets from inhibitory effects of methylamine but cause damage by generation of hydrogen peroxide, aldehydes and ammonia. In the long run the increased enzyme activities could also contribute to vascular damage by direct cytotoxic action on endothelial cells, including increased oxidative stress and glycosylation of proteins. [Diabetologia (1999) 42: 233–237]

Pindolol acts as beta-adrenoceptor agonist in orthostatic hypotension: therapeutic implications.

Three bedridden patients with severe orthostatic hypotension due to chronic autonomic failure were treated with pindolol (15 mg/day), a beta-adrenoceptor antagonist with partial agonist activity. While taking this drug the patients were free of orthostatic symptoms: they could walk, and standing blood pressure was maintained above 90/50 mm Hg. Supine heart rate rose during treatment by 12-21 beats/minute, and stroke volume and cardiac output by 12-24 ml and 1.5-3.1 l/min respectively. Supine blood pressure rose by 21-68 mm Hg systolic and 14-49 mm Hg diastolic. Pindolol 15 mg/day was therapeutically effective in these three patients with severe orthostatic hypotension due to chronic autonomic failure. Further studies in a larger series of patients are needed to confirm this result.

Cardiovascular variability in major depressive disorder and effects of imipramine or mirtazapine (Org 3770).

Spectral analysis of fluctuations in heart rate (HR) and blood pressure (BP) was applied to assess sympathetic and parasympathetic cardiovascular control mechanisms in patients with unipolar affective disorder before and after treatment with imipramine (IMI) or mirtazapine (MIR). In a double-blind randomized study, 10 patients received treatment with IMI and 10 patients received treatment with MIR. Cardiovascular parameters were studied before and after 4 weeks of treatment: HR and BP (Finapres) were recorded continuously during supine rest (SR) and orthostatic challenge (OC; 60-degrees head-up tilting). During SR and OC, power spectra were calculated for HR and systolic BP. Spectral density was assessed for three frequency bands: low (0.02-0.06 Hz), mid (0.07-0.14 Hz), and high (0.15-0.50 Hz). Before treatment, the depressed patients (N = 20) differed from age-matched controls (N = 20) only in their response to OC: the depressed patients showed more suppression of HR variability (both mid- and high-frequency band fluctuations), indicating stronger vagal inhibition, and a reduced increase of BP variability (mid-frequency band fluctuations), indicating reduced sympathetic activation. After 4 weeks of treatment, patients treated with either antidepressant drug showed significant changes of HR (increase) and HR variability (decrease) during SR and OC; the suppression of mid- and high-frequency fluctuations of HR was larger for IMI than for MIR. The increase in HR and decrease in HR variability may be attributed to the anticholinergic properties of IMI (strong) and MIR (weak), resulting in cardiac vagal inhibition. Whereas MIR had no effect on BP or BP variability, IMI specifically reduced mid-frequency band fluctuations of BP as the result of a suppression of central sympathetic activity. Our data confirm and extend previous observations on the presence of autonomic dysfunctions in unmedicated depressed patients: spectral analysis of HR and BP fluctuations suggested that both parasympathetic and sympathetic mechanisms are involved, specifically during OC. The preexisting autonomic cardiovascular dysfunctions were not normalized by antidepressant drugs. In fact, some of the components of the cardiovascular autonomic dysfunction were further aggravated, depending on the pharmacologic profile of the drug under investigation.