M. A. D. H. Schalekamp

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.

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.

Comparison of Finapres non-invasive beat-to-beat finger blood pressure with intrabrachial artery pressure during and after bicycle ergometry.

To evaluate the accuracy of continuous non-invasive blood pressure measurements in the finger during exercise, Finapres blood pressures of six normotensive healthy males were measured during increasing levels of bicycle exercise, using simultaneously registered ipsilateral intrabrachial artery pressures as a reference. At rest, finger systolic blood pressure was higher and finger diastolic and mean arterial pressures were lower than the corresponding intrabrachial pressures in five of the six subjects. During exercise, average finger diastolic and mean arterial pressures did not differ further from these intrabrachial pressures, but finger systolic pressure increased considerably more than the direct systolic pressure, exceeding it by 26 +/- 20 mmHg (mean +/- s.d.) at maximal exercise. This latter finding potentially limits the use of finger blood pressure measurements during exercise.

Effects of selective and nonselective beta-agonists on plasma potassium and norepinephrine.

The effects of graded infusions of the β-agonists isoproterenol (nonselective), l-prenalterol β1-selective), and salbutamol (β2-selective) on plasma potassium and norepinephrine were compared in subjects with borderline hypertension. Potassium levels fell with all three agonists, and norepinephrine levels rose with isoproterenol and salbutamol. These effects on potassium and norepinephrine were closely correlated and occurred at the same dose ranges as the cardiovascular responses. The fall in plasma potassium was probably caused by activation of β-receptors, mainly on skeletal muscle, with subsequent stimulation of active sodium-potassium transport across the cellular membrane. The rise in plasma norepinephrine may have been due to activation of β-receptors on sympathetic nerve endings. Activation of these presynaptic receptors is known to enhance the release of norepinephrine during nerve stimulation. For a given increase in heart rate and cardiac contractility, as measured by the heart rate-corrected duration of total electromechanical systole, which are mainly β1-responses, the effects on potassium and norepinephrine were in the order: salbutamol > isoproterenol > prenalterol. β-Blockade with propranolol (nonselective), 80 mg four times a day, or atenolol (β1-selective), 100 mg once a day, antagonized the hypokalemic effect of isoproterenol as well as the rise in norepinephrine, but when isoproterenol was infused in doses high enough to overcome the blockade of the heart rate response, the effects on norepinephrine and potassium were abolished by propranolol and not by atenolol. Thus, the receptors in question appear to be of the β2-subtype. Epinephrine, which is known to circulate in high concentrations under stressful conditions, is generally considered to be the endogenous activator of these receptors. β-Blockers may prevent hypokalemia and may suppress sympathetic activity, which could contribute to their so-called cardioprotective action. The evidence presented here and in other studies that β2-type receptors are involved in stress-induced hypokalemia and in presynaptic facilitation of norepinephrine release warrants further consideration of the clinical significance of β-blocker selectivity.

The Place of Renal Scintigraphy in the Diagnosis of Renal Artery Stenosis: Fifteen Years of Clinical Experience

BACKGROUND Renal scintigraphy with radiolabeled pentetic acid (diethylenetriamine pentaacetic acid [DTPA]) or, more recently, mertiatide (mercaptoacetyltriglycine [MAG3]), with or without captopril challenge, is widely recommended as a diagnostic test for renal artery stenosis. OBJECTIVES To address (1) whether the diagnostic accuracy has been improved by the use of captopril and the introduction of mertiatide and (2) whether a renal scan that shows abnormalities is a useful criterion to select patients for renal arteriography. PATIENTS AND METHODS A standard diagnostic protocol, using both scintigraphy and arteriography, was followed in 505 consecutive high-risk hypertensive patients who were evaluated for renovascular hypertension at the University Hospital Dijkzigt, Rotterdam, the Netherlands, from 1978 to 1992. RESULTS Renal artery stenosis (> or = 50%) was present in 263 patients. When the single-kidney fractional uptake was used as a diagnostic criterion, a specificity of 0.90 was obtained at a cutoff value of 35% for the worst kidney in scintigraphy using pentetic acid without captopril challenge (n = 225) and at a cutoff value of 37% after captopril challenge (n = 280). This was associated with sensitivity levels of 0.65 and 0.68, respectively. The difference between the uptake of pentetic acid with and without captopril challenge in the 85 patients who were studied under both circumstances was no more accurate as a predictor of renal artery stenosis. In the 93 patients who were studied with mertiatide as well as with pentetic acid, both after captopril challenge, the diagnostic accuracy was no better with mertiatide than with pentetic acid; mertiatide failed to offer any advantage not only when the single-kidney fractional uptake was used as a criterion, but also with the use of other scintigraphic parameters (eg, time to peak, time to pyelum, overall shape of renographic curve, and kidney size). CONCLUSIONS The diagnostic accuracy of renal scintigraphy has not been improved by the introduction of mertiatide or by the use of captopril. The usefulness of scintigraphy as a diagnostic test for the presence of renal artery stenosis remains questionable. The physician will always confront either a substantial number of arteriograms that do not show abnormalities when renal scintigraphy is omitted as a screening step or a substantial number of missed diagnoses when a renal scan that shows abnormalities is used as a prerequisite for arteriography.

Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension.

OBJECTIVE--To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN--Exploratory study in which active treatment was preceded by placebo. SETTING--Inpatient unit of teaching hospital. PATIENTS--Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS--Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS--With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS--The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.

Cyclosporin A Impairs the Nocturnal Blood Pressure Fall in Renal Transplant Recipients

In renal transplant recipients, hypertension and a diminished nocturnal blood pressure fall are frequently found. To investigate whether this diminished nocturnal blood pressure fall is related to the use of cyclosporin A or to other factors, such as the use of glucocorticoids, we measured 24-hour ambulatory blood pressure in 18 renal transplant recipients both before and 16 weeks after conversion from cyclosporin A to azathioprine. Renal blood flow and glomerular filtration rate were estimated from 131I-hippurate and 125I-iothalamate clearances, respectively, and plasma concentrations of renin, atrial natriuretic peptide, norepinephrine, prostaglandin E2, and thromboxane B2 were determined. During cyclosporin A treatment, mean 24-hour blood pressure was 117 +/- 3 mm Hg, and the nocturnal fall in blood pressure was 4 +/- 9 mm Hg. A nondipping diurnal blood pressure pattern was present in 13 patients. After conversion to azathioprine, mean 24-hour blood pressure decreased to 109 +/- 3 mm Hg (P < .001), the nocturnal fall increased to 9 +/- 6 mm Hg, and the number of patients with a nondipping diurnal blood pressure pattern decreased to 9. The nocturnal fall in heart rate (17 +/- 10 beats per minute) during cyclosporin A did not change after conversion. Body weight and plasma concentrations of norepinephrine and renin did not change. Plasma concentrations of prostaglandin E2 and thromboxane B2 decreased after conversion, as did plasma atrial natriuretic peptide. Renal blood flow and glomerular filtration rate increased after conversion. In conclusion, cyclosporin A appears to be involved in the disturbance of the circadian blood pressure rhythm in renal transplant recipients. Although the precise mechanism is unclear. the elevated plasma atrial natriuretic peptide and slightly suppressed plasma renin concentrations suggest that intravascular volume expansion may contribute to the observed hemodynamic alterations.

High concentrations of immunoreactive renin, prorenin and enzymatically-active renin in human ovarian follicular fluid

Summary. Prorenin (enzymatically inactive) and renin (active) were measured by radioimmunoassay, üsing monoclonal antibodies reacting either with both prorenin and renin or with renin alone, in preovulatory follicular fluid (FF) from women in an in‐vitro fertilization programme who were stimulated with human menopausal/human chorionic gonadotrophin. The concentration of prorenin in FF was 40 times higher than in plasma taken a! the time of FF collection; renin in FF was 10 times higher. The plasma concentration of prorenin, but not of renin, in these women was higher than in non‐stimulated women in the late follicular phase of the menstrual cycle. The concentration of renin‐substrate and angiotensin‐converting enzyme in FF was 60% of that in plasma. Contamination of blood, which may occur at the time of FF collection, was less than 5%. Prorenin in FF was irreversibly converted into renin after adding trypsin or by endogenous serine protease, using procedures that also cause conversion of prorenin in plasma. These results support the hypothesis that the increased plasma level of prorenin in women whose ovulation is stimulated for the collection of oocytes has originated from the ovary and is under gonadotrophic control. This may also be true for the increase of plasma prorenin that has been observed in non‐stimulated women during the luteal phase of the cycle and in early pregnancy.