Wenting Gj

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.

5-HT, alpha-adrenoceptors, and blood pressure. Effects of ketanserin in essential hypertension and autonomic insufficiency.

The serotonin (5-hydroxytryptamine, 5-HT) antagonist, ketanserin, has a high affinity for 5-HT2-receptors but it also binds to alpha 1-adrenoceptors. The compound (10 mg i.v.) lowered mean arterial pressure by 22% +/- 2% (mean +/- SEM, p less than 0.001) in 30 patients with essential hypertension. Measurements of heart rate, cardiac output, cardiac filling pressures, forearm blood flow, renal blood flow, and glomerular filtration rate revealed a hemodynamic pattern compatible with vasodilation of both resistance and capacitance vessels. This was accompanied by moderate reflex cardiostimulation. Ketanserin did not alter the pressor effect of bolus injections of (-)-phenylephrine hydrochloride (25, 50, 100, and 200 micrograms i.v.). Ketanserin also had a distinct hypotensive effect in four normotensive patients with autonomic insufficiency due to an efferent sympathetic lesion, who were unresponsive to phentolamine (20 mg i.v.). Thus, ketanserin in the dose we have used appears to lower blood pressure independently of alpha 1-adrenoceptor blockade. On the other hand, in patients with essential hypertension the antihypertensive effect of ketanserin was blunted by pretreatment with prazosin (12 mg/day). Therefore, a certain degree of alpha 1-adrenergic tone seems to be required for the compound to exert its full antihypertensive action. The findings are indirect evidence for a role of 5-HT in the maintenance of increased vascular resistance in essential hypertension. This may be related, at least in part, to the alleged amplifying effect of 5-HT on alpha 1-adrenoceptor-mediated vasoconstriction.

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.

Blood pressure response of nephrectomized subjects and patients with essential hypertension to ramipril: Indirect evidence that inhibition of tissue angiotensin converting enzyme is important

The kinetics of blood pressure changes and plasma angiotensin converting enzyme (ACE) inhibition in response to ramipril (HOE 498), 10 mg orally, were studied in 6 nephrectomized subjects 12 hours after ultrafiltration and in 10 patients with essential hypertension. Ramipril lowered supine and standing blood pressure in both groups, but the effect was greater in essential hypertension. The maximal blood pressure response followed the effect on plasma ACE after a lag time of 3 to 4 hours in both groups. These data provide indirect evidence that ramipril lowers blood pressure, at least in part, independently of its effect on the circulating renin-angiotensin system, possibly by acting on tissue ACE.

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)

Hemodynamic effects of captopril in essential hypertension, renovascular hypertension and cardiac failure: Correlations with short- and long-term effects on plasma renin

Abstract The hemodynamic effects of captopril were investigated in 22 patients with essential hypertension, 22 with hypertension and renal artery stenosis and 14 with refractory chronic heart failure. The effects of a first dose of captopril, 50 mg orally, were observed for 2 hours, and the effects of repeated doses, 450 mg/day in combination with mild dietary sodium restriction, for at least 4 weeks. Short-term captopril treatment caused similar reductions in blood pressure in the three patient groups, that is, 21 ± 3 mm Hg in essential hypertension, 29 ± 6 mm Hg in renovascular hypertension and 21 ± 2 mm Hg in heart failure (mean ± standard error of the mean) despite large differences in pretreatment plasma renin. Heart rate and cardiac output did not change in hypertensive patients, and cardiac filling pressures decreased. The changes in right atrial pressure, pulmonary artery pressure and pulmonary capillary wedge pressure in essential hypertension and in renovascular hypertension did not differ. Heart rate decreased and cardiac output increased in heart failure, whereas cardiac filling pressures decreased. Blood pressure responses to long-term captopril therapy in essential and in renovascular hypertension were similar and, as with short-term treatment, changes in blood pressure were largely determined by changes in peripheral resistance. Several measurements of extracellular fluid volume showed no evidence of fluid retention by the kidneys. Short-term but not long-term blood pressure responses were correlated with pretreatment plasma renin (percent change in mean arterial pressure, short-term, versus log renin, r = 0.47, p

A new model for diurnal blood pressure profiling. Square wave fit compared with conventional methods.

For the characterization of diurnal blood pressure variation, we developed a simple mathematical model that nevertheless does justice to the specific form characteristics of individual blood pressure registrations. Analysis was based on 24-hour continuous intra-arterial measurement of blood pressure obtained in 23 hospitalized patients with mild-to-moderate untreated essential hypertension (mean +/- SD, 112 +/- 13 mm Hg). The day-night difference for mean arterial pressure varied markedly (mean, 18.6 mm Hg; range, 6.8-36.0). Inspection of profiles suggested a model of blood pressure as two contiguous, complementary periods of constant pressure, a so-called square wave. Determination of the times of transience between both periods (segmentation) was performed individually using a least-square error criterion. Results were compared with those obtained by conventional methods, including analysis by Fourier modeling. The square wave fit accounted for a larger fraction (66%) of circadian variance of mean arterial pressure than modeling based on segmentation by visual inspection (59%, considerable observer bias) or by clock time (50%). Application of the Minnesota Cosinor Method resulted in the poorest description (47%). Segmentation based on harmonic modeling (61%) appeared to be cumbersome (10 harmonics needed), and the significance of additional information offered over the square wave fit is dubious. Observer bias makes segmentation by visual inspection unsuitable for assessment of the circadian variance of blood pressure. Even when daily activities are strictly regulated (hospital environment), circadian variance is not well modeled by clock time. As compared with harmonic analysis, square wave fitting is simple, and it appears to best model the circadian variance. The method can also be applied to data obtained from noninvasive ambulatory blood pressure monitoring.

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 aldmterone. 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.