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Biomedical subjects

F H Derkx

Publications and source records attributed to F H Derkx.

At least 109 records · Page 6Linked to original sources
PubMed1988

Association of high plasma prorenin with diabetic retinopathy.

Plasma prorenin, but not renin, is elevated in long-standing diabetes mellitus. Nephropathy and autonomic neuropathy have been implicated as causes. However, we found no arteriovenous difference in prorenin across the kidney, despite high levels of circulating prorenin and a very low renal plasma flow, in five diabetics with combined end-stage nephropathy and proliferative diabetic retinopathy. Moreover, plasma prorenin was normal in 16 non-diabetics with autonomic neuropathy. The presence of a high level of prorenin was closely associated with the presence of diabetic retinopathy, particularly the proliferative type, in 223 consecutive patients. This association was independent of insulin requirements, metabolic control and of the presence of nephropathy or neuropathy. These data are evidence that part of the elevated plasma prorenin in diabetics is produced by an extrarenal source and that perhaps the eye affected by diabetic retinopathy is that source.

Blood Pressure↗
PubMed1988

Twenty-four hour pressor effect of infused adrenaline in normotensive subjects: a randomized controlled double-blind cross-over study.

Stimulation of prejunctional beta 2-adrenoceptors on sympathetic nerve terminals increases vasoconstrictor nerve activity by facilitating release of noradrenaline. Therefore, man's endogenous beta 2-adrenoceptor agonist adrenaline has been implicated in the pathogenesis of hypertension. To test this hypothesis, adrenaline (15 mg/kg per min), noradrenaline (30 ng/kg per min) and saline (0.9% NaCl, 5.4 ml/h) were infused in 10 supine, resting healthy volunteers for 6 h (1000-1600 h) in random order 2 weeks apart in a double-blind crossover fashion. During infusion of noradrenaline and adrenaline, venous plasma concentrations rose to 705 +/- 58 (mean +/- s.e.m) and 230 +/- 28 pg/ml, respectively. Mean arterial pressure rose by 4% (P less than 0.001) during noradrenaline and fell by 5% (P less than 0.001) during the adrenaline infusion compared with the saline infusion. In the postinfusion period (1600-0900 h) mean arterial pressure was 7% higher (P less than 0.01) after adrenaline compared with the saline infusion, whereas after the noradrenaline infusion, values of mean arterial pressure were not different from those during the saline infusion. The pressor effect of adrenaline could not be explained by a central mechanism or by activation of the renin-angiotensin system. Thus, 'stress levels' of adrenaline mediate a delayed and protracted pressor effect. This is most likely due to stimulation of prejunctional beta 2-adrenoceptors, since 'stress levels' of noradrenaline are devoid of such activity. Our data support the 'adrenaline-hypertension' hypothesis in man.

Adult↗
PubMed1988

Acute and long-term effects of acebutolol on systemic and renal hemodynamics, body fluid volumes, catecholamines, active renin, aldosterone, and lymphocyte beta-adrenoceptor density.

Acebutolol is a relatively new beta-adrenoceptor blocking antagonist, possessing both beta 1-adrenoceptor selectivity and partial agonist activity (PAA). Its acute (24 h, 400 mg, twice daily) and long-term effects (3 weeks) on systemic and renal hemodynamics, body fluid volumes, hormones, and beta-adrenoceptor density on lymphocytes were studied in a single-blind placebo-controlled trial, in 10 hypertensive patients. The initial response to acebutolol (1-2 h) was a fall in heart rate (HR) (-9.6 +/- 2.7%), cardiac output (-16.0 +/- 3%), and stroke volume (SV) (-10.7 +/- 0.2%), and an increase in systemic vascular resistance (SVR) (18.0 +/- 3.9%). Mean arterial pressure (MAP) began to fall 2-3 h after dosing in parallel with a decrease in SVR. At the end of the acute study, MAP and SVR were decreased by 18.1 +/- 2.7% and 15.6 +/- 5.6%, respectively. By that time, HR and SV had returned to control values despite blockade of beta-adrenoceptors. After 3 weeks of treatment (mean dose of acebutolol 480 mg twice daily), the fall in MAP was 10.1 +/- 2.7% and HR was decreased by 13.0 +/- 2.3%. Renal blood flow and glomerular filtration rate did not change. Acute and long-term treatment had no effect on the density of lymphocyte-membrane beta-adrenoceptors. This could be explained by acebutolol's beta 1 selectivity or, alternatively, this could be due to the drug's PAA.

Acebutolol↗
PubMed1988

Human prorenin: pathophysiology and clinical implications.

Renin and prorenin, the latter after conversion to renin, are usually measured by indirect RIA using antibodies against angiotensin I. They can now also be measured by direct RIA using monoclonal antibodies reacting with total immunoreactive renin (renin plus prorenin) or with renin alone. Results of measurements in renal and peripheral venous plasma indicate that normally a large proportion of prorenin in plasma is of renal origin and they support the concept of separate pathways for prorenin and renin secretion by the JG-cells. Acute stimulation causes a prompt increase of plasma renin without any change in prorenin. During chronic stimulation both renin and prorenin are increased, in such a way that the ratio between the two is higher the stronger the stimulus. Thus, with acute stimulation only the release of stored renin appears to be increased (regulated pathway), whereas during chronic stimulation the synthesis and secretion of prorenin are also (constitutive pathway). During pregnancy, in the early luteal phase of the menstrual cycle and after ovarian hyperstimulation with gonadotropins, a normal or somewhat elevated plasma level of renin is associated with a disproportionally high level of prorenin. This is an indication of extrarenal production of prorenin and in these conditions the ovary, probably corpus luteum, seems to be the main source. In most patients with renin-producing tumors plasma prorenin is also disproportionally high. In diabetes mellitus complicated by micro-angiopathy plasma prorenin is also elevated whereas renin is normal or even low. In diabetics with end-stage nephropathy we found no significant veno-arterial difference in prorenin across the kidneys, despite high circulating prorenin and a very low blood flow through these kidneys, suggesting that also in these patients part of the increased prorenin in plasma is of extrarenal origin. Thus, measurements of prorenin in plasma in various pathological conditions may contribute to a better understanding of the physiological role of the renal and extrarenal renin-angiotensin systems.

Diabetic Angiopathies↗
PubMed1987

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.

Administration, Oral↗
PubMed1987

Two-step prorenin-renin conversion. Isolation of an intermediary form of activated prorenin.

Prorenin is an inactive form of the aspartic protease renin. Like pepsinogen, it is activated at low pH. The kinetics of acid activation of prorenin were studied in human amniotic fluid and plasma and in preparations of purified prorenin isolated from amniotic fluid and plasma. Conversion of prorenin (pR) into active renin (R) appeared to be a two-step process involving the generation of an intermediary form of activated prorenin (pRa). The pR----pRa step is an acid-induced reversible change in the conformation of the molecule, and the pRa----R step is proteolytic. pRa----R conversion occurred in amniotic fluid at low pH by the action of an endogenous aspartic protease. In plasma pRa----R conversion occurs after restoration of pH to neutral and is caused by the serine protease plasma kallikrein. pRa----R conversion did not occur in purified preparations of prorenin. Thus, in contrast to pepsinogen, the acid-induced reversible conformational change is not followed by autocatalysis. pRa of amniotic fluid and plasma could be separated from R by affinity chromatography on Cibacron blue F3GA-agarose, and R but not pRa was detected by an immunoassay using monoclonal antibodies reacting with R and not with pR. The first-order rate constant for pR----pRa conversion depends on the protonation of a polar group (or groups) with pK approximately 3.4, the rate constant being proportional to the fraction of pR molecules that have this group protonated. This is analogous to the reversible acid-induced conformational change of pepsinogen that occurs before its proteolytic conversion into pepsin. kcat/Km for pRa----R conversion by plasmin and plasma kallikrein at pH 7.4 and 37 degrees C was 7.8 X 10(6) and 5.2 X 10(6) M-1 min-1, respectively, which was about 50-70 times greater than for pR----R conversion. The susceptibility of pRa to proteolytic attack is high enough for the intrinsic factor XII-kallikrein pathway to cause rapid pRa----R conversion at 37 degrees C even in whole blood with its abundance of serine protease inhibitors. Formation of pRa may occur in vivo in an acidic cellular compartment, such as exo- or endocytotic vesicles.

Enzyme Activation↗
PubMed1987

The clinical pharmacology of bopindolol, a new long-acting beta-adrenoceptor antagonist, in hypertension.

Bopindolol is a new long-acting, nonselective beta-adrenoceptor antagonist with partial agonist activity. Its acute (24 hours, 2 mg, administered orally) and long-term (3 weeks, 2 to 4 mg) hemodynamic and hormonal effects were studied in a single-blind placebo-controlled trial in 10 hypertensive subjects. The initial response (mean +/- SE) to bopindolol was a fall in cardiac output (-12% +/- 2%) and heart rate (-11% +/- 2%). Mean arterial pressure began to fall 3 to 4 hours after administration in parallel with a decrease in systemic vascular resistance, which had increased initially. Twenty-four hours after administration, mean arterial pressure and systemic vascular resistance were reduced by 12% +/- 2% and 12% +/- 5%, respectively. By that time heart rate and cardiac output did not differ from baseline values despite beta-blockade. After 3 weeks of treatment mean arterial pressure had fallen by 9% +/- 2% and renal blood flow and glomerular filtration rate were not changed. One week after withdrawal from treatment mean arterial pressure and heart rate were no longer reduced, but beta-blockade could still be demonstrated, establishing the long duration of action of the drug.

Adrenergic beta-Antagonists↗
PubMed1987

Who should be converted from cyclosporine to conventional immunosuppression in kidney transplantation, and why.

Twenty-three cadaveric renal allograft recipients with stable but compromised kidney function were electively converted from cyclosporine to azathioprine one year after transplantation. Within a few weeks glomerular filtration rate (GFR) rose by 40% and serum creatinine fell from 171 +/- 12 (mean +/- SEM) to 129 +/- 7 mumol/L. The increase in GFR was due to an increase in effective renal plasma flow of 21%. This suggests that one year of continuous cyclosporine (CsA) therapy does not result in irreversible structural renal damage. Although antihypertensive treatment was not changed, blood pressure fell from 142 +/- 4/90 +/- 3 to 123 +/- 3/77 +/- 2 mmHg. In addition a significant drop in serum cholesterol and triglycerides and an improvement in glucose tolerance were found. The beneficial effects on renal function, blood pressure, and metabolic indices were, however, outweighed by a high incidence of postconversion rejection in recipients of a second allograft. For these patients conversion from CsA to azathioprine seems therefore contraindicated. Recipients of a first kidney allograft can be converted safely, as long-term CsA administration in these patients induced a solid engraftment. The sequelae of the mode of treatment--impaired renal function, hypertension, and metabolic disturbances--are reversible even after late conversion.

Azathioprine↗
PubMed1987

Evaluation of a microcomputer program (OPT) for parameter optimisation in clinical pharmacokinetics: gentamicin and tobramycin.

1. Several nomograms and computer programs are available to aid in aminoglycoside dosing. 2. Due to the variability in the relationship between dosage and serum drug levels, monitoring through the acquisition of serum drug levels is mandatory. 3. All clinical data, including serum drug levels, are subject to errors. 4. The program we have evaluated, OPT, calculates the most likely set of pharmacokinetic parameter estimates for individual patients by applying Bayes' theorem and the principle of Maximum Likelihood Estimation. Through a feedback process all available data are used, taking possible errors into account. 5. Our study shows that OPT is able to predict serum aminoglycoside levels accurately in the routine clinical setting. It may thus contribute to the quality of aminoglycoside therapy.

Adolescent↗
PubMed1987

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

Prorenin (enzymatically inactive) and renin (active) were measured by radioimmunoassay, using monoclonal antibodies reacting either with both prorenin and renin or with renin alone, in pre-ovulatory 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 at 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 reninsubstrate 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.

Adult↗
PubMed1987

Is beta 1-antagonism essential for the antihypertensive action of beta-blockers?

Both nonselective beta-blockers and beta 1-selective blockers are effective antihypertensive agents. beta 1-Blockade generally is considered to be responsible for their antihypertensive action, whereas beta 2-blockade is regarded as undesirable. These common assumptions notwithstanding, the mechanism by which beta-blockers lower blood pressure remains unknown. To examine the possibility that beta 2-blockade may contribute to the antihypertensive action of beta-blocker therapy, we studied the cardiovascular effects of compound ICI 118551, a beta 2-selective blocker. First, we showed that 50 mg t.i.d. orally is a beta 2-selective dose. In contrast to propranolol, 80 mg t.i.d., or atenolol, 100 mg once a day, 50 mg of ICI 118551 t.i.d. failed to block beta 1-mediated inotropic stimulation and stimulation of renin by isoproterenol. We then performed a double-blind, placebo-controlled trial in patients with mild essential hypertension to compare this compound with propranolol, 80 mg t.i.d., and showed that ICI 118551 significantly decreased systolic and diastolic blood pressure. This antihypertensive effect was demonstrated by direct as well as by indirect blood pressure measurements. Thus, contrary to prevailing thought, beta 2-blockade has an antihypertensive effect independent of, and distinct from, beta 1-blockade.

Adrenergic beta-Antagonists↗
PubMed1987

Source of plasma prorenin in early and late pregnancy: observations in a patient with primary ovarian failure.

The plasma levels of enzymatically active renin (active renin) and inactive renin (prorenin) were measured in a woman with primary ovarian failure, in whom pregnancy was established by the induction of an artificial cycle and in vitro fertilization of a donated oocyte fertilized with the sperm of her husband. The results were compared with those in nine normal pregnant women. Prepregnancy plasma active renin and prorenin levels were normal in the patient. Active renin rose 2-fold during pregnancy in both the patient and the normal pregnant women. In the first 8 weeks of pregnancy prorenin rose by 156 microU/mL in the patient, whereas it rose by 869 +/- 169 microU/mL (mean +/- SD) in the normal pregnant women. Thus, the rise in prorenin in our patient was much less than normal. Prorenin remained abnormally low throughout the pregnancy, which lasted 40 weeks. Therefore, the high prorenin levels that occur normally during pregnancy may depend on normal ovarian function. Amniotic fluid prorenin in the patient was similar to that in normal pregnant women and was 75 times higher than that in plasma. This finding suggests that prorenin production by the chorionic cells was normal in the patient and that chorionic prorenin does not contribute in any major degree to the level of prorenin in maternal plasma. Because of these findings and in light of recent evidence that the ovary secretes prorenin and produces high plasma prorenin levels in women with hyperstimulated cycles, we conclude that the ovary is the main source of the elevated plasma prorenin levels in pregnant women.

Adult↗
PubMed1987

Renal vein immunoreactive renin in patients with renal artery stenosis and essential hypertension.

In 36 patients with unilateral renal artery stenosis and in 24 with essential hypertension the plasma levels of total immunoreactive renin, and enzymatically active renin were measured in both renal veins (V) and in the aorta (A) by direct RIA by using monoclonal renin antibodies. Active renin and trypsin-activatable inactive renin were also measured by indirect RIA with angiotensin-I antibodies. The V/A ratio for the different forms of renin calculated from the results of direct and indirect RIA were not different. The V/A ratio of active renin for the kidney with the stenotic artery was 3.04 +/- 0.28 (mean +/- sem) with direct and 3.02 +/- 0.25 with indirect RIA. The contralateral ratio was 1.04 +/- 0.02 with the direct and 1.05 +/- 0.02 with the indirect RIA. In essential hypertension it was 1.28 +/- 0.04 with direct RIA and 1.28 +/- 0.04 with indirect RIA. Chronic treatment with captopril had no influence on this ratio in both patients groups. The V/A ratio of total immunoreactive renin was lower than that of active renin and this ratio had lost discriminative power for lateralization. This ratio was significantly greater than one on the affected side in renal artery stenosis but not contralaterally and in essential hypertension. This study shows that renin activity after trypsin-activation of plasma is an accurate measure of the total renin concentration, i.e. active renin plus prorenin. It also shows that a kidney with a stenotic artery secretes inactive renin, which is immunologically related to active renin and is likely to be prorenin. Direct RIA for measuring active renin is technically more simple than indirect RIA. Direct RIA however is somewhat less sensitive. For measuring the V/A ratio for active renin in patients with renal artery stenosis this can be overcome by stimulating the renin-angiotensin system for instance by captopril.

Antibodies, Monoclonal↗
PubMed1986

Immunoreactive renin, prorenin, and enzymatically active renin in plasma during pregnancy and in women taking oral contraceptives.

Direct RIA of renin with monoclonal renin antibodies and indirect RIA with angiotensin I antibodies were performed in plasma of 44 pregnant women, 44 women taking an oral contraceptive (OC), and 54 normal women. The following parameters were measured: immunoreactive renin, naturally occurring enzymatically active renin (active renin), trypsin-activatable inactive renin (prorenin), PRA, and renin substrate. Immunoreactive renin (mean, 95% confidence interval) was significantly higher in pregnant women (1090; 420-2800 pg/ml; third trimester) than in normal women (248; 101-562 pg/ml; P less than 0.001) and was lower in OC-treated women (131; 41-415 pg/ml; P less than 0.001). Prorenin and active renin also were increased in pregnant women and decreased in OC-treated women. The fraction of renin that was in the active form was lower in pregnant women (4.8; 1.4-18%) than in OC-treated women (8.8; 3.0-25%; P less than 0.001) and normal women (9.1; 2.9-29%; P less than 0.001). Renin substrate was increased to comparable levels in pregnant women and OC-treated women, but PRA was increased in pregnant women and normal in OC-treated women. The maximum velocity per unit weight of renin was the same for active renal renin as for active plasma renin and trypsin-activated plasma prorenin. Maximum velocity and Km values measured in mixtures of purified active renin and renin substrate and the concentrations of active renin and renin substrate measured in whole plasma were entered into the Michaelis-Menten equation for calculating PRA. The calculated values were similar to the measured results in all three groups, indicating that PRA was determined by the molar concentrations of enzyme and substrate. Thus, we found no evidence of unknown substances in plasma interfering with the enzyme-substrate reaction. The percentage of circulating renin in the active form was much lower during pregnancy than in other conditions where the renal release of active renin is stimulated and prorenin is as high as during pregnancy. This suggests that a smaller fraction of prorenin is intrarenally converted into active renin before its release into the circulation or that a larger fraction of circulating prorenin is of extrarenal origin. The finding that PRA is normal during OC treatment suggests that the estrogen-induced increase in renin substrate is compensated for by suppressed renal release of active renin.

Adult↗