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Biomedical subjects

F H Derkx

Publications and source records attributed to F H Derkx.

At least 73 records · Page 4Linked to original sources
PubMed1993

1-Desamino-8-D-arginine vasopressin (DDAVP) in patients with congenital nephrogenic diabetes insipidus.

In healthy subjects, intravenous infusion of the selective V2-vasopressin receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP, 400 ng/kg in 10 min) causes a marked increase in heart rate with a slight decrease in diastolic blood pressure. These haemodynamic responses are associated with increments in the plasma levels of renin, noradrenaline (NA), clotting factor VIII (FVIII:C), von Willebrand factor (vWF:ag), and tissue-type plasminogen activator (t-PA), and a fall in the plasma level of plasminogen activator inhibitor (PAI). None of these changes was observed in 3 patients with congenital nephrogenic diabetes insipidus (NDI), who had a genetic defect of the V2-receptor. Plasma AVP levels in these patients were normal or slightly elevated, which makes it unlikely that the lack of DDAVP responsiveness was caused by down-regulation of vasopressin V1-receptors. In one NDI patient, arginine vasopressin (AVP) was given in incremental doses (62.5-4000 pg/kg/min). The heart rate and blood pressure responses to AVP were normal, indicating the absence of a V1-receptor defect. The responses of vWF:ag and t-PA to venous occlusion in the patients with NDI were similar to those in 5 healthy volunteers, which indicates that in NDI the endothelial release of both vWF:ag and t-PA is normal. We conclude that DDAVP causes its effects on heart rate and blood pressure, and on the plasma levels of renin, noradrenaline, FVIII:C, vWF:ag, and t-PA through V2-receptor stimulation.

Adult↗
PubMed1992

Nonproteolytic "activation" of prorenin by active site-directed renin inhibitors as demonstrated by renin-specific monoclonal antibody.

Incubation of human plasma prorenin (PR), the enzymatically inactive precursor of renin (EC 3.4.23.15), with a number of nonpeptide high-affinity active site-directed renin inhibitors induces a conformational change in PR, which was detected by a monoclonal antibody that reacts with active renin but not with native inactive PR. This conformational change also occurred when inactive PR was activated during exposure to low pH. Nonproteolytically acid-activated PR, and inhibitor-"activated" PR, as well as native PR, were retained on a blue Sepharose column, in contrast to proteolytically activated PR. Kinetic analysis of the activation of plasma prorenin by renin inhibitor (INH) indicated that native plasma contains an open intermediary form of prorenin, PRoi, in which the active site is exposed and which is in rapid equilibrium with the inactive closed form, PRc. PRoi reacts with inhibitor to form a reversible complex, PRoi.INH, which undergoes a conformational change resulting in a tight complex of a modified open form of prorenin, PRo, and the inhibitor, PRoi.INH-->PRo.INH. The PRoi-to-PRo conversion leads to the expression of an epitope on the renin part of the molecule that is recognized by a renin-specific monoclonal antibody. Presumably, PRo corresponds to the enzymatically active form of PR that is formed during exposure to low pH. Thus, it seems that the propeptide of PR interacts with the renin part of the molecule not only at or near the enzyme's active site but also at some distance from the active site. Interference with the first interaction by renin inhibitor leads to destabilization of the propeptide, by which the second interaction is disrupted and the enzyme assumes its active conformation. The results of this study may provide a model for substrate-mediated prorenin activation and increase the likelihood that enzymatically active prorenin is formed in vivo.

Antibodies, Monoclonal↗
PubMed1992

Metabolism of angiotensin I by different tissues in the intact animal.

To quantify regional conversion of angiotensin (ANG) I to ANG II and its degradation to peptides other than ANG II, monoiodinated 125I-labeled ANG I was given to anesthetized pigs by constant infusion into the left cardiac ventricle. At steady state, blood samples were taken from the aorta and various regional veins. Distribution volume of ANG I appeared to be 24% of body weight. After angiotensin-converting enzyme (ACE) inhibitor treatment, fractional ANG I metabolism (fraction of arterially delivered ANG I that was metabolized during a single passage of blood) was 10% in the lungs (conversion 4%), compared with 56% in the combined systemic vascular beds (conversion 1%). Fractional ANG I metabolism during ACE inhibition was 93% in the kidney; 50-70% in myocardium, skeletal muscle, head, and skin; 21% in the left cardiac cavity; and 14% in the right cardiac cavity. Without ACE inhibition, fractional ANG I metabolism was 29% in the lungs (conversion 25%); 49% in the combined systemic vascular beds (conversion 10%); 38% in the left cardiac cavity (conversion 11%); and 14% in the right cardiac cavity (conversion 0%). It may thus be concluded that 1) extrapulmonary vascular beds make an important contribution to the conversion of circulating ANG I and 2) there is rapid extrapulmonary ANG I degradation that does not depend on ANG I-II conversion.

Angiotensin I↗
PubMed1992

Production of angiotensins I and II at tissue sites in intact pigs.

To estimate the contribution of angiotensin (ANG) I and II production at tissue sites to the circulating levels, ANG I and II and their radiolabeled counterparts were measured in arterial and venous plasma across various vascular beds during constant infusion of 125I-ANG I into the left cardiac ventricle of anesthetized pigs. In the combined systemic vascular beds, ANG I production was closely correlated with plasma renin activity (PRA) and ANG II production was greater than in the lungs. In the lungs virtually no ANG I but 31% of ANG II in venous plasma was derived from de novo production, which could be fully accounted for by conversion of circulating ANG I. In myocardium, head, skin, skeletal muscle, and kidney, respectively, 40, 58, 55, 67, and 94% of venous ANG I, and 32, 49, 40, 59, and 85% of venous ANG II were derived from de novo production. In these extrapulmonary beds part of de novo produced ANG I and II appeared not to be generated, respectively, by PRA and by conversion of circulating ANG I. These results indicate that production of ANG I at tissue sites contributes to its circulating level and that some circulating ANG II may not be derived from circulating ANG I.

Angiotensin I↗
PubMed1992

Renin inhibitors, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists: relationships between blood pressure responses and effects on the renin-angiotensin system.

AIM: To compare the effects of angiotensin converting enzyme (ACE) inhibitors, renin inhibitors and angiotensin II (Ang II) antagonists. METHOD: Survey of data from recent studies. DISCREPANCY BETWEEN BLOOD PRESSURE REDUCTION INDUCED BY ACE INHIBITORS AND PLASMA ANG II LEVELS: Studies on the effects of ACE inhibition in hypertensive subjects have suggested that with chronic ACE inhibitor treatment, blood pressure remains lowered even when plasma Ang II returns to normal. However, this discrepancy may be largely an artefact related to difficulties in measuring low Ang II levels in the presence of high angiotensin I (Ang I) levels. Even with modern sensitive and specific Ang II assays it can be difficult to monitor in vivo ACE inhibition (Ang II:I ratio in plasma) because of ex vivo Ang II formation. Recently, in measuring 24-h blood pressure responses to ACE inhibitor treatment, we have obtained good correlations between the time-course of the blood pressure response and the change in circulating Ang II. PROBLEMS IN MEASURING RENIN ACTIVITY: Routine assays of renin activity in plasma can lead to an overestimate of the degree of in vivo inhibition during renin inhibitor treatment, because some protease inhibitors that are used in these assays can cause an ex vivo displacement of protein-bound renin inhibitor, thereby increasing its free concentration. This must be taken into account when using the ratio of enzymatically active renin to immunoreactive renin as an index of in vivo renin inhibition. BLOOD PRESSURE RESPONSE AND ANG II LEVELS WITH RENIN INHIBITORS AND ANG II ANTAGONISTS: Results published so far seem to indicate that with these drugs, as with the ACE inhibitors, the magnitude of the blood pressure effect is correlated with the decrease in the 'effective' Ang II concentration at the receptor sites. However, the time-course of the two effects may be different; with the renin inhibitors, the maximum effect on pressure was delayed compared with the effect on Ang II. CONCLUSIONS: Further studies are needed to establish the exact time-course of renin and Ang II changes and their relationship to blood pressure. Only with rigorously controlled assays will it be possible to answer the question whether, for a given change in 'effective' Ang II concentration at the receptor sites, the effect on blood pressure is different with the three classes of anti-renin-angiotensin drugs.

Angiotensin Receptor Antagonists↗
PubMed1992

Plasma prorenin as an early marker of microvascular disease in patients with diabetes mellitus.

To test the hypothesis that a high plasma prorenin can be used as an early marker of microvascular complications in patients with diabetes mellitus plasma prorenin was measured in 44 patients with urinary albumin excretion between 30 and 300 mg/24 h (microalbuminuria) and 120 patients with urinary albumin excretion below 30 mg/24 h (normoalbuminuria). A high plasma prorenin was associated with diabetic retinopathy, particularly the proliferative type, serum creatinine and the 24 h urinary albumin excretion rate. Plasma prorenin was not correlated with age, duration of diabetes, glycosylated hemoglobin, blood glucose, and blood pressure. The association between elevated plasma prorenin and retinopathy remained significant after adjustment for serum creatinine and albumin excretion. Independent of the presence or absence of microalbuminuria, the mean plasma level of prorenin was not above normal in patients without retinopathy and was 2 to 3 times normal in patients with proliferative retinopathy. Thus retinopathy appears to be an important determinant of abnormally high plasma prorenin. Angiotensin converting enzyme (ACE) was elevated in the patients with diabetes mellitus as compared to control subjects but the plasma levels of ACE in diabetics with normoalbuminuria was not significantly different from the group with microalbuminuria. Plasma prorenin was not associated with ACE. A plasma level of prorenin of 225 mU/L had a sensitivity of 0.84 and a specificity of 0.82 for detecting the presence of microalbuminuria.

Adult↗
PubMed1992

Partial escape of angiotensin converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment: does it exist and does it affect the antihypertensive response?

OBJECTIVE: To investigate whether the compensatory rise in renin and plasma angiotensin I in response to repeated angiotensin converting enzyme (ACE) inhibitor treatment results in a partial escape of ACE inhibition over a 24-h dosing interval. DESIGN: A single-blind placebo-controlled study in two parallel groups of eight hypertensive subjects receiving a once-daily dose of the ACE inhibitor, spirapril, of either 12.5 or 25 mg. Detailed 24-h studies were performed at the end of 2 weeks of placebo, and after the first dose and 2 weeks administration of spirapril. METHODS: Twenty-four-hour ambulatory blood pressure was measured invasively. True' angiotensins I and II were measured by radioimmunoassay after high-performance liquid chromatography separation. RESULTS: Both for the lower and higher doses of spirapril, the time-course of changes of spiraprilat, the active metabolite of spirapril, and ACE activity was similar but the maximal rise in angiotensin I was twofold higher after 2 weeks administration than after the first dose. Angiotensin II after the first dose of spirapril fell rapidly, with lowest values 2 to 4 h after dosing. At the end of dosing interval angiotensin II had returned to values seen under placebo with the 12.5-mg dose, but at the end of the 24-h period it was still suppressed with the 25-mg dose. Compared with these first-dose responses the initial maximal degree of angiotensin II suppression after 2 weeks administration of either dose was similar, but during the subsequent hours the degree of angiotensin II suppression tended to be less with the lower and was significantly less with the higher dose of spirapril. With the lower dose of spirapril responses of 24-h ambulatory blood pressure to the first dose and to 2 weeks of administration were almost superimposable, although blood pressures in the second half of the dosing interval tended to be higher during chronic treatment. With the higher dose the response of nocturnal blood pressure after 2 weeks administration was diminished by 8.8 mmHg systolic and 6.8 mmHg diastolic. CONCLUSIONS: Repeated ACE inhibitor treatment with once-daily spirapril leads to a partial escape of ACE inhibition, as reflected by a shorter duration of angiotensin II suppression. This escape also affects the antihypertensive response in the second half of the dosing interval.

Adult↗
PubMed1991

Renal hemodynamics and the renin-angiotensin-aldosterone system in normotensive subjects with hypertensive and normotensive parents.

BACKGROUND AND METHODS: The kidney is important in blood-pressure regulation, but its role in the development of essential hypertension is still subject to debate. We compared renal hemodynamics, measured in terms of the clearance of para-aminohippuric acid and inulin, and the characteristics of the renin-angiotensin-aldosterone system in three groups of normotensive subjects at different degrees of risk for hypertension: 41 subjects with two normotensive parents, 52 with one normotensive and one hypertensive parent, and 61 with two hypertensive parents. The subjects ranged in age from 7 to 32 years. RESULTS: The mean renal blood flow was lower in the subjects with two hypertensive parents than in those with two normotensive parents (mean difference [+/- SE], 198 +/- 61 ml per minute per 1.73 m2 of body-surface area; P = 0.002). Moreover, both the filtration fraction and renal vascular resistance were higher in the subjects with two hypertensive parents (filtration fraction: mean difference, 3.0 +/- 1.1 percentage points; P = 0.006; renal vascular resistance: mean difference, 2.7 +/- 0.8 mm Hg per deciliter per minute per 1.73 m2; P = 0.006). The subjects with two hypertensive parents had lower plasma concentrations of renin (mean difference, 3.3 +/- 1.6 mU per liter; P = 0.03) and aldosterone (mean difference, 111 +/- 36 pmol per liter; P = 0.003) than those with two normotensive parents. The differences could not be explained by the small differences in blood pressure between the groups. The values in the subjects with one hypertensive and one normotensive parent fell between those for the other two groups. CONCLUSIONS: Renal vasoconstriction is increased and renin and aldosterone secretion is decreased in young persons at risk for hypertension. These findings support the hypothesis that alterations in renal hemodynamics occur at an early stage in the development of familial hypertension.

Adolescent↗
PubMed1991

A neonate with idiopathic hyperaldosteronism.

A boy with functional abnormalities of the gastro-intestinal tract, hyponatraemia, hypokalaemia and hypertension is described. All symptoms developed within the first 2 months of life. Increased aldosterone levels were associated with suppressed values in the renin-angiotensin system. The diagnosis of idiopathic hyperaldosteronism was made because of adrenal hyperplasia and the failure to suppress aldosterone to undetectable levels with glucocorticoids. Treatment with spironolactone alone, or in combination with either intravenous dopamine or ibopamine orally, amiloride, enalapril, hydralazine or clonidine corrected serum potassium values but failed to normalize blood pressure and to correct plasma renin activity and plasma aldosterone. However, the combination of spironolactone with nifedipine decreased blood pressure. Abnormal gastro-intestinal motility was corrected by low doses of oral magnesium hydroxide. To assess intracellular calcium homeostasis, the patient's peripheral blood mononuclear cells were incubated with increasing concentrations of calcium. As these cells failed to maintain physiological calcium concentration, a defect in intracellular calcium homeostasis was suspected.

Aldosterone↗
PubMed1991

Nonparallel effects of renin inhibitor treatment on plasma renin activity and angiotensins I and II in hypertensive subjects. An assay-related artifact.

Nonparallel effects of renin inhibitor treatment on plasma renin activity (PRA) and the plasma levels of angiotensins (ANG), as well as on blood pressure, have been observed in subjects with hypertension. This study addresses the possibility that renin inhibitors may show a high degree of plasma protein binding in vivo and that displacement of protein-bound inhibitor during the assay of PRA in vitro may lead to overestimation of renin inhibition. Indeed, with the ultrafiltration technique it was found that 96% of the novel renin inhibitor Ro 42-5892, when added to EDTA plasma, was bound to protein. The angiotensinase inhibitors phenylmethylsulfonyl fluoride (PMSF) and 8-hydroxy-quinoline sulfate (8-OHQ), which are currently used in PRA assays, caused a displacement of protein-bound inhibitor, thereby increasing its free concentration. This displacement was sufficient to explain the reduction in IC 50 of Ro 42-5892, which was seen in the PRA assay when PMSF and 8-OHQ were added to plasma. Such reductions in IC 50 were also seen with the renin inhibitors CGP 29-287, CGP 38-560A, and SR 43-845. When Ro 42-5892 was given, 1 mg/kg intravenously in 10 min, to subjects with hypertension, it appeared that plasma ANG I and II returned to baseline after 6-8 h, whereas PRA measured in the presence of PMSF and 8-OHQ was still suppressed. However, when PRA was measured without these angiotensinase inhibitors, the inhibition of PRA was parallel to the suppression of ANG I and II.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Plasma immunoreactive endothelin-1 in pregnant women with and without pre-eclampsia.

In normotensive nonpregnant women (n = 23), the plasma concentrations of immunoreactive endothelin-1 (ir-ET-1) were not different from nonpregnant women with essential hypertension (n = 15): 3.6 (2.0-5.4) ng/L (mean, range) versus 3.8 (2.4-5.8) ng/L. In normotensive pregnant women (n = 25), the plasma level of ir-ET-1 was 2.1 (1.3-3.4) ng/L (p less than 0.01) lower than in normotensive nonpregnant women. Pre-eclamptic patients (n = 25) had elevated ir-ET-1 plasma levels of 5.0 (2.1-12.4) ng/L (p less than 0.001 for normotensive pregnant women, p less than 0.01 for nonpregnant women). The low level of ir-ET-1 in normotensive pregnant women may be explained by the increase in the distribution volume of ir-ET-1 during the course of pregnancy. Damage of vascular endothelium is a consistent morphological abnormality in pre-eclampsia. Elevated ir-ET-1 in plasma might be a biochemical marker of this abnormality and may contribute to the pathogenesis of pre-eclampsia.

Biomarkers↗