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Biomedical subjects

F H Derkx

Publications and source records attributed to F H Derkx.

At least 91 records · Page 5Linked to original sources
PubMed1990

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.

Administration, Oral↗
PubMed1990

Normal homeostasis of fibrinolysis in nephrogenic diabetes insipidus in spite of defective V2- receptor-mediated responses of tissue plasminogen activator release.

Three patients with congenital, nephrogenic diabetes insipidus (NDI) from two unrelated families were tested for haemostatic and fibrinolytic responses to DDAVP infusion and venous occlusion. None of the three patients showed a response of factor VIII:C, vWF:Ag or t-PA to DDAVP, a V2-agonist. However, the baseline levels of these factors in the patients' plasma were normal and during venous occlusion a rise in t-PA antigen and t-PA activity was observed in all patients. One patient showed a definite response of the t-PA antigen level to exercise. It is concluded that (extrarenal) V2-receptor-mediated responses are absent in these patients, but that baseline homeostasis and the response to venous occlusion and physical exertion are intact. Presumably, these depend on other mechanisms. This observation denies a central role for vasopressin receptors in the on-demand regulation of clotting and clot dissolving properties of the blood.

Adult↗
PubMed1990

Increase in plasma prorenin during the menstrual cycle of a bilaterally nephrectomized woman.

To investigate the origin of the prorenin peak that occurs during the normal menstrual cycle, plasma levels of prorenin, renin, oestradiol, progesterone, LH and FSH were measured serially in a nephrectomized woman having regular haemodialysis. The prorenin peak coincided with the LH surge and preceded the rise of progesterone, whereas renin was below the detection limit during the whole cycle. These findings indicate that the rise in prorenin during the menstrual cycle is not of renal origin but is probably due to increased production by the ovary and supports the increasing evidence for the existence of a local renin-angiotensin system in the ovary.

Adult↗
PubMed1990

Raised plasma renin and prorenin in rheumatoid vasculitis.

The value of plasma renin and its inactive precursor, prorenin, were examined as a marker for vasculitis in rheumatoid arthritis (RA). Plasma renin and prorenin rise when the renin-angiotensin system is activated; an isolated increase of prorenin may be a marker for microvascular complications in diabetes mellitus. Renin concentrations in plasma obtained from 34 patients with RA (seven with vasculitis, 27 controls) were measured under standard conditions, before and five days after stopping non-steroidal anti-inflammatory drugs; creatinine clearance was also measured. At first the median renin concentration in the patients with vasculitis was 19 (range 12-63) mU/l (normal less than 61 mU/l) and in the controls 9 (3-43) mU/l. The median prorenin concentration in patients with vasculitis was 233 (144-428) mU/l (normal less than 358 mU/l) and in the controls 144 (25-364) mU/l. Renin and prorenin concentrations increased significantly in both groups after withdrawal of nonsteroidal anti-inflammatory drugs. The creatinine clearance was similar in both groups and did not correlate with renin concentrations. In conclusion, it was found that, unlike patients with diabetes mellitus, patients with RA with vasculitis had slightly raised concentrations of both renin and prorenin. These findings signal activation of the renin-angiotensin system and might indicate early cardiac or renal involvement by vasculitis.

Aged↗
PubMed1990

Metabolism and production of angiotensin I in different vascular beds in subjects with hypertension.

To study the metabolism and production of angiotensin I, highly purified monoiodinated [125I] angiotensin I was given by constant systemic intravenous infusion, either alone (n = 7) or combined with unlabeled angiotensin I (n = 5), to subjects with essential hypertension who were treated with the angiotensin converting enzyme inhibitor captopril (50 mg b.i.d.). Blood samples were taken from the aorta and the renal, antecubital, femoral, and hepatic veins. [125I]Angiotensin I and angiotensin I were extracted from plasma, separated by high-performance liquid chromatography, and quantitated by gamma counting and radioimmunoassay. Plasma renin activity was measured at pH 7.4. The plasma decay curves after discontinuation of the infusions of [125I]angiotensin I and unlabeled angiotensin I were similar for the two peptides. The regional extraction ratio of [125I]angiotensin I was 47 +/- 4% (mean +/- SEM) across the forearm, 59 +/- 3% across the leg, 81 +/- 1% across the kidneys, and 96 +/- 1% across the hepatomesenteric vascular bed. These results were not different from those obtained for infused unlabeled angiotensin I. Despite the rapid removal of arterially delivered angiotensin I, no difference was found between the venous and arterial levels of endogenous angiotensin I across the various vascular beds, with the exception of the liver where angiotensin I in the vein was 50% lower than in the aorta. Thus, 50-90% of endogenous angiotensin I in the veins appeared to be derived from regional de novo production. The blood transit time is 0.1-0.2 minute in the limbs and in the kidneys and 0.3-0.5 minute in the hepatomesenteric vascular bed. This is too short for plasma renin activity to account for the measured de novo angiotensin I production. It was calculated that less than 20-30% in the limbs and in the kidneys and approximately 60% in the hepatomesenteric region of de novo-produced angiotensin I could be accounted for by circulating renin. These results indicate that a high percentage of plasma angiotensin I may be produced locally (i.e., not in circulating plasma).

Adult↗
PubMed1990

Intrarenal de novo production of angiotensin I in subjects with renal artery stenosis.

To estimate the renal extraction and de novo production of angiotensin I and to assess the contribution of blood-borne renin to renal angiotensin I production, the aortic and renal venous plasma levels of renin and intact [125I]angiotensin I and endogenous angiotensin I during continuous systemic intravenous infusion of monoiodinated [125I]angiotensin I were measured in subjects with unilateral renal artery stenosis (n = 8) who were treated with captopril (50 mg b.i.d.). Results demonstrated that 80% of angiotensin I delivered by the renal artery was extracted both by the affected and the unaffected kidney and that on both sides a major part of angiotensin I in the renal vein was derived from intrarenal de novo production. Production of plasma angiotensin I was in excess over extraction (p less than 0.01) on the affected side, whereas extraction was in excess over production (p less than 0.01) on the contralateral side. The plasma level of de novo intrarenally produced angiotensin I in the renal vein was seven times higher on the affected side than the contralateral side. This difference was by far too big to be explained by a difference in the transit time of blood between the two kidneys, by an augmented production of angiotensin I in the circulating blood passing through the affected kidney due to the higher level of venous plasma renin activity in that kidney, or by the combination of both.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Identification and quantification of renin and prorenin in the bovine eye.

Angiotensin-II, the most important biologically active product of the renin-angiotensin system, has been reported to play a role in neovascularization, and prorenin has been found in the vitreous of human eyes, particularly in those affected by proliferative diabetic retinopathy, a disease characterized by neovascularization. The prorenin level in these eyes was, relative to that of plasma albumin, higher than in eyes without neovascularization. These findings suggested that an intraocular renin-angiotensin system exists, which might be involved in the development of retinal neovascularization in diabetes mellitus. In this study angiotensin-I-generating activity was measured in bovine aqueous humor and vitreous and in extracts of bovine retina, pigment epithelium-choroid, and anterior uveal tract before and after subjecting these extracts to procedures known to convert prorenin to renin. The measurements were made by incubation at 37 C with plasma from nephrectomized rats at pH ranging from 5.0-8.5. True renin in the ocular samples could be separated from nonrenin acid protease by alpha-casein-Sepharose affinity column chromatography at pH 3.5; true renin did not bind to the column, whereas acid protease did. True renin was further identified by its relatively high pH optimum (6.5-7.0) for angiotensin-I generation, its complete inhibition with specific renin antiserum, and its high affinity for specific renin inhibitors. More than 75% of angiotensin-I-generating activity of the ocular samples consisted of true renin. Approximately 90% or more of total renin (renin plus prorenin) in aqueous humor, vitreous, and ocular tissue could not be explained by trapped plasma. Total renin in aqueous humor and renin in vitreous were near the detection limit of the assay of angiotensin-I-generating activity. In vitreous prorenin comprised 99% of the total renin, in retina 81%, and in pigment epithelium-choroid and anterior uveal tract less than 50%. Prorenin in ocular fluids showed a concentration gradient, posterior vitreous greater than anterior vitreous greater than aqueous humor, suggesting that the main source of extracellular prorenin was in the posterior eye. These data support the contention of local renin and/or prorenin synthesis in the eye and are in accordance with the observations in other tissues that extrarenal synthesis of renin is often associated with the release of mainly, or exclusively, prorenin into extracellular fluid.

Angiotensin I↗
PubMed1990

High plasma prorenin in diabetes mellitus and its correlation with some complications.

Plasma prorenin is abnormally high, whereas renin is normal or even low, in many patients with long-standing diabetes mellitus complicated by microvascular disease. Nephropathy or autonomic neuropathy has been put forward as a cause. We found that in 223 consecutive diabetics prorenin correlated positively with serum creatinine, the presence of macroalbuminuria (greater than 250 mg/L), and the presence of diabetic retinopathy, particularly the proliferative type. This correlation did not depend on the presence of neuropathy or whether the patient was receiving insulin. It was also independent of sex, age, duration of diabetes, blood pressure, and blood levels of glucose and hemoglobin-A1c. The association between elevated prorenin and retinopathy remained significant after adjustment for creatinine and the presence of macroalbuminuria. Of the whole group of diabetics 94 consecutive patients were assessed for the presence of microalbuminuria (30-300 mg/24 h). Independently of the presence of micro- or macroalbuminuria, the mean level of prorenin was not above normal in the patients without retinopathy and was 2-3 times normal in those with proliferative retinopathy. Thus, retinopathy appears to be a more important determinant of abnormally high prorenin than nephropathy. In addition, the renal vein to artery ratio of prorenin in 7 diabetics with both advanced nephropathy and proliferative retinopathy was not elevated, despite the high peripheral venous prorenin level and the impaired renal perfusion. Thus, the abnormally high prorenin level in these patients could not be explained by abnormal secretion by the kidneys. Finally, prorenin was not high in 16 nondiabetics with loss of sympathetic activity due to chronic autonomic neuropathy, which indicates that in the absence of diabetes, this type of autonomic failure is not sufficient to cause the high prorenin levels seen in diabetics. Our findings are evidence that abnormally high plasma prorenin levels in diabetics are not an immediate consequence of altered glucose metabolism. This abnormality is related to the development of microvascular disease in the eye and kidney and is at least in part due to decreased clearance of prorenin from the circulation, increased production from extrarenal sources, or both.

Albuminuria↗
PubMed1989

Renin in the bovine eye.

Recently, high levels of prorenin were found in human vitreous and subretinal fluid. In this study we attempted to identify and quantitate renin and prorenin in the bovine eye. Both these substances are present in the bovine eye in concentrations that cannot be explained by plasma contamination. Concentrations of total renin, i.e. renin plus prorenin, are highest in the posterior uveal tract [15.4 ng angiotensin (Ang) l/g per h]; in the anterior uveal tract the total renin concentration was 10.1, in plasma 6.3, in vitreous fluid 5.7 and in the retina 5.1 ng Ang l/g per h. Vitreous fluid contains mainly prorenin (99%), whereas the retina, and the anterior and posterior uveal tract contain less prorenin (respectively, 78, 47 and 32%). The absence of renin in vitreous fluid is consistent with the general finding that extrarenal renin synthesis is often associated with the release of mainly or exclusively prorenin into the extracellular fluid. Synthesis of renin and prorenin may take place in the eye.

Animals↗
PubMed1989

In vivo production of plasma angiotensin I: is plasma renin sufficient?

Production and metabolism of angiotensin I (Ang I) were studied during a constant intravenous infusion of mono-iodinated 125I-Ang I in seven patients with essential hypertension taking 50 mg captopril twice a day. The elimination of arterially delivered 125I-Ang I reached 80% in the kidneys, 45% in the forearm, 58% in the leg and 95% in the hepatomesenteric vascular bed. Despite the high level of elimination of Ang I, plasma levels of Ang I in the leg, forearm and renal vein were not different from that of arterial plasma. In the hepatic vein the plasma level of Ang I was 50% lower than in the aorta. Thus, 50-90% of endogenous Ang I in the veins is derived from new regional production. The blood transit time through the kidneys, limbs and hepatomesenteric region is too short for plasma renin activity to account for the measured new Ang I production. Our results indicate that a high percentage of plasma Ang I may be produced locally in the tissues, and not in circulating plasma.

Adult↗
PubMed1989

Effects of complete renal denervation and selective afferent renal denervation on the hypertension induced by intrarenal norepinephrine infusion in conscious rats.

To test the hypothesis that continuous intrarenal norepinephrine (NE) infusions produce hypertension via activation of afferent renal nerves (ARN), rats were subjected to complete renal denervation (RN-x), selective renal deafferentation (ARN-x) or sham surgery, prior to infusion of NE. In the pre-infusion period, mean arterial pressure (MAP) was significantly lower in RN-x than in ARN-x or sham-operated rats. Plasma renin concentration (PRC) was significantly reduced following ARN-x, but not RN-x. During 5-day intrarenal infusions of 4, 12 or 36 micrograms NE/kg per h, MAP rose to similar levels in RN-x and sham-RN-x rats. However, RN-x rats exhibited significantly elevated PRC levels, suggesting that denervation supersensitivity masked the possible effects of RN-x. In sham-RN-x rats, MAP increased significantly more during intrarenal infusion of 12 micrograms NE/kg per h than during intravenous infusion of the same amount. In ARN-x rats, MAP rose to a similar degree during intravenous and intrarenal infusions. The pressor responses in the ARN-x rats, however, were not significantly smaller at any point than those in intact rats. PRC rose to comparable levels in ARN-x and intact rats. Thus, in normotensive rats, efferent renal nerves (ERN) but not ARN are of functional significance in maintaining basal blood pressure. ARN may be involved in the control of renin release. Since neither RN-x nor ARN-x attenuated the development of hypertension, renal nerves are not necessary for the full expression of hypertension in this model.

Afferent Pathways↗
PubMed1989

Estimation of regional metabolism and production of angiotensins in hypertensive subjects.

1. We attempted to collect information on the metabolism and production of angiotensins (ANG) in different vascular beds in humans by constant i.v. infusion of mono-iodinated [125I]-ANG I into subjects with essential hypertension, at the time of renal vein catheterization as part of the diagnostic work-up for renovascular hypertension. 2. Blood samples were taken from the aorta and the renal, antecubital, femoral and hepatic veins. ANG I, ANG II, [125I]-ANG I and [125I]-ANG II were extracted from plasma, separated by h.p.l.c. and quantitated by radio-immunoassay or gamma counting. 3. Our studies so far are restricted to subjects on captopril 50 mg twice daily. Under ACE inhibition (4-6 h after dosing of captopril) no differences in elimination half-life and regional extraction were found between infused [125I]-ANG and unlabelled ANG I. Extraction of arterially delivered [125I]-ANG I was 80% in the kidney, 45% in the forearm, 58% in the leg and 95% in the hepato-mesenteric vascular bed. 4. Measurements of arterial and venous [125I]-ANG II levels indicated that [125I]-ANG I-II conversion had occurred in the cardio-pulmonary vascular bed. 5. ANG I production in the hepato-mesenteric region could be largely accounted for by the renin activity of circulating plasma, but in kidney and limbs only 20-30% of regionally produced ANG I could be accounted for by plasma renin activity. 6. Thus, a major fraction of regionally produced ANG I appears to be formed locally, i.e. not in circulating plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Renin, prorenin, and immunoreactive renin in vitreous fluid from eyes with and without diabetic retinopathy.

Renin, prorenin, and immunoreactive renin were present in vitreous and subretinal fluid of eyes from subjects with and without diabetic retinopathy. Renin substrate, albumin, transferrin, and immunoglobin G were also found in these ocular fluids. In many samples renin levels were close to the detection limit of the assay. The levels of renin substrate, albumin, transferrin, and immunoglobulin G varied widely among ocular fluid samples, but in each individual sample the levels were, relative to each other, similar to those in plasma. In contrast, the prorenin level in ocular fluid was up to 100 times higher than expected on the basis of the plasma protein content of ocular fluid. Moreover, there was little difference in prorenin concentrations between samples with low and high plasma protein contents. Prorenin, relative to albumin and other plasma proteins, was higher in vitreous fluid from eyes with proliferative diabetic retinopathy complicated by traction retinal detachment than in eyes of nondiabetic subjects with spontaneous retinal detachment. It appears that prorenin (and possibly renin) in ocular fluid is controlled by an active and specific process, possibly local synthesis within the eye. In view of the vascular actions of angiotensin II, an intraocular renin-angiotensin system may play a role in diabetic retinopathy.

Adult↗
PubMed1989

Changes in plasma renin activity and renal immunohistochemically demonstrated renin in carbadox treated pigs.

Carbadox is known to induce toxic effects on the adrenal cortex, resulting in hypoaldosteronism. To study the involvement of carbadox on the renin-angiotensin system, weaned piglets of five weeks old received feed supplemented with 0 (control group), 50, 100, 150 or 200 ppm carbadox. After four weeks the 100 and 150 ppm groups had significantly higher plasma renin activity levels than the control group and after nine weeks plasma renin activity levels of all treated groups were significantly higher than the control group. Five and 10 weeks after carbadox administration, three and two pigs, respectively, of all groups were necropsied and the kidneys were screened for immunohistochemically demonstrated renin. All dosed pigs demonstrated an increase of immunoreactive renin, which was dose- and time-related. From these results it is concluded that carbadox induces activation of the renin-angiotensin system, secondary to the suppressing effect on mineralocorticoid secretion and that these changes may be responsible for part of the clinical picture.

Administration, Oral↗
PubMed1988

Support for adrenaline-hypertension hypothesis: 18 hour pressor effect after 6 hours adrenaline infusion.

In a double blind, crossover study 6 h infusions of adrenaline (15 ng/kg/min; 1 ng = 5.458 pmol), noradrenaline (30 ng/kg/min; 1 ng = 5.911 pmol), and a 5% dextrose solution (5.4 ml/h), were given to ten healthy volunteers in random order 2 weeks apart. By means of intra-arterial ambulatory monitoring the haemodynamic effects were followed for 18 h after the infusions were stopped. Adrenaline, but not noradrenaline, caused a delayed and protracted pressor effect. Over the total postinfusion period systolic and diastolic arterial pressure were 6 (SEM 2)% and 7 (2)%, respectively, higher than after dextrose infusion (ANOVA, p less than 0.001). Thus, "stress" levels of adrenaline (230 pg/ml) for 6 h cause a delayed and protracted pressor effect. These findings are strong support for the adrenaline-hypertension hypothesis in man.

Adult↗
PubMed1988

Renal and hepatic handling of endogenous tissue-type plasminogen activator (t-PA) and its inhibitor in man.

In eight male patients with normal liver and kidney function fibrinolytic components were measured in arterial blood and in renal and hepatic vein blood, obtained during catheterization for analysis of hypertension. Blood samples were collected simultaneously from veins und corresponding arteries before and 5 minutes after the completion of intravenous injection of desmopressin (DDAVP), 0.4 micrograms/kg body weight over a 10 minute period. DDAVP induced a rise in t-PA antigen and activity, and in von Willebrand factor, accompanied by a decrease in free PA-inhibitor level. We failed to detect a significant rise in plasma urokinase activity. The concentrations of fibrinogen, plasminogen, alpha 2-antiplasmin, antithrombin III and coeruloplasmin did not change either. Renal production of t-PA under basal conditions was inferred from a negative arterio-venous (A-V) difference in t-PA-activity and in t-PA-antigen levels but this could not be confirmed by orthogonal regression analysis of the same data. A-V differences of other fibrinolytic factors were negligible. In the hepatic vessels a significant positive A-V difference of t-PA-activity and of t-PA-antigen levels was a uniform finding. After DDAVP, when plasma levels were elevated, the mean A-V difference was proportionally higher, consistent with a constant fractional elimination rate. Free PA-inhibitor was virtually absent from arterial blood after DDAVP, but appeared in hepatic vein blood, indicating either production of the inhibitor by the liver or dissociation of a circulating complex of t-PA and its inhibitor in the liver. The blood levels of the other investigated components did not show any change upon passage through the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Atrial wall stress rather than pressure per se might be responsible for the increased secretion of atrial natriuretic factor after heart transplantation.

Plasma atrial natriuretic factor (ANF) concentrations were measured, and relationships to intracardiac pressures and atrial dimensions were assessed in a series of 17 heart transplant recipients undergoing cardiac catheterization during their annual evaluation. Despite excellent cardiac function (normal filling pressures, adequate cardiac output, ejection fraction above 60%), plasma levels of ANF were elevated. Step-up levels across the heart were consistent with increased cardiac secretion, whereas both the metabolic clearance rate and plasma half-life were normal. Correlations between plasma concentrations of ANF at different cardiac sites and atrial filling pressures were low. However, right and left atrial dimensions in our patients were greatly enlarged. These findings suggest that increased atrial size (by virtue of the atrial anastomoses) and augmented wall stress (law of Laplace) rather than pressure per se are responsible for the increased ANF production after heart transplantation.

Atrial Natriuretic Factor↗