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Biomedical subjects

F H Derkx

Publications and source records attributed to F H Derkx.

At least 127 records · Page 7Linked to original sources
PubMed1985

Captopril-induced changes on active and inactive renin in a patient with factor XII congenital deficiency.

A linkage between prorenin, renin, and intrinsic coagulation systems has been suggested recently. We studied the behavior of renin, prorenin, and kallikrein in a patient affected by congenital factor XII deficiency. Captopril test, upright posture, and furosemide administration provoked in our patients changes of renin and prorenin similar to those found in normal and hypertensive subjects. Unchanged kallikrein levels confirmed that no interaction between prorenin activation and factor XII-kallikrein system appears to be present.

Adult↗
PubMed1985

The effects of lead on the renin-angiotensin system.

Acute lead treatment of rabbits resulted in significant increases in both plasma renin activity and aldosterone concentration. No significant changes were observed in blood pressure, heart rate and plasma angiotensin-converting enzyme activity. The calcium channel-blocking drug verapamil attenuated the renin and aldosterone response in vivo. Lead increased renin release in a dose-dependent manner in a renal cortex slice preparation. Both verapamil and diltiazem attenuated the lead-induced renin release in vitro, but only with diltiazem did this attain statistical significance.

Aldosterone↗
PubMed1985

Use of captopril in the diagnostic work-up of renovascular hypertension.

A total of 179 patients were selected for a diagnostic work-up of renovascular hypertension from a consecutive series of hypertensive patients referred to a single outpatient clinic between January 1978 and January 1985. Selection criteria were: (1) diagnostic blood pressure > 120 mmHg in patients of 40 years or younger, irrespective of whether they were on treatment or not, and/or (2) diastolic blood pressure > 100 mmHg despite combination therapy with at least three drugs. All patients underwent renal angiography. The diagnostic value of the responses of blood pressure and plasma renin 1 h after 50 mg captopril was assessed while the patients were untreated for at least 2 weeks. The captopril test had a predictive value of 0.92 using a concentration of enzymatically active renin in plasma > 200 microU/ml as criterion for a positive test. The predictive value of a negative test was 0.81. Predictive values were not improved by combining blood pressure response with renin level after captopril. The prevalence of renal artery stenosis was 50% (unilateral stenosis 34%). In a hypertension clinic where patients with severe or therapy-resistant hypertension and a high prevalence of renal artery stenosis are seen, the captopril test proves to be useful for selecting cases for renal angiography.

Adult↗
PubMed1984

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.

Adult↗
PubMed1984

The inability of propranolol and aspirin to inhibit the response of fibrinolytic activity and factor VIII-antigen to infusion of DDAVP.

We tested the response of the fibrinolytic activity and factor VIII-antigen levels to infusion of DDAVP in healthy volunteers and we studied the influence of propranolol and aspirin on this response. After DDAVP, 0.4 microgram/kg in 10 min i.v., the fibrinolytic activity of redissolved euglobulins rose from 179 to 452 mm2 (lysis area of fibrin plates); after pretreatment with propranolol, 320 mg per day during 7 days, DDAVP induced a similar rise (from 166 to 471 mm2) and after pretreatment with a single dose of aspirin, 600 mg, ingested 5 hr before the DDAVP infusion, the lysis area increased from 159 to 455 mm2. Factor VIII-antigen level increased within 60 min after DDAVP from 104 to 208%; after pretreatment with propranolol from 111 to 230% and after a single dose of aspirin, DDAVP induced a rise from 107 to 206%. From these data we conclude that neither baseline levels nor the release of plasminogen activator or factor VIII after DDAVP infusion are influenced by beta-blockade or by interference with prostaglandin synthesis.

Antigens↗
PubMed1984

Clinical pharmacokinetics: a comprehensive system for therapeutic drug monitoring and prescribing.

Clinical pharmacokinetics is an expanding scientific discipline which can make an impact on treatment in coronary care, intensive care, paediatrics, general medicine and surgery, and general practice. The aim of this study was to establish a rapid system of drug assay, to report the result, to assess the influence of pathological and clinical factors on the pharmacokinetics of certain drugs, and to use a computer to determine the optimum dosage of drugs. The clinical pharmacokinetics laboratory in Stobhill is available to all clinical departments and to general practitioners in the area. Digoxin, theophylline, and phenytoin have been assessed. Initial samples of these drugs showed that only about a third were in the therapeutic range; samples obtained after the issue of the laboratory report showed an improvement. The predictive performance of the computer program improved with feedback of one or two drug concentrations. Dosages of drugs chosen on an empirical basis may not lead to optimum treatment, and by testing samples early the dosage of the drug can be adjusted. It is hoped that the results achieved will encourage other clinical, pharmaceutical, and scientific colleagues to develop laboratories along similar lines.

Digoxin↗
PubMed1984

Prorenin-renin conversion by the contact activation system in human plasma: role of plasma protease inhibitors.

Acid-pretreated normal human plasma generates renin activity at 0 degree C and neutral pH by the activation of prorenin. The activation is caused by kallikrein generated from prekallikrein by activated factor XII. Nonacidified plasma also generates renin at 0 degree C, but at a lower rate (cold-promoted activation). In normal plasma, 14% +/- 1% of prorenin (mean +/- SEM, n = 30) was activated during incubation at 0 degree C for 7 days (range 6% to 26%). Cold-promoted activation of prorenin was within the normal range in plasma deficient in factor XI, X, IX, VIIIC, VII, V, prothrombin, or high mol wt kininogen. Cold-promoted activation of prorenin was less than or equal to 1% in plasma deficient in factor XII or prekallikrein. Reconstitution of these plasmas with highly purified factor XII or prekallikrein restored normal prorenin activation. Correction of high mol wt kininogen deficiency had no effect. Thus cold-promoted activation of prorenin depends on the presence of factor XII and prekallikrein, whereas the other clotting factors are not essential. The influence of the inhibitors C1 esterase-inhibitor, alpha 2-macroglobulin, antithrombin III, and alpha 1-antitrypsin on the activation of prorenin was studied in factor XII-deficient plasma from which one or more of these inhibitors had been selectively removed by immunoadsorption. Factor XII was subsequently added, and the generation of renin at 37 degrees C was observed after complete factor XII-high mol wt kininogen-mediated activation of prekallikrein induced by dextran sulfate. No activation of prorenin was observed at 37 degrees C after depletion of C1 esterase inhibitor, alpha 2-macroglobulin, antithrombin III, or alpha 1-antitrypsin. When prekallikrein was activated in plasma depleted of both C1 esterase-inhibitor and alpha 2-macroglobulin, 6% of prorenin was activated in 2 hours at 37 degrees C. After additional depletion of antithrombin III, the activation increased to 47%. These results indicate that the contact activation system is capable of activating prorenin in plasma at physiologic pH and temperature when the three most important kallikrein inhibitors, C1 esterase-inhibitor, alpha 2-macroglobulin, and antithrombin III, are absent.

Binding Sites↗
PubMed1983

Cardioprotection by blockade of beta 2-adrenoceptors.

The effects of different beta-adrenoceptor agonists and antagonists on plasma noradrenaline and potassium concentrations were studied in patients with borderline hypertension. Heart rate, arterial pressure and the heart rate corrected duration of total electromechanical systole (QS2I) were also measured. Infusion of the beta-adrenoceptor agonists isoprenaline (non-selective) and salbutamol (beta 2-selective), but not prenalterol (beta 1-selective) caused dose-dependent increments in plasma noradrenaline. Isoprenaline and salbutamol decreased plasma potassium dose-dependently. For a given effect on heart rate and QS2I the fall in potassium was less pronounced after prenalterol. The effects of isoprenaline were also studied after the beta-adrenoceptor antagonists propranolol, 320 mg day-1 for 1 week (non-selective) and atenolol, 100 mg day-1 for 1 week (beta1-selective). The effects of isoprenaline, when infused in equipotent chronotropic doses, on noradrenaline and potassium were not affected by atenolol, whereas they were completely abolished by propranolol. The rise in noradrenaline during beta-adrenoceptor stimulation could be explained by presynaptic facilitation of noradrenaline release. The fall in potassium probably reflects stimulation of Na-K-ATPase dependent transport of potassium into the cell. Both effects were seen after beta 2- but not after beta 1-adrenoceptor stimulation. Hypokalaemia and raised levels of noradrenaline are also known to occur under such stressful conditions as acute myocardial infarction, when circulating levels of the endogenous beta 2-adrenoceptor agonist adrenaline are high. Blockade of these effects by beta-adrenoceptor antagonists may contribute to the cardioprotective effect of these drugs. This warrants further consideration of the clinical significance of beta-blocker selectivity.

Adrenergic beta-Agonists↗
PubMed1983

DDAVP (1-desamino-8-D-arginine vasopressin): an antagonist of the pressor action of endogenous vasopressin?

The pressor effect of arginine vasopressin (AVP) is thought to be mediated by a calcium-dependent mechanism (V1-receptor) whereas its antidiuretic effect depends on c-AMP (V2-receptor). 1-Desamino-8-D-arginine-vasopressin (DDAVP) is possibly an antagonist on the V1-receptor and may therefore be used for assessing the role of endogenous AVP in blood pressure regulation. This possibility was tested using the following models: aggregation of human platelets, renin secretion by rabbit kidney slices, and blood pressure and renin responses in normal human subjects (n = 11) and patients with autonomic insufficiency (n = 4). AVP 10(-10)-10(-7) mol/l caused dose-dependent platelet aggregation and inhibition of renin secretion. These effects were absent in a calcium free medium or in the presence of the calcium antagonist verapamil 5 X 10(-5) mol/l. DDAVP up to 10(-5) mol/l had no effect but shifted the dose-response curves of AVP to the right. AVP infusion into normal subjects is known to lower heart rate and plasma renin with little change in blood pressure. DDAVP 400 ng/kg in 10 min caused no change in systolic pressure but diastolic pressure was lowered by 14 +/- 2 mmHg (mean +/- s.e.m.). Heart rate rose by 24 +/- 2 beats/min and renin rose from 21 +/- 4 to 57 +/- 9 muu/ml (P less than 0.01). In the patients with autonomic insufficiency both systolic and diastolic pressures fell by 20-50 mmHg after DDAVP 200 ng/kg without any change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Plasma kallikrein-mediated activation of the renin-angiotensin system does not require prior acidification of prorenin.

Activation of prorenin in the neutral phase after pH 3.3 dialysis of human plasma depends on clotting factor XII-initiated prekallikrein to kallikrein conversion. Acid dialysis may be necessary for destroying kallikrein inhibitors or rendering prorenin susceptible to attack by kallikrein. If the latter possibility proves true, it is difficult to see how the factor XII-kallikrein pathway could activate prorenin in vivo. Plasma prorenin was therefore separated from active renin and from the protease inhibitors alpha 2-macroglobulin, C1-inactivator, alpha 1-antitrypsin, inter-alpha-trypsin inhibitor, and antithrombin III by gel filtration on Sephadex G-100 and affinity chromatography on Blue Sepharose CL-6B at neutral pH. The resulting prorenin preparation could be activated at pH 7.5 by highly purified human plasma kallikrein, which was prepared from prekallikrein by activation with active factor XII fragment beta-factor XII a. Activation proceeded at 4 and 37 C at a kallikrein concentration of 2 micrograms/ml, which is approximately 5% of the prekallikrein concentration in normal plasma. It appears that an acid-induced conformational change of the prorenin molecule is not required for its activation by plasma kallikrein.

Angiotensin I↗
PubMed1982

Recurrence of hypertension in primary aldosteronism after discontinuation of spironolactone. Time course of changes in cardiac output and body fluid volumes.

Hemodynamic mechanisms underlying the hypertensive action of long-standing sodium overload were studied in ten subjects with aldosterone-producing adenoma. Arterial pressure was 129+/-4/91+/-4 mm Hg (mean+/-SEM) during spironolactone treatment, 177+/-5/114+/-3 mm Hg six weeks after the drug had been stopped, and 136+/-4/94+/-3 mm Hg two months after operation. In the six weeks following cessation of spironolactone, cardiac output, stroke volume, blood volume and sodium space were determined at weekly intervals. In each subject the biochemical syndrome of aldosterone-excess had been fully developed in two weeks. The hemodynamic changes in that period were also uniform. Mean arterial pressure in week 2 was increased by 20+/-3% with parallel increments of cardiac output and stroke volume of 22+/-5 and 30+/-6%. Blood volume and sodium space were increased by 11+/-2 and 29+/-4%. The patterns in weeks 2-6 were not uniform. In five subjects (age 33-49 yr) the hypertension was maintained through increased cardiac output; in week 6 it was 34+/-7% above its initial value, and stroke volume and blood volume were 37+/-4 and 16+/-4% above control. In the remaining five subjects (age 50-60 yr) cardiac output, stroke volume and blood volume returned to their initial values, and total peripheral resistance in week 6 was 36+/-13% above control. Sodium space remained expanded in both groups. The measurements after surgery confirmed the existence of the high-flow and high-resistance patterns; there was a decrease in cardiac output in the former group of subjects and a decrease in resistance in the latter. Apparently, increased resistance is not a direct consequence of increased flow. The observed age-related differences in hemodynamic patterns of sodium overload bear some resemblance to essential hypertension where a high-flow state of long duration may precede the ultimate phase of low vascular capacitance and high resistance.

Aldosterone↗
PubMed1982

Role of intrinsic inhibitors in acid-activation of inactive plasma renin (prorenin).

Inactive plasma renin is converted into an active form of renin during dialysis of plasma against a pH 3.3-buffer. This form of renin is inactivated at neutral pH. When plasma, after acid-dialysis, is kept at neutral pH a different form of active renin is generated, which remains active. The irreversible activation of prorenin depends on factor XII-initiated kallikrein formation. C1-inhibitor (C1-INH) and alpha 2-macroglobulin (alpha 2M) can be selectively denaturated by treatment of plasma at low pH values to which kallikrein and renin are resistant. After denaturation of C1-INH at pH 4-5, factor XII becomes capable of activating prekallikrein. The kallikrein that is formed after restoration of pH is complexed with alpha 2M. This complex has little activity towards natural protein substrates including prorenin. alpha 2M is denaturated at pH 3-4 and, as a consequence, kallikrein that is formed after restoration of pH is not complexed with alpha 2M. This kallikrein is able to attack both high-molecular weight kininogen and prorenin as manifested by the generation of bradykinin-forming and angiotensin-forming activities. These observations show a crucial role for C1-INH and alpha 2M in prorenin activation and explain, at least in part, why the pH of the acid-treatment step has to be less than 4 before irreversible activation of prorenin at neutral pH can occur.

Cold Temperature↗
PubMed1982

Activation of plasma prorenin by plasminogen activators in vitro and increase in plasma renin after stimulation of fibrinolytic activity in vivo.

Plasminogen can be activated by intrinsic activators that circulate in plasma in a precursor form, by extrinsic activator originating from tissues or the vessel wall and by the exogenous activators, urokinase and streptokinase. Tissue activator and vascular activator are probably identical. Dialysis of plasma against pH 4.0 buffer causes denaturation of the plasmin inhibitors, alpha 2-antiplasmin and C1-inhibitor, while alpha 2-macroglobulin is left intact. Incubation of pH 4.0-pretreated plasma with urokinase or streptokinase at pH 7.5 led to activation of plasminogen and prorenin. Incubation of a plasma fraction, which contained plasminogen and prorenin but no alpha 2-antiplasmin and renin, with highly purified tissue plasminogen activator also led to activation of prorenin. The vasopressin analogue, 1-desamino-8-D-arginine vasopressin (DDAVP), is a potent stimulant for the release of extrinsic activator into the bloodstream. After infusion of DDAVP, 0.4 micrograms/kg, into normal subjects, parallel increments in plasma fibrinolytic activity and renin were observed. Infusion of DDAVP into patients with type IV hyperlipoproteinaemia had little effect on plasma fibrinolytic activity and the response of plasma renin was also subnormal. These observations warrant further studies on a possible role for plasminogen activators in prorenin activation in vivo.

Cold Temperature↗