Biomedical subjects
Publications and source records attributed to F H Derkx.
1. Rat plasma was subjected at 4 degrees C to various treatments known to convert inactive renin into its active form in human plasma. 2. No statistical differences in plasma renin concentration were found when the levels after the various treatments were compared with that of untreated rat plasma. 3. It is concluded that, in contrast to human plasma, no inactive form of renin is present in rat plasma.
The effects of captopril 450 mg/day for 4 weeks on blood pressure, heart rate, cardiac output and extracellular fluid volume were compared in severe, often drug-resistant hypertension (n = 23), mild to moderate hypertension associated with renal artery stenosis (n = 10) and mild to moderate essential hypertension (n = 20). Plasma renin in the three groups was 52 +/- 19, 58 +/- 17 and 20 +/- 4 microU/ml (mean +/- SEM), respectively. Blood pressure fell by 18 +/- 4%, 21 +/- 2% and 18 +/- 1%. The pressure drop was mainly due to a fall in peripheral vascular resistance. Addition of the diuretic hydrochlorothiazide (25-100 mg/day) caused a further fall in resistance. Despite the vasodilator effect of captopril, reflex cardiostimulation and reactive fluid retention were not observed. In severe hypertension, captopril alone was more effective in lowering blood pressure than combined diuretic-betablocker-vasodilator therapy. Moreover, cardiac output in these patients was higher and resistance was lower after captopril than during combined treatment. Thus, captopril was capable of normalising the abnormal haemodynamic state in patients with essential hypertension, and in hypertension associated with renal artery stenosis. Despite marked differences in pre-treatment plasma renin, the effects of captopril on systemic haemodynamics were similar in all the patients.
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1. Inactive renin in human plasma can be activated by pH 3.3-dialysis (generation of acid-activated renin), by clotting factor XII-mediated prekallikrein to kallikrein conversion after pH has been restored to neural (generation of acid-kallikrein-activated renin) or by the addition of trypsin (generation of trypsin-activated renin). 2. Natural active renin, acid-kallikrein-activated renin and trypsin-activated renin behave similarly during affinity chromatography on Blue-Sepharose CL-6B and during gel filtration on Sephadex G-100. They also show similar reaction kinetics with similar pH-optimum curves when acting on sheep renin substrate. 3. Acid-activated renin is different. It is retained on Blue-Sepharose columns and it is inactivated at neutral pH during incubation at 37 degrees C. This contrasts with the other forms of renin activated in vitro and with natural active renin. The pH-optimum curve of acid-activated renin, when acting on sheep renin substrate, is also different from that of the other forms of active renin. 4. It is to be proven that the renins generated in vitro by neutral serine proteinases are identical with natural active renin, but clearly they bear more resemblance to natural renin than acid-activated renin does. Our preliminary conclusion is that acid-activated renin is a 'laboratory renin', which does not circulate in normal peripheral venous plasma.
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Randomised, double-blind cross-over trials were performed in seven anephric patients to determine the effect of the orally active angiotensin-converting enzyme inhibitor captopril on blood pressure in fluid-depleted and fluid-replete patients. Patients were given captopril, 100 mg orally, or placebo one hour after haemodialysis, when they were fluid depleted. Their mean (+/- SEM) supine blood pressure fell from 127 +/- 12/71 +/- 6 mm Hg before captopril to 106 +/- 13/54 +/- 4 mm Hg 24 hours after the drug, while on placebo it rose from 123 +/- 11/73 +/- 5 mm Hg to 134 +/- 10/82 +/- 8 mm Hg. All patients developed orthostatic hypotension after captopril. In the fluid-replete state, two days after haemodialysis, captopril had no effect on blood pressure. The plasma concentration of active renin was extremely low and did not rise after fluid withdrawal or captopril. Thus the hypotensive effect of captopril did not appear to depend on circulating renin concentrations. The concept of "renin-dependent" hypertension, which is responsive to captopril, as opposed to "volume-dependent" hypertension, which is not responsive to captopril, may therefore be invalid.
1. The haemodynamic effects of 100 mg of captopril in renovascular hypertension (n = 11), essential hypertension (n = 12) and the anephric state (n = 7) were compared. Brachial artery pressure was measured in all patients, and changes in right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure and cardiac output were followed in renovascular and essential hypertension. Nephrectomized patients were studied before and after fluid withdrawal by ultrafiltration. 2. The pretreatment concentration of active renin in plasma was 100 +/- 24 mu-units/ml (mean +/- SEM) in renovascular hypertension, and 24 +/- 4 mu-units/ml in essential hypertension. In nephrectomized patients pretreatment renin was 1.7 +/- 0.3 mu-units/ml, and renin was unresponsive to withdrawal of 1.8 +/- 0.21 of body fluid. 3. The effects of captopril were maximal after 60-90 min. Mean arterial pressure after 90 min was lowered by 19 +/- 4% in renovascular hypertension, by 17 +/- 4% in essential hypertension and by 16 +/- 3% in fluid-depleted nephrectomized patients. These changes were not significantly different despite the marked differences in renin. Captopril had no effect on arterial pressure in the fluid-replete anephric state. 4. The effects of captopril on cardiac filling pressures and cardiac output in renovascular and essential hypertension were also not different. 5. It is concluded that the antihypertensive action of captopril may be largely independent of circulating renin.
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The release of both active and acid-activatable (inactive), renin was determined in piglets ranging in age from 3 to 53 days. The concentration of active renin in arterial plasma during control periods decreased from 4.4 +/- 1.1 ng/ml in 3--5-day-old animals to 0.7 +/- 0.1 ng/ml in 42-53-day-old animals, while the rate of release of active renin was unchanged (11.8 +/- 5.1 ng/min and 7.5 +/- 3.4 ng/min, respectively). Both isoproterenol and furosemide stimulated release of renin in all age animals while propranolol supressed renin release. The data indicate that the qualitative control of renin release is similar in animals of various ages and stages of development. However, the differences in the concentration of renin in plasma of newborn and more mature animals may depend on factors other than release of renin by the kidney. Newborn animals release both active and inactive renin from the kidney.
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1. In eight patients with essential hypertension (EHT) and six patients with renovascular hypertension (RVHT) peripheral venous enzymatically active and inactive renin values were followed after acute stimulation of renin release by the vasodilating agent diazoxide (300 mg intravenously). Active renin rose during the first hour after diazoxide and remained high during the following 15 h, but inactive renin fell during the first hour and rose thereafter. Peripheral venous active and inactive renin were not different from arterial values both before and after diazoxide. 2. Sixteen patients with EHT received propranolol, 80 mg, four times a day. Six of them had a first injection of diazoxide the day before propranolol was started and a second one after 10--14 days of propranolol treatment. Peripheral vein active renin was lowered by propranolol, but inactive renin was raised. Both the diazoxide-induced rapid rise of active renin and the fall of inactive renin observed in untreated patients were absent during treatment with propranolol. 3. In four patients with EHT and seven patients with RVHT renal vein sampling was performed before and 30 min after diazoxide. Increased release of active renin from kidneys that were not markedly contracted was associated with a fall of the renal vein to peripheral vein ratio of inactive renin to a value less than one. 4. It is concluded that under certain circumstances stimulated release of active renin is associated with removal of inactive renin from the circulation by the kidney. This may in fact be due to intrarenal transformation of circulating inactive renin into its active counterpart. The findings suggest that a beta-adrenoreceptor might be involved in this activation process.
1. Normal human plasma contains a proactivator of inactive renin. The pro-activator is activated at physiological pH in plasma that has been pretreated with acid. This activation in vitro leads to the conversion of inactive renin into the active form with simultaneous generation of kallikrein activity. 2. The endogenous activator of inactive renin has the same pH profile and inhibitor spectrum as plasma kallikrein. 3. Inactive renin can also be activated by exposure of plasma to exogenous trypsin, and in normal plasma the quantities of inactive renin that are activated after acidification and with trypsin are identical. Prekallikrein (Fletcher factor)-deficient plasma, however, has much lower renin activity after acidification than with trypsin. Thus acid activation of inactive renin depends on plasma prekallikrein, whereas the action of trypsin is independent of prekallikrein. 4. Highly purified tissue (pancreatic) kallikrein, in a concentration of less than 2 X 10(-8) mol/l, activates inactive renin that has been isolated from plasma by ion-exchange chromatography. In this respect it is at least 100 times more potent than trypsin. 5. It is therefore possible that plasma and/or tissue (renal) kallikreins are also involved in the activation of inactive renin in vivo.
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It has been reported that inactive (acid-activable) human renin could be converted into the active form by adding urinary kallikrein to acid-pretreated plasma. Without prior acidification, however, only a small portion of the total amount of inactive renin present in plasma was converted (activated) by kallikrein, probably because native plasma contains protease (kallikrein) inhibitors that are destroyed by acid. We have separated inactive and active renin by DEAE-Sepharose column chromatography of normal human plasma at pH 7.5 and a linearly increasing sodium gradient. Inactive renin isolated in this way could be activated at pH 7.5 by highly purified pancreas and urinary kallikreins. With the semipurified preparation of inactive renin, prior acidification was not required for obtaining virtually complete activation by kallikrein. The kallikreins were effective at concentrations as low as 1 x 10(-8) mol/liter. It is therefore possible that one or more tissue kallikreins act as physiological activators of inactive renin.
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