F. Bandiera

Comparison of Sublingual and Oral Captopril in Hypertension

The use of sublingual captopril has been recently suggested in hypertensive crisis on the assumption of a faster absorption and thus a more rapid effect on blood pressure than with the oral route. To verify this hypothesis we have compared the hypotensive effect of oral and sublingual captopril in 40 essential hypertensives who were randomly allocated to either route of administration. Captopril was administered orally dissolved in water or allowed to dissolve under the tongue. After 5, 10, 20, 30, 40, 60 and 90 minutes blood pressure, Plasma Renin Activity (PRA) and Angiotensin Converting Enzyme (ACE) were measured. No significant differences were found between the two groups in the time course of blood pressure decrease, PRA increase and ACE inhibition. The changes of the parameters studied was superimposable irrespective of the route of administration thus not supporting the hypothesis that sublingual captopril might be absorbed more rapidly.

Immunoradiometric Assay of Active Renin in Human Plasma: Comparison with Plasma Renin Activity

The direct measurement of active renin with monoclonal antibodies (IRMA) in plasma from hypertensive patients was compared with the traditional PRA method. Two monoclonal antibodies were used: 3E8 and 4G1. The first was coupled to magnetizable beads and was used to trap both active and inactive renin from plasma. The second antibody, 4G1, was iodinated and used to detect active renin trapped by 3E8. The correlation coefficient between the two methods was very high (r = 0.98, p less than 0.001) in plasma samples whose PRA values were higher than 2 ng/ml/h; in low renin samples (PRA lower than 2 ng/ml/h) no significant correlation was found (r = 0.12 n.s.). When PRA and IRMA were performed before and after trypsin activation of inactive renin, the percentage of inactive over total renin was 86.8% and 84% as calculated with PRA and IRMA respectively. The direct monoclonal antibodies method for measuring active renin can be usefully adopted, in conjunction with the traditional PRA procedure, in studying both clinical and pathophysiological aspects of the renin-angiotensin system.

The effects of aprotinin, a kallikrein inhibitor, on renin release and urinary sodium excretion in mild essential hypertensives.

The effects of aprotinin on renin release and renal function were evaluated in 24 male essential hypertensive patients, on unrestricted (n = 17) and on chronic low as well as on high sodium intake. Aprotinin (1 X 10(6) kallikrein inhibitor units) or saline (200 ml) were infused in all patients for 6 h. Blood samples were taken for plasma renin activity (PRA) and 6-h urine collections were obtained for active and inactive kallikrein, sodium and potassium excretion measurement. In patients on unrestricted sodium diet, aprotinin had no effect on blood pressure (BP), glomerular filtration rate, renal plasma flow, urinary sodium and potassium excretion. However, an inverse relationship was found between pretreatment urinary sodium excretion and the per cent reduction of the latter after aprotinin. A significant reduction in urinary sodium excretion was induced by aprotinin in patients on high sodium intake, whereas no change was observed in the same patients when on a low sodium diet. Aprotinin reduced the urinary excretion of active kallikrein by 81% and the active to total kallikrein ratio from 24 to 6%. Infusion of aprotinin induced a significant decline in active renin but did not modify inactive renin levels in patients on unrestricted sodium diet as well as in patients on low or high sodium intake. Our data suggest that the inhibition of kallikrein and/or other serine proteases by aprotinin can interfere with renal release of active renin and also support the hypothesis that the renal kallikrein system exerts a regulatory control on sodium excretion in salt replete hypertensives.

Natriuretic effect of acute nifedipine administration is not mediated by the renal kallikrein-kinin system

Despite their vasodilating action, calcium antagonists increase renal sodium excretion. To ascertain whether renal kallikrein plays a role in the renal effects of calcium antagonists, nifedipine (N) (10 mg orally) or placebo (P) was given to 17 male patients with mild to moderate essential hypertension during a 6-h infusion of either saline (S) or aprotinin (A) (2 x 106 KIU in 200 ml of saline). Blood pressure (BP) and heart rate (HR) were measured every 10 min, and blood samples were taken at - 10, 0, 30, 60, 120, 240, 360 min for plasma renin activity (PRA), creatinine, and osmolarity determinations. Urinary kallikrein, aldosterone, creatinine, and electrolytes were measured in 6-h urine collections. The acute administration of N induced a significant systolic BP (SBP) and diastolic (DBP) fall and a transient PRA increase that peaked at 30 min and were not modified by A infusion. Urinary volume ( + 47|X%), Na+ ( + 54|X%) and C1- ( + 58|X%) excretion were significantly enhanced by N. There were less pronounced and statistically not significant increases in urinary excretion of Ca2+ ( + 38|X%) and K+ ( + 29|X%). Infusion of A did not interfere with the natriuretic effect of N. Our data do not support the hypothesis that the kallikrein-kinin system plays an important role in mediating the renal effects of nifedipine in humans.

Angiotensin converting enzyme inhibition reduces ACTH release due to hypoglycaemia.

To investigate the role of Angiotensin II in the release of ACTH, the response of adrenocorticotrophic hormone to hypoglycaemia was studied before and during treatment with an angiotensin converting enzyme inhibitor, enalapril, in 15 male patients with essential hypertension. Plasma levels of ACTH were measured before and 60, 90 and 120 min after an i.v. bolus of normal saline, as placebo, and, 3 days later, after an i.v. bolus of regular insulin (0.15 U/Kg b.w.). Enalapril treatment was then started and both placebo and hypoglycaemic tests were repeated 15 days thereafter. No changes in ACTH plasma levels were observed after acute normal saline either before or during enalapril treatment. On the contrary, hypoglycaemia induced a sharp increase of ACTH before enalapril (from 19.5 +/- 4.1 to 74.4 +/- 13.0 pg/ml, p less than 0.01 60 min after insulin) but not during ACE inhibition (from 26.1 +/- 6.2 to 34.6 +/- 5.9 pg/ml, NS, at min 60 of the study). The present data confirm our previous observation on the reduction of the hypoglycaemic-induced ACTH release during ACE inhibition with captopril and support the hypothesis that circulating Ang II may exert a facilitating role on adrenocorticotrophic hormone release.

Effect of nifedipine and verapamil on carbohydrate metabolism in hypertensive patients with impaired glucose tolerance.

Intracellular Ca2+ influx is an essential step in insulin (I) release. Calcium antagonists are reported to reduce I release in vitro and in patients with impaired glucose tolerance (IGT) during acute administration. Their effects during long-term therapy are still controversial. To evaluate the effects of chronic verapamil (V) and nifedipine (N) on carbohydrate metabolism, 12 hypertensive patients (WHO II; aged 37-64 years) with IGT underwent intravenous glucose tolerance tests (IVGTT) (0.33 g/kg body weight in 3 min), arginine (A) infusion (30 g/30 min), and hypoglycemic stress (regular insulin 0.15 U/kg body weight) during which blood levels of glucose (G), I, growth hormone (GH), glucagon (IRG), and cortisol (C) were measured. The patients were then randomized to V (120 mg b.i.d.) or N (20 mg b.i.d.) treatment and, 1 month later, both IVGTT and A infusion were repeated. Hormone determinations were performed by the radioimmunoassay (RIA) and G by the enzymatic method. The patients were maintained on their usual diet for the duration of the study. The rate of decline of G during IVGTT was expressed as Conards K coefficient (K; normal values greater than 1.3). I and GH during IVGTT were evaluated as the differences between basal and peak values. I, IRG, and GH during A infusion were analyzed as incremental areas. Our results show that neither V nor N impaired carbohydrate metabolism in hypertensive patients with IGT.

Increase of plasma atrial natriuretic peptide levels after sublingual administration of nifedipine in essentially hypertensive patients

To see whether the acute natriuretic effect of nifedipine is accompanied by changes in atrial natriuretic peptide levels, a group of eight hypertensive patients were studied. After at least a week of constant sodium intake, placebo or nifedipine (10 mg s.I.) were administered and blood pressure, heart rate, plasma renin activity, plasma aldosterone and atrial natriuretic peptide plasma levels, urinary sodium, urinary volume and creatinine clearance were monitored for 2 hours. While placebo did not induce changes in any of the above parameters, nifedipine administration was followed by a significant decrease in blood pressure and an increase in urinary sodium, urinary volume and creatinine clearance; these changes were accompanied by a significant rise in atrial natriuretic peptide levels from 19.4 +/- 2.8 pg/ml to a maximum of 23.9 +/- 2.5 pg/ml and 24.1 +/- 2.2 pg/ml (P less than 0.05) at 60 and 90 minutes, respectively. In conclusion, our data do not rule out the possibility that atrial natriuretic peptide participates in the nifedipine-induced increase in sodium and water excretion.

Studies on trypsin activation of inactive renin in rat plasma

The experimental conditions of trypsin activation of inactive renin in rat plasma have been studied. Our results showed that the pH optimum of trypsin-activated renin is 6.2, the same as that of rat plasma active renin. Trypsin concentration and incubation time might also interfere with the activation process. Trypsin concentration below 2 mg/ml cannot activate inactive renin. Trypsin at a concentration of 6 mg/ml for 1 min. can cleave dialyzable fragments from renin substrate which can generate Angiotensin I at 37 degrees C with a pH optimum of 5.3 but which do not affect Angiotensin generation at pH 6.2. Longer incubations (more than 2 min.), on the contrary, can produce a cleavage at 4 degrees C of Angiotensin I containing fragments directly from renin substrate strongly interfering with measurements of renin activity at pH 6.2. Trypsin concentrations lower than endogenous rat plasma anti-trypsin activity do not activate inactive renin. Much higher concentrations of trypsin, however, are needed to obtain optimum activation of inactive renin. In average, 40% of the total circulating renin in rat plasma can be activated by trypsin.