Gerd Bönner

Converting enzyme inhibition in kinin-deficient brown Norway rats.

The contribution of endogenous kinins to the acute antihypertensive actions of the converting enzyme inhibitor ramipril was investigated in kinin-deficient Brown Norway rats and in Brown Norway-Hannover rats and Wistar rats as controls. In Brown Norway rats, urinary kinin excretion was measurable but extremely low when compared with control strains. The depressor responses to intra-arterial bradykinin injections 1) were not different between Brown Norway and Brown Norway-Hannover rats, 2) were potentiated by intravenous ramipril (60 micrograms), and 3) were attenuated by intra-arterial infusion of the bradykinin antagonist B4146 (40 micrograms/kg/min) to a similar extent in both strains. In renal hypertensive (two-kidney, one clip) Brown Norway rats, the blood pressure reductions to intravenous bolus injections of ramipril (100 micrograms) were significantly reduced both in extent and duration when compared with hypertensive Brown Norway-Hannover and Wistar rats. Intra-arterial infusion of B4146 (40 micrograms/kg/min) attenuated the depressor response to ramipril in Wistar and Brown Norway-Hannover rats but had no effect in Brown Norway rats. In contrast, all three groups showed similar depressor responses to intravenous infusions of the angiotensin II receptor antagonist saralasin. These responses were not influenced by the bradykinin antagonist. Our data support the hypothesis that kinins are important for the acute antihypertensive actions of converting enzyme inhibitors.

Effects of sodium loading, desoxycorticosterone acetate, and corticosterone on urinary kallikrein excretion.

In male Sprague-Dawley rats, changes in kallikrein activity in urine were produced by high sodium intake (1% saline as drinking fluid for 14 days), and administration of desoxycorticosterone acetate (DOCA, 15 mg/kg s.c. for 5 days), and of corticosterone (2 x 0.2 or 2 x 20 mg/kg s.c. daily for 5 days). Salt loading caused a decrease in urinary kallikrein excretion (p less than 0.005), while DOCA produced an increase (p less than 0.001). While corticosterone, administered in the low dose, had no effect on urinary kallikrein excretion, the high dose, given for 5 days, diminished kallikrein excretion to about half the basal value (p less than 0.001). Simultaneously, the excretion of aldosterone decreased to about one third the amount measured in the corresponding control rats.

Relationship between the renal kallikrein activity and the urinary excretion of kallikrein in rats.

Adrenalectomy reduces, and sodium depletion increases, both the daily urinary excretion of kallikrein and the kallikrein activity in the renal cortex. These 2 variables were found to correlate significantly in normal, sodium depleted and adrenalectomized rats, thus supporting the view that kallikrein excretion reflects the activity of the enzyme in the kidney.

Effect of Changes in Perfusion Pressure on Renal and Urinary Kallikrein in the Isolated Perfused Rat Kidney

Kallikrein activity in urine and in the renal cortex of the isolated rat kidney, perfused at constant pressure, decreased, while renal perfusate flow, glomerular filtration rate, excretion of sodium and of potassium and urine flow remained unchanged. Abrupt changes in perfusion pressure resulted in corresponding changes in renal perfusate flow, glomerular filtration rate, excretion of sodium and of potassium and urine flow. Urinary kallikrein increased little and transiently only, each time perfusion pressure was elevated. At the end of the experiments, a marked decrease in kallikrein activity in the renal tissue was found. From these results, it might be concluded that the excretion of kallikrein from the isolated perfused rat kidney resulted in a marked depletion of kallikrein stores in the kidney, probably due to an insufficient kallikrein synthesis.

Comparison of the efficacy and safety of losartan (50-100 mg) with the T-type calcium channel blocker mibefradil (50-100 mg) in mild to moderate hypertension.

Abstract— The objective of this study was to compare the antihypertensive efficacy and safety of losartan and mibefradil. 324 outpatients (57 ± 9.2 years) with mild to moderate hypertension were randomly allocated in a double‐blind fashion to receive 50 mg of losartan or mibefradil once daily p.o. for 6 weeks after 2 weeks of placebo run‐in. Titration was then forced to 100 mg of losartan or mibefradil for an additional 6 weeks. Patients were assessed at baseline, 6 and 12 weeks. The primary efficacy variable was change in predose sitting diastolic (SDBP) and systolic (SSBP) blood pressure at 12 weeks. Secondary variables included change in mean 24‐hour ambulatory blood pressure and comparison of safety and tolerability. Both treatments lowered SSBP and SDBP at 6 and 12 weeks (week 6: mibefradil −14/−9 mm Hg; losartan −12/−7 mm Hg) (p < 0.001). The primary objective, a difference between treatments in reduction of SSBP and SDBP at week 12 could be demonstrated (mibefradil −22/−16 mm Hg; losartan −16/−10 mm Hg) (p = 0.003 and P = 0.001, respectively). Twenty‐four‐hour SBP and 24‐hour DBP were reduced (p < 0.001) within each treatment group at weeks 6 and 12. The secondary objective, a difference between treatments in reduction of 24‐hour blood pressure at week 12 could be demonstrated (P < 0.001). Twenty‐four‐hour heart rate was lowered in the mibefradil group at weeks 6 and 12 (P < 0.001). Responder rates at 6 and 12 weeks were 56.2% and 78.5% for mibefradil versus 56.1% and 55.3% for losartan (P = 0.001). Both treatments were equally well tolerated. This study demonstrates that 50 mg losartan is comparably effective to 50 mg mibefradil in the treatment of mild to moderate hypertension with 100 mg mibefradil being more potent than losartan.

Ureteral contractions induced by rat urine in vitro: Probable involvement of renal kallikrein

Rat urine, even at a 1∶10 final dilution in Tyrodes solution, stimulates contraction of the ureteral musculature in vitro. This effect can be ascribed to the presence of kallikrein or a kallikrein-like enzyme in urine. Isometric contractions of ureters were prevented by previous addition of aprotinin to the organ bath. Urine also lost its activity after inactivation of enzymes by heat or acid treatment.

Effect of dihydralazine on the renal kallikrein-kinin system of the rat.

Dihydralazine (0.1 mg/kg), injected intravenously into male Sprague-Dawley rats, caused a decrease in mean arterial blood pressure and an increase in renal plasma flow, while urine volume remained unchanged. Dihydralazine had no effect on kallikrein excretion in the urine and on kallikrein activity in the renal cortex. No correlation was found between renal kallikrein and either renal plasma flow or mean arterial blood pressure. The excretion of kinins in the urine rose markedly after the administration of dihydralazine; no correlation between urinary kinins and urinary or renal kallikrein was observed. Dihydralazine had no influence on the kininogen content of blood-free renal cortex. The enzymatic activity of kininase II in renal cortex was not impaired by dihydralazine. It is suggested that the increased formation of kinins within the kidney could be involved in the vasodilating and blood pressure lowering effect of dihydralazine.