An ATP-sensitive potassium channel blocker suppresses sodium-induced hypertension through increased secretion of urinary kallikrein

Abstract

It is suggested that an ATP-sensitive potassium channel blocker suppresses sodium-induced hypertension through increased secretion of urinary kallikrein. We reported that glibenclamide, an ATP-sensitive potassium channel blocker, accelerated dose-dependent secretion of renal kallikrein in sliced kidney cortex and in vivo in rats. In vehicle-treated normal BrownNorway-Kitasato (nBN-Ki) rats, the administration of glibenclamide increased urinary kallikrein secretion, but changed neither the systolic blood pressure nor the urinary sodium on low (0.3%) NaCl diets. Although on high (8%) NaCl diets, the systolic blood pressure of the nBN-Ki rats administrated glibenclamide was significantly lower (Po0.05). The urinary levels of kallikrein and sodium of the nBN-Ki rats administrated glibenclamide were significantly increased (Po0.05, glibenclamide vs. vehicle). A similar result was obtained with a kidney-selective ATP-sensitive potassium blocker, N,N¢-dicyclohexyl-4-morpholinecarboxamidine (U18177), in SD rats. Mutant kininogen-deficient Brown-Norway Katholiek (muBN-Ka) rats fed high (8%) NaCl diets showed an increase in urinary kallikrein levels, but showed neither hypotensive nor natriuretic actions by glibenclamide. A bradykinin B 2 receptor antagonist,-dichlorobenzyloxy]-2-methylquinoline (FR173657), which was administrated to SD rats, together with glibenclamide, abolished the hypotensive and natriuretic effects of glibenclamide in high-sodium (8%NaCl) hypertension, despite an accelerated secretion of urinary kallikrein. Therefore, these results indicate that glibenclamide, an ATP-sensitive potassium channel blocker suppressed sodium-induced hypertension through sodium excretion from the kidney resulting from accelerated secretion of urinary kallikrein.

Comparison between the effect of glibenclamide and captopril on experimentally induced diabetic nephropathy in rats

“…In contrast to the present data were the data of Yosefy et al, 13 that glibenclamide worsened blood pressure control possibly by activation of the sympathetic system. On the other hand, Kamata et al 36 reported that glibenclamide suppressed sodiuminduced hypertension through sodium excretion from the kidney resulting from accelerated secretion of urinary kallikrein.…”

A Novel Category of Anti-Hypertensive Drugs for Treating Salt-Sensitive Hypertension on the Basis of a New Development Concept

“…Intravenous injection of glibenclamide (1 to 30 mg/kg) during physiological saline infusion in anesthetized rats causes a dose-dependent increase in urinary kallikrein [66]. Despite the administration of glibenclamide, rats showed slightly (but insignificantly), lower blood glucose levels (0.3% NaCl: 177 ± 13 mg/100 mL; glibenclamide 30 mg/kg daily: 159 ± 4 mg/100 mL; glibenclamide 60 mg/kg daily: 160 ± 8 mg/100 mL) than that of normal control (0.3% NaCl intake) and no rats died during the experiments [71]. In rats, this may have been attributable to the constant, ad libitum , dietary intake.…”

“…High sodium (8%) in diet increased high SBP of SD strain rats. Glibenclamide (a K ATP channel blocker) reduced the increased SBP and increased the levels of urinary kallikrein and hence increased urinary sodium excretion [71]. Sodium contents in erythrocytes was increased by taking diet containing 8% NaCl.…”

“…The NaCl contents in aorta took the same pattern as that of erythrocytes. Namely, increase of the sodium contents during taking 8% NaCl in diet was clearly decreased dose-dependently by glibenclamide (30 and 60 mg/kg), and the decreased sodium contents of the aorta were tended to be increased by additional BK-B 2 antagonist, FR173657 [71]. …”

“…The reduction of SBP by U18177 was accompanied with significant increase in urinary kallikrein levels on day 4 (7.1 ± 0.3 AU/mgCr), compared with the level in vehicle- treated rats on day 4 (5.8 ± 0.2 AU/mgCr)(P < 0.01). Consequently, urinary sodium levels were largely increased to 84.5 ± 7.3mg/24 hr in U18177-treated rats, compared with 50.5 ± 2.1 mg/24 h in vehicle treated rats (P < 0.01) [71]. …”