Results from previous experiments in our laboratory suggested that a H(+)-K(+)-adenosinetriphosphatase (H(+)-K(+)-ATPase) was present in vascular smooth muscle. Here we analyzed the effects on regulation of renal vascular function in anesthetized dogs of inhibition of the H(+)-K(+)-ATPase by a highly specific inhibitor, NC-1300-B. The compound was injected intravenously, 15 mg/kg (5.8 x 10(-5) mol wt/kg), into one group of six dogs, whereas saline was given to a control group of eight. Renal function was measured at controlled levels of renal perfusion pressure ranging from 110 to 60 mmHg. Renal blood flow (RBF) was higher in the treated group at all levels of perfusion pressure; at 70 mmHg, the treated group RBF was 5.85 +/- 1.00 ml.min-1.g kidney wt-1, 71% greater than that of the control group. Glomerular filtration rate (GFR) mean values of the two groups were not significantly different at any perfusion pressure level. Renin release was inhibited (P < 0.01) by H(+)-K(+)-ATPase inhibition; at 90 mmHg, the control group mean was 14.3 +/- 4.3 units, 4.47 times greater than the treated group mean of 3.2 +/- 1.6 units. H(+)-K(+)-ATPase inhibition with NC-1300-B causes profound renal vasodilation and inhibition of renin release without affecting regulation of GFR.

01 Jun 1992·American Journal of Physiology-Heart and Circulatory Physiology

Evidence of a K(+)-H(+)-ATPase in vascular smooth muscle cells

Article

Author: Young, D. B. ; McCabe, R. D.

In earlier studies Na(+)-K(+)-adenosinetriphosphatase (ATPase) and Na(+)-K(+)-2Cl- cotransport partially accounted for vascular smooth muscle cell (VSMC) K+ (Rb+) uptake. In other cells Rb+ is taken up by a K(+)-H(+)-ATPase that is sensitive to NC-1300-B, SCH28080, omeprazole, and N-ethylmaleimide (NEM). This study examines the effects of K(+)-H(+)-ATPase inhibitors on VSMC. Rubidium uptake by primary cultures of canine coronary artery (CCA) VSMC or cultured rat aortic (CRA) VSMC line A7r5 was reduced 19-37% by NC-1300-B, SCH28080, or omeprazole. N-ethylmaleimide reduced CCA VSMC K+ content from 1.55 +/- 0.02 to 1.24 +/- 0.06 mu eq/mg protein. The NC-1300-B-sensitive portion of CRA VSMC Rb+ uptake was not blocked by ouabain (0.1 mM) or bumetanide (0.1 mM), but was reduced by alkalinization with 7.5 mM NH4Cl, and increased by acidification with 7.5 mM Na-acetate. Intracellular pH (pHi) of CRA VSMC was reduced 0.14 +/- 0.03 U by NC-1300-B and 0.22 +/- 0.03 U by NEM. pHi of CCA VSMC was reduced 0.20 +/- 0.03 U by omeprazole (1 mM) and 0.20 +/- 0.03 U or 0.20 +/- 0.05 U by amiloride in the absence or presence of omeprazole, respectively. Fluorescence of 2',7'-bis(carboxyethyl)-5-(6')- carboxyethyl)-5-(6')-carboxyfluorescein due to excitation at 500:441 nm in rat aortic strips was reduced by 0.21 +/- 0.02 U by omeprazole and 0.22 +/- 0.03 U by K+ removal and increased by 0.21 +/- 0.06 U by K+ repletion. We conclude that VSMC possess a previously unknown Rb+ uptake mechanism. This newly discovered mechanism helps to maintain K+ gradient and pHi by extruding H+ in exchange for K+, and is presumably a K(+)-H(+)-ATPase similar to those described in other tissues.

01 Nov 1988·Digestive Diseases and SciencesQ3 · MEDICINE

Effects of NC-1300-B, A new benzimidazole derivative, on hog gastric H+, K+-ATPase, gastric acid secretion and HCl-ethanol-induced gastric lesions in rats

Q3 · MEDICINE

Article

Author: Hitoshi Nagai ; Yasushi Akimoto ; Shinichi Yamasaki ; Susumu Okabe

This study was designed to determine the effect of a newly synthesized benzimidazole derivative NC-1300-B on H+, K+-ATPase (proton pump) in the hog gastric mucosa and on the basal gastric acid secretion and necrotizing agent-induced gastric lesions in rats. NC-1300-B inhibited the proton pump in a concentration-dependent manner and concentrations which inhibited the enzyme activity by 50% were 4.4 x 10(-6) M at pH 6.0 and 3.1 x 10(-5) M at pH 7.4. NC-1300-B administered orally or intraperitoneally 0.5 hr before ligating the pylorus inhibited the gastric acid secretion in a dose-dependent manner. The ED50 values (doses which inhibit acid output or lesion formation by 50%) for acid secretion were 11.5 and 11.0 mg/kg with oral and intraperitoneal administration, respectively. The antisecretory effect in a dose of 100 mg/kg persisted for up to 72 hr. NC-1300-B administered orally or intraperitoneally 0.5 hr before HCl.ethanol administration protected against damage of the gastric mucosa in a dose-dependent manner. The ED50 values for lesion formation were 13.3 and 23.0 mg/kg with oral and intraperitoneal administration, respectively. This protection with an oral dose of 100 mg/kg persisted for up to 72 hr. While pretreatment with 5 mg/kg of indomethacin given subcutaneously did not appreciably reverse the NC-1300-B protection, the pretreatment with 10 mg/kg of N-ethylmaleimide given subcutaneously potently reversed the NC-1300-B protection. NC-1300-B administered intragastrically at 30 mg/kg significantly inhibited the amplitude of gastric contraction for 50 min after intragastric administration. These effects of NC-1300-B on gastric secretion and lesion formation are much the same as those of the established proton pump inhibitor omeprazole, except for the short duration of the action of omeprazole (less than 24 hr).

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Indication	Highest Phase	Country/Location	Organization	Date
Stomach Ulcer	Phase 1	-	Nippon Chemiphar Co., Ltd.	-

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