title: Lack of direct action of atriopeptidase inhibitor on cellular pH regulation in rabbit S2 proximal straight tubules.
abstract: While the in vivo diuretic and antihypertensive effects of the newly-developed drug Candoxatril (UK-79300), a prodrug of a selective atriopeptidase inhibitor UK-73967 (API) are well established, the mechanism of its diuretic action is not yet fully understood due to the lack of information about its direct effects on proximal tubules. To elucidate whether this atriopeptidase inhibitor has any direct effects on proximal tubules, we examined the effect of API on intracellular pH (pHi) of the in vitro microperfused proximal S2 segment of rabbit kidney, using the pH-sensitive fluorescent dye, (2',7')-bis(carboxyethyl)-(5,6)-carboxyfluorescein (BCECF). In the steady-state condition, pHi was 7.13 +/- 0.02 (n = 19). Atriopeptidase inhibitor (API) at 100 microM added to the bath changed pHi by only 0.02 +/- 0.07 unit (n = 7, p > 0.05) in 10 min. The same concentration of API in the lumen changed pHi by 0.03 +/- 0.02 unit (n = 6, p > 0.05). To test whether the synergistic effects of API on the luminal and basolateral transport systems prevented the apparent change in pHi, we also examined the effect of API in the presence of amiloride in the lumen. The inhibition of Na+/H+ antiporter by the addition of 1 mM of amiloride to the lumen caused no change in pHi response to basolateral API application. API was without effect on pHi also in the presence of atrial natriuretic polypeptide (ANP). These results suggest that API per se has no significant effect on the process of proximal acidification over a short time period.
authors.affiliation: Department of Clinical Biology and Hormonal Regulation, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Kondo
authors.forename: K
authors.initials: K
authors.lastname: Kudo
authors.forename: Y
authors.initials: Y
authors.lastname: Igarashi
authors.forename: O
authors.initials: O
authors.lastname: Ito
authors.forename: K
authors.initials: K
authors.lastname: Abe
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology*; D005260:Female; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010477:Perfusion; D011422:Propionates / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D004232:Diuretics; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007189:Indans; D011422:Propionates; C043829:2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; D009320:Atrial Natriuretic Factor; C062766:candoxatril; D015260:Neprilysin