GLYBURIDE ATTENUATES CALMODULIN ANTAGONIST-STIMULATED RENIN RELEASE FROM ISOLATED MOUSE JUXTAGLOMERULAR CELLS

Previous reports have shown that K+ channel openers elevate plasma renin activity in vivo and stimulate renin release (RR) from juxtaglomerular (JG) cells in vitro. Therefore, we examined whether the K+ channel blocker, glyburide, inhibits basal RR or RR stimulated by elevating cAMP or by inhibiting Ca2+/calmodulin activity in cultures of isolated mouse JG cells. Glyburide treatment (10-300 mu M) had no effect on basal RR, which measured similar to 10% or 30% of the total cellular renin activity after 4 or 24 h, respectively. RR stimulated by elevating cAMP with isoproterenol, forskolin, or 3-isobutyl-1-methylxanthine was also unaffected by glyburide. In contrast, glyburide significantly attenuated RR stimulated by the calmodulin antagonists, calmidazolium, trifluoperazine, and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7). Calmidazolium-stimulated RR returned to basal levels with 100 mu M glyburide cotreatment. Blockade of voltage-gated calcium channels with verapamil or inhibition of calcium release from intracellular stores with 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8) had no effect on the ability of glyburide to attenuate calmidazolium-stimulated RR. However, lowering of the extracellular calcium concentration by the addition of EGTA abolished the inhibitory effects of glyburide. We conclude that modulation of K+ channels may influence RR by affecting Ca2+/calmodulin-regulated secretion, but not cAMP-mediated secretion, from JG cells. Furthermore, the inhibitory effects of K+ channel blockers on RR are dependent on extracellular calcium.