Voltage-gated Ca2+entry and ryanodine receptor Ca2+-induced Ca2+release in preglomerular arterioles

We have previously shown that in afferent arterioles, angiotensin II (ANG II) involves activation of the inositol trisphosphate receptor (IP3R), activation of adenine diphosphoribose (ADPR) cyclase, and amplification of the initial IP3R-stimulated release of cytosolic Ca2+([Ca2+]i) from the sarcoplasmic reticulum (SR) (Fellner SK, Arendshorst WJ. Am J Physiol Renal Physiol 288: F785–F791, 2004). The response of the ryanodine receptor (RyR) to local increases in [Ca2+]iis defined as calcium-induced calcium release (CICR). To investigate whether Ca2+entry via voltage-gated channels (VGCC) can stimulate CICR, we treated fura 2-loaded, freshly isolated afferent arterioles with KCl (40 mM; high KCl). In control arterioles, peak [Ca2+]iincreased by 165 ± 10 nM. Locking the RyR in the closed position with ryanodine (100 μM) inhibited the [Ca2+]iresponse by 59% ( P < 0.01). 8-Br cADPR, a specific blocker of the ability of cyclic ADPR (cADPR) to sensitize the RyR to Ca2+, caused a 43% inhibition. We suggest that the lower inhibition by 8-Br cADPR ( P = 0.02, ryanodine vs. 8-Br cADPR) represents endogenously active ADPR cyclase. Depletion of SR Ca2+stores by inhibiting the SR Ca2+-ATPase with cyclopiazonic acid or thapsigargin blocked the [Ca2+]iresponses to KCl by 51% ( P not significant vs. ryanodine or 8-Br cADPR). These data suggest that about half of the increase in [Ca2+]iinduced by high KCl is accomplished by activation of CICR through the ability of entered Ca2+to expose the RyR to high local concentrations of Ca2+and that endogenous cADPR contributes to the process.