Mechanisms underlying angiotensin II-induced calcium oscillations

Abstract

Edwards A, Pallone TL. Mechanisms underlying angiotensin II-induced calcium oscillations. Am J Physiol Renal Physiol 295: F568-F584, 2008. First published June 18, 2008 doi:10.1152/ajprenal.00107.2008.-To gain insight into the mechanisms that underlie angiotensin II (ANG II)-induced cytoplasmic Ca 2ϩ concentration ([Ca]cyt) oscillations in medullary pericytes, we expanded a prior model of ion fluxes. ANG II stimulation was simulated by doubling maximal inositol trisphosphate (IP3) production and imposing a 90% blockade of K ϩ channels. We investigated two configurations, one in which ryanodine receptors (RyR) and IP3 receptors (IP3R) occupy a common store and a second in which they reside on separate stores. Our results suggest that Ca 2ϩ release from stores and import from the extracellular space are key determinants of oscillations because both raise [Ca] in subplasmalemmal spaces near RyR. When the Ca 2ϩ -induced Ca 2ϩ release (CICR) threshold of RyR is exceeded, the ensuing Ca 2ϩ release is limited by Ca 2ϩ reuptake into stores and export across the plasmalemma. If sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA) pumps do not remain saturated and sarcoplasmic reticulum Ca 2ϩ stores are replenished, that phase is followed by a resumption of leak from internal stores that leads either to [Ca]cyt elevation below the CICR threshold (no oscillations) or to elevation above it (oscillations). Our model predicts that oscillations are more prone to occur when IP 3R and RyR stores are separate because, in that case, Ca 2ϩ released by RyR during CICR can enhance filling of adjacent IP 3 stores to favor a high subsequent leak that generates further CICR events. Moreover, the existence or absence of oscillations depends on the set points of several parameters, so that biological variation might well explain the presence or absence of oscillations in individual pericytes. mathematical model; sarcoplasmic reticulum stores; ryanodine receptors; inositol trisphosphate receptors; medullary pericytes DESCENDING VASA RECTA (DVR) arise from juxtamedullary efferent arterioles and provide the sole route through which blood flow reaches the renal medulla. DVR are surrounded by smooth remnants (pericytes) that react to vasoconstrictors and vasodilators to modulate luminal diameter (36). In a series of prior studies, we showed that angiotensin II (ANG II) stimulation of DVR pericytes induces cytoplasmic Ca 2ϩ concentration ([Ca] cyt ) elevation (36,52,56), activation of Ca 2ϩ -dependent Cl Ϫ channels (ClCa) (34 -36), inhibition of K ϩ channels (9, 34), and depolarization. In addition, during voltage clamp experiments, a large fraction of pericytes responded to ANG II with spiking oscillations of inward Cl Ϫ current, synchronized to underlying [Ca] cyt oscillations (35,52). The inward currents were inhibited by blockade of Cl Ϫ channels (niflumic acid), ryanodine receptor (RyR) stimulation (ryanodine, caffeine), or nonselective cation channel inhibition (SKF-96365) (52). Together, these observations suggested that initiation of...

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“…Not shown are KCa, Kir, KATP, and Kv channels. (13) As shown by Lee et al (34), there is a good correlation between this fraction and the contractile force in arterial smooth muscle. Interpolation of the data shown in their Fig.…”

“…The other equations of the model, those that yield the K ϩ , Na ϩ , Cl Ϫ , and Ca 2ϩ currents, as well as transmembrane electrical potential differences, were described in detail in our previous work and are summarized in the appendix of reference (13).…”

“…The affinity of SERCA for Ca 2ϩ in the absence of cGMP (K mf * ) is taken as 0.59 M so that the affinity (Kmf) equals 0.31 M under resting conditions (21). The parameters Kmr and H are respectively taken as 1.7 mM and 2 (13).…”

“…The value of K PMCA M, cGMP is taken as 1 M, and the maximum current in the absence of cGMP (I PMCA, max * ) is taken as 2.9 pA so that the maximum current (IPMCA, max) equals 12 pA under resting conditions (13).…”

“…1, the model accounts for plasma membrane (PM) and sarcoplasmic reticulum (SR) pumps, exchangers and ion channels, cytosolic and store Ca 2ϩ buffering, and the existence of subplasmalemmal microdomain spaces in which Na ϩ /Ca 2ϩ exchangers and the ␣ 2 isoform of the Na ϩ -K ϩ -ATPase are exclusively expressed (30,39). We recently examined two configurations for ryanodine receptors (RyR) and IP 3 receptors (IP 3 R), and concluded that oscillatory behavior is most consistently reproduced if they reside on separate SR stores in DVR pericytes (13), hence our assumption of separate RyR and IP 3 R store compartments here.…”