Abstract
When angiotensin II stimulates aldosterone secretion, it causes a rapid but transient mobilization of calcium from an intracellular pool and a sustained increase in the influx of calcium in adrenal glomerulosa cells. The present studies were undertaken to determine the respective roles of the two angiotensin II-induced changes in cellular calcium metabolism in modulating events during the sustained phase of cellular response which is thought to be mediated by the C-kinase branch of the calcium messenger system. The sustained response to angiotensin II is only 50% of maximal in cells pretreated with dantrolene in a concentration sufficient to inhibit the angiotensin II-induced mobilization of intracellular calcium. Also, if A23187 is added to cells simultaneously with 1-oleoyl-2-acetylglycerol (OAG), the aldosterone secretory response is similar to that seen after angiotensin II. However, if A23187 is added first and the transient aldosterone secretory response allowed to decay, and OAG then added, the sustained aldosterone secretory response is only 45-50% of maximal. Addition of the calcium channel agonist, BAY K 8644, with OAG leads to an aldosterone secretory response which is only 50% of maximal, but if upon addition of OAG and BAY K 8644 the cells are also exposed for 5 min to media containing 8 mM K+, then the sustained secretory response is maximal. These data imply that the initial transient rise in the [Ca2+] of the cell cytosol plays a role in determining the extent to which C-kinase is shifted from its calcium-insensitive to its calcium-sensitive form. The second group of experiments examined the relationship between the sustained angiotensin II-induced increase in plasma membrane calcium influx and the sustained aldosterone secretory response. The results show that in the presence of 1 microM nitrendipine or 2 mM extracellular K+, angiotensin II causes no increase in calcium influx and only a transient rather than a sustained increase in the rate of aldosterone secretion indicating that the sustained phase of the response is dependent upon a continued high rate of Ca2+ influx which regulates the rate of turnover of the activated C-kinase.
Highlights
From a dantrolene-sensitive intracellular pool (9, lo),presumably the endoplasmic reticulum, which precedes a monotonic increase in the aldosterone secretory rate to asustained plateau [9,10,11,12]
The results show that in thepresence of 1PM nitrendipine transiently activated by a transient rise in the cytosolic free calcium and is largely responsible for the initiation of the cellular response; and a C-kinase branch which undergoes sustained activation in response to a sustained increase in diacylglycerol production and islargely responsible for the sustained phaseof the cellular response
2 mM extracellular K’, angiotensin I1 causes no Previous studies have shown that angiotensin I1 induces a increase in calcium influx and only a transient rather transient increase in both calcium influx and calcium efflux than a sustained increase in the rate of aldosterone and a sustained increase in diacylglycerol production in glosecretion indicating that the sustained phase of the merulosa cells [8,9,10,11,12]
Summary
Effect of Dantrolene and Nitrendipine on the Time Course of Angiotensin ZI Action-To explore the respective roles of the two calcium pools (intra- andextracellular) in the action of angiotensin 11, the experiments shown in Fig. 1 were performed. FluCxeaslcium and Aldosterone Secretion is added 20 min after angiotensin I1 addition to dantrolenepretreated cells being perifused with angiotensin 11, the rate of aldosterone production falls rapidly to values below the basal level (Fig. 1D).To exclude the possibility that dantrolene has an inhibitory effect on calcium influx, the effect of dantrolene on calcium influx was measured in the presence and absence of angiotensin 11. To evaluate the role of this calcium influx in mediating the sustained aldosterone secretory response, the effect of angiotensin I1 on the time course of aldosterone secretion and the time course of Ca2+ influx were determined in the perifusion system using media containing different potassium concentrations (Fig. 2). When extracellular potassium is 3.5 mM, angiotensin 11 causes a monotonic rise in aldosterone secretion to a sustained 4.5fold increase in rate and a rapid andsustained ( A = 0.80 nmol/min/mg of protein) increase in plasma membrane calcium influx (Fig. 2B). Noteworthy is the fact that during the late phase of the responses
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