An Official 'Journal of the American Heart Association BRIEF REVIEWS. Stimulus-Secretion Coupling of Renin. Role of Hemodynamic and Other Factors






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Circulation Research

OCTOBER 1980 VOL. 47 NO. 4

An Official 'Journal of the American Heart Association


Stimulus-Secretion Coupling of Renin

Role of Hemodynamic and Other Factors


IT IS generally agreed that three intrarenal recep-tors control renin secretion. The macula densa re-ceptor responds to some yet unknown function of the fluid passing the distal nephron (Thurau, 1964; Vander, 1967; Kotchen et al., 1978). The neurogenic receptor, which presumably is on the juxtaglomer-ular cell membrane, stimulates renin secretion by a /?-adrenergic mechanism and inhibits by an a mech-anism (Ganong, 1972; Vandongen et al., 1973; Cap-poni and Valloton, 1976). The vascular stretch re-ceptor, presumably the juxtaglomerular cell itself, responds to the degree of stretch of the afferent arteriole such that a decreased stretch increases renin secretion (Tobian, 1960; Fray, 1976). Since it has been demonstrated that the neurogenic recep-tor and the stretch receprecep-tor can function indepen-dently of the macula densa (Davis and Freeman, 1976), several investigators have sought to deter-mine the chemical or physical events connecting the receptors to the secretory process. If we accept the proposition that decreased stretch and jS-adre-nergic stimulation increase renin secretion, then it is natural to enquire about the hemodynamic fac-tors that affect the stretch and about the cellular mechanism by which 0 stimulation leads to in-creased secretion.

In one approach to seek answers to these enqui-ries, a mathematical formula has been developed to account for the hemodynamic factors and to point to possible mechanisms by which these factors ac-tivate the release process (Fray, 1976; Fray, 1978a). Recent reports have provided compelling evidence confirming some predictions of the formula and provided fresh clues to the stimulus-secretion cou-pling process. In another approach, it has been postulated that the cellular mechanisms controlling renin secretion are analogous to those controlling smooth muscle relaxation (Peart, 1977). This ap-proach has been particularly useful, for it has al-From the Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts.

This research was supported by National Institutes of Health Grant HL23516.

lowed us to identify possible mechanisms by which /?-adrenergic and other agents may trigger the se-cretory process. Both approaches have converged on this single conclusion, that the movement of calcium ion plays a central role in the mechanisms controlling renin secretion.

However, the role the movement of calcium plays in renin secretion must be exactly opposite to the one it plays in other secretory systems, despite the fact that several workers have drawn the analogy between catecholamine secretion and renin secre-tion. Douglas and Rubin (1961) suggested that ace-tylcholine interacts with the chromaffin cell to de-polarize the cell membrane and to increase the calcium permeability of the cell; since calcium con-centration usually is higher outside the cell than inside, it enters the cell and this initiates the secre-tion process. When calcium is removed from the perfusion fluid, acetylcholine still induces depolari-zation but not catecholamine secretion. When cal-cium is added in excess of normal physiological levels, acetylcholine induces depolarization and subsequently a greater release of catecholamines (Douglas, 1968). In fact, the chromaffin cells can be depolarized directly by perfusing glands with high concentrations of potassium (56 HIM) but, again, catecholamine secretion is induced only when cal-cium is present in the perfusion fluid. This general scheme, stimulus —* membrane depolarization —» increased calcium permeability —» increased cal-cium influx and cytoplasmic calcal-cium —» increased secretion, has been defined in several contexts (Douglas, 1968; Rubin, 1970). It is understandable, then, that some workers have suggested that the stimulus-secretion coupling process for renin secre-tion may be similar to that of catecholamine release from the adrenal medulla (Morimoto et al., 1970; Michelakis, 1971; Chen and Poisner, 1976; Abe et al., 1977; Lester and Rubin, 1977; Harada and Rubin, 1978).

However, it is becoming increasingly clear that the sequence in the stimulus-secretion coupling for renin may not be parallel to that for catecholamine


486 CIRCULATION RESEARCH VOL.47, No.4, OCTOBER 1980 release. The process of renin secretion under normal

physiological conditions may be initiated by hyper-polarization of the juxtaglomerular cell membrane (instead of depolarization), and by a subsequent reduction of cytoplasmic calcium (instead of an elevation). Several lines of evidence support this hypothesis. It now seems proper to review some of the evidence concerning the manner in which he-modynamic and other factors control renin secre-tion by this process. Because the theoretical anal-ysis used to identify the hemodynamic factors is fairly new, it will be discussed briefly.

Hemodynamic Control of Renin Secretion

Tobian (1960) postulated that renin secretion is inversely related to the stretch of the afferent ar-teriole. This hypothesis has been approximated by assuming that renin secretion (RS) is inversely

proportional to the stretch (RS = k [STRETCH]"1,

where k is a constant of proportionality) (Fray, 1976). From this first approximation the following formula was derived:

RS = K l - ( r i / r )2

(ri/r)2Pi-P (1)

where K = kE/2(l - 2v)\ E and v are Young's modulus of elasticity and Poisson's ratio for the arteriole; rj and ro are the internal and external radii

of the afferent arteriole; Pi is the mean perfusion pressure, and Po is the mean extravascular or

intra-renal tissue hydrostatic pressure.

Figure 1 represents a graph of renin secretion as a function of each independent variable, and illus-trates three distinct effects of hemodynamic vari-ables on renin secretion. First, renin secretion is related inversely to renal perfusion pressure (Fig. 1A); second, renin secretion is related directly to extravascular or interstitial pressure (Fig. IB); third, renin secretion is related directly to the ratio of the radii such that when the ratio decreases (as in vasoconstriction), renin secretion is stimulated, and when it increases (as in vasodilation), renin secretion is inhibited (Fig. 1C). The above equation also indicates that renin secretion is directly pro-portional to the elastic modulus E, but this point will be discussed below. It might be of importance to note that renin secretion is not influenced by transmural pressure (Pi — Po) directly, but by a

more complex function of transmural pressure, namely (ri/ro)2 Pj - Po.

An important observation emerges when two of the variables change simultaneously. Increasing Po

stimulates renin secretion (Fig. IB), whereas in-creasing Pi inhibits secretion (Fig. 1A). However, when both variables are increased simultaneously, renin secretion may increase, decrease, or remain unchanged, depending on the magnitude of the increase in each variable. It has been shown that Po

is twice as effective as Pi for the same magnitude of change (Fray, 1976), implying that in the formula

(ri/ro)2 Pi — Po, (ri/ro)2 may be 0.5 in some

circum-stances. A similar phenomenon can be demon-strated by changing ri/ro and Pi simultaneously.

Thus the renin secretion induced by vasoconstric-tion (lowering ri/ro) can be counteracted by raising

Pi, and the secretion induced by lowering Pi can be counteracted by vasodilation (raising ri/ro). In

cer-tain circumstances, as in autoregulation, inhibitory effects of vasodilation may mask the stimulatory effect of lowering Pi to a certain extent. Thus in any study relating the effects of hemodynamic variables on renin secretion, these variables must be mea-sured carefully.

The mathematical analysis has indicated that tissue elasticity, extravascular and intravascular pressures, and afferent arteriolar radii modulate renin secretion. Some experimental evidence sup-ports this indication. Raising the modulus of the elasticity (E) of the afferent arteriole increases renin secretion. Although direct demonstration re-lating afferent arteriolar elasticity to renin secretion is difficult to obtain, indirect evidence supports the concept. For example, vasopressin reduces the elas-ticity of arteries in vitro (Monos et al., 1978) and reduces renin secretion. An intact tubular organi-zation is not required for the inhibitory action of vasopressin on renin secretion (Davis and Freeman, 1976), but an intact vascular organization may be required, since vasopressin is ineffective in kidney slices (DeVito et al., 1970). Sympathetic nerve stim-ulation also increases tissue elastic modulus (Som-lyo and Som(Som-lyo, 1968) and renin secretion. There-fore, at least one of the mechanisms whereby va-sopressin infusion and increased sympathetic nerve stimulation increase renin secretion might involve increasing the modulus of elasticity.

Intrarenal Tissue Pressure

Raising renal extravascular or tissue hydrostatic pressure increases renin secretion. Skinner et al.

(1964) have demonstrated that the direct raising of extravascular or tissue pressure by 20-40 mm Hg caused increased renin secretion that was indepen-dent of changes in renal perfusion pressure and afferent arteriolar resistance. When extravascular pressure was raised 35 mm Hg in their experiments, renin secretion increased substantially, but re-turned toward control when perfusion pressure was raised by 70 mm Hg. This suggests that the effective pressure is not a straightforward transmural pres-sure (Pi — Po), but rather /?P; — Po. If it were a

straightforward transmural pressure, then a 35 mm Hg rise in perfusion pressure would be required to abolish completely the effect of a 35 mm Hg rise in extravascular pressure. From the experiments of Skinner et al. (1964), it appears that /? might be close to 0.5 under certain circumstances. By analogy with the equation for renin secretion, we might speculate that /? might actually be (ri/ro)2, in which

case the effectiveness of renal perfusion pressure




P, (mmHB) PjmmHg) r,/ro

FIGURE 1 Hemodynamic factors controlling renin secretion (RS) through an intrarenal stretch receptor as plotted from Equation 1. For all calculations v = 0.3 and E = l(f dynes/cm1. The point (<&) on each curve represents control

renin secretion (50 ng/min), assuming Pi = 70 mm Hg, Po = 5 mm Hg, and rjro = 0.75. From these values k was

calculated to be 2.645 X 10~3 ng-cm2-mm Hg/dynes-min. This value was calculated for animals receiving a normal

sodium chloride diet. The value is different for other diets (Fray, 1978b).

(Pi) and extravascular pressure (Po) to stimulate

renin secretion might depend very strikingly on the resistance of the afferent arteriole (Fray, 1976).

Other maneuvers may stimulate renin secretion by raising intrarenal tissue pressure. For example, ureteral occlusion and renal venous pressure ele-vation increase renal tissue pressure and renin se-cretion (Eide et al., 1977; Kaloyanides et al., 1973; Ott et al., 1971; Kishimoto et al., 1972). This rise in renin secretion can be inhibited by simultaneously raising renal perfusion pressure (Kaloyanides et al., 1973), as predicted by the theoretical analysis. The infusion of mannitol and some other diuretics is associated with a rise in intrarenal tissue pressure and renin secretion (Raeder et al., 1975; Eide et al., 1975). In addition, Tobian (1960) has suggested that the renin secretion induced by renal encapsulation may be mediated by an increase in renal tissue pressure. Thus, although direct measurements are not immediately available, the renin secretion in-duced by ureteral occlusion, mannitol and other diuretic infusion, and renal encapsulation may in-volve a rise in intrarenal tissue pressure.

Perfusion Pressure and Vascular Resistance

It is difficult to discuss the effect of renal perfu-sion pressure on renin secretion without at the same time discussing the effect of renal resistance. The formula predicts that lowering perfusion pressure

stimulates renin secretion, whereas raising pressure inhibits secretion. This has been demonstrated ex-perimentally (Fray, 1976; Davis and Freeman, 1976; Hofbauer et al., 1976). However, in most instances a reduction of renal perfusion pressure is associated with dilation of the afferent arteriole (Navar, 1978), and it is often difficult to separate the stimulatory effect of pressure reduction from the inhibitory effect of vasodilation. Nevertheless, recently it has been shown that lowering renal perfusion pressure stimulates renin secretion in the absence of vaso-dilation, although this occurred below the autoreg-ulatory range. On the other hand, vasodilation in-hibited renin secretion when renal perfusion pres-sure was kept constant (Fray, 1976). In fact, the effect of vasodilation, which is associated with low pressure-induced renin secretion, can be completely dissociated from the effect of low pressure with inhibitors of prostaglandin synthesis (Blackshear et al., 1979). Similarly, the vasodilation and renin se-cretion induced by ureteral occlusion (Eide et al., 1977) may be attributed to increased renal tissue pressure (see above).

Despite these observations, some workers have proposed that renal vasodilation itself is the stim-ulus activating the stretch receptor to secrete renin (Eide et al., 1973, 1975, 1977; Kiil, 1975). There are, however, at least four reasons why afferent arter-iolar dilation itself may not be a stimulus that


488 CIRCULATION RESEARCH VOL. 47, No. 4, OCTOBER 1980 triggers renin secretion. The first is that agents such

as papaverine, acetylcholine, bradykinin, eledoisin, and prostaglandins dilate arterioles, but only a few prostaglandins stimulate renin secretion (Davis and Freeman, 1976; Osborn et al., 1978; Gerber et al, 1979; Seymour and Zehr, 1979). In fact, the vaso-dilation induced by papaverine has a decidedly inhibitory effect on renin secretion under a variety of circumstances (Davis and Freeman, 1976).

The mechanism by which prostaglandins stimu-late renin secretion is unclear, but the fact that prostaglandins are effective, even in kidney slices (Weber et al., 1976; Whorton et al., 1977) suggests that their sole mechanism of action may not be afferent arteriolar dilation (Seymour and Zehr, 1979; Osborn et al., 1978). Ito and Tajima (1979) have suggested that prostaglandins may affect nor-epinephrine release by modifying calcium channels. If this proposition is applicable to the juxtaglomer-ular cell, it suggests that prostaglandins stimulate renin secretion either by preventing influx of cal-cium into the cell or by promoting its efflux from the cell. Furthermore, prostaglandins hyperpolarize cells in the pulmonary artery and portal vein (Ki-tamura et al., 1976), and this suggests that they also may stimulate renin secretion by hyperpolarizing the juxtaglomerular cells.

The second reason why renal vasodilation may not be a powerful stimulus for renin secretion is that in the physiological and pathophysiological instances, where the greatest increases in renin secretion have been observed, increased secretion is associated with renal vasoconstriction, not vaso-dilation (Davis and Freeman, 1976). In fact, in most of such instances, vasodilation inhibits renin secre-tion (Davis and Freeman, 1976). The third reason is that the vasodilation-induced renin secretion hy-pothesis holds that renin secretion peaks when the kidney is maximally dilated and hemodynamic stimuli are no longer effective (Kiil, 1975). It has been shown recently that, even in a maximally dilated state, hemodynamic stimuli still have a pow-erful effect in stimulating renin secretion (Fray and Karuza, in press). The fourth reason is that the increased rate of renin secretion which results from direct pharmacological constriction of the renal vas-culature provides additional evidence against the vasodilation-induced secretion hypothesis (Fray, 1976; Fray and Karuza, in press; Nolan and Reid, 1978). Taken together, these lines of evidence sup-port the concept that low perfusion pressure and renal vasoconstriction stimulate renin secretion, whereas vasodilation inhibits secretion; and though, in certain circumstances, vasodilation may be as-sociated with a rise in renin secretion, this associa-tion may not be causal.

Low perfusion pressure, which hyperpolarizes vascular smooth muscles (Anderson, 1976), and vas-oconstriction stimulate renin secretion by hyper-polarizing the juxtaglomerular cell membrane and

lowering the cytoplasmic calcium according to the current hypothesis. Two lines of evidence support this view. First, high concentrations of extracellular potassium (56 mM) which depolarize the juxtaglo-merular cell completely abolish the stimulatory ef-fects of renal hypotension and renal vasoconstric-tion (Fray, 1978a). Second, low perfusion pressure stimulates renin secretion only when calcium is present in the extracellular fluid, and it becomes less effective as calcium concentration is raised (Fray and Park, 1979). High perfusion pressure, on the other hand, inhibits renin secretion when cal-cium is present in the extracellular fluid, but stim-ulates secretion when calcium is absent (Fray and Park, 1979).

This single discovery has provided a clue for the cellular mechanism by which stretch controls the secretory process. Stretch must somehow control calcium movement across the juxtaglomerular cell. In fact, as calcium is raised in the perfusion fluid, high perfusion pressure becomes more effective in inhibiting renin secretion (Fray, in press), presum-ably by promoting a greater net influx of calcium. Verapamil, which blocks inward movement of cal-cium in other secretory cells (Eto et al., 1974; Wol-lheim et al., 1978), prevents the renin inhibitory effect of high pressure (Fray, in press). One inter-esting finding is that high concentrations of extra-cellular potassium, which depolarize the juxtaglo-merular cell membrane (Fishman, 1976), mimic high perfusion pressure in its calcium dependence and in its inhibitory effect on renal vasoconstrictor-and /?-adrenergic-induced renin secretion (Park vasoconstrictor-and Malvin, 1978; Fray, 1978a). Since verapamil and its derivative, D600, block voltage-dependent calcium permeability channels in stretch receptors and other cells (Hunt et al., 1978; Baker and Glitsch, 1975), it is likely that high perfusion pressure in-creases calcium permeability in the juxtaglomerular cell (Fray and Park, 1979). Supporting this view is the observation that changing calcium concentra-tion in the medium bathing kidney slices has no effect on renin secretion, but when the slices are depolarized with high concentrations of potassium (59 mM) then changing calcium has a dramatic effect on renin secretion (Park and Malvin, 1978). Whether the increased calcium permeability results from a direct effect of high pressure or an indirect effect linked to membrane depolarization has not been ascertained. Since renal prostaglandins have been implicated in the mechanisms by which pres-sure controls renin secretion (Berl et al., 1979; Oates et al., 1979), it is quite possible that renal prosta-glandins may play some intermediate role between changes in perfusion pressure and changes in cal-cium permeability.

Humoral Control of Renin Secretion

Several lines of evidence suggest that humoral agents which stimulate renin secretion



ize cell membranes and lower cytoplasmic calcium and those which inhibit secretion depolarize cell membranes and raise calcium.


Catecholamines that stimulate renin secretion (Ganong, 1972; Vandongen et al., 1973; Davis and Freeman, 1976) also hyperpolarize the juxtaglomer-ular cell membrane (Fishman, 1976) and extrude calcium from the perfused kidney, and presumably the juxtaglomerular cell (Harada and Rubin, 1978). The stimulatory effect of catecholamines can be prevented by high concentrations of potassium which depolarize the juxtaglomerular cell mem-brane (Fishman, 1976; Fray, 1978a) and by lan-thanum, the potent blocker of net calcium efflux (Logan et al., 1977). Raising extracellular calcium or lowering extracellular sodium attenuates the powerful stimulatory effect of catecholamines (Fray and Park, 1979), and ouabain or potassium depri-vation completely obliterates it (Fray, in press). Since these observations are entirely consistent with the mechanism by which catecholamines lower cytoplasmic calcium in smooth muscle (Scheid et al., 1979), a similar mechanism has been proposed for the effect of catecholamine on the juxtaglomer-ular cell (Fray, in press). That is, catecholamines stimulate renin secretion by hyperpolarizing the juxtaglomerular cell membrane and thereby pre-vent the influx of extracellular calcium and by ex-truding cellular calcium through a cascade of events which begins with the Na-K pump and ends with Na-Ca exchange (Fray and Park, 1979; Fray, in press).

The stimulatory effects of catecholamines can be overcome completely by the inhibitory effect of high perfusion pressure (Fray, 1978a) and angioten-sin (Vandongen and Peart, 1974). This suggests that factors which inhibit renin secretion by raising cy-toplasmic calcium are more potent than those which stimulate by lowering calcium.

Parathyroid Hormone and Glucagon

Parathyroid hormone and glucagon, which have no known adrenergic activity, stimulate renin secre-tion (Powell et al., 1978; Smith et al., 1979; Vandon-gen et al., 1973; Lester and Rubin, 1977). Parathy-roid hormone also extrudes calcium from kidney cells and, presumably, from juxtaglomerular cells (Borle, 1973), whereas glucagon hyperpolarizes some cell membranes (Somlyo et al., 1971; Dam-bach and Friedmann, 1974) and extrudes calcium from the juxtaglomerular cells (Harada and Rubin, 1978). Since parathyroid hormone and glucagon produce their physiological effect by increasing cyclic AMP production, it might be well to ask whether adenosine compounds affect renin secre-tion. Cyclic AMP and dibutyryl-cyclic AMP stim-ulate renin secretion (Davis and Freeman, 1976), hyperpolarize cell membranes (Dambach and

Friedmann, 1974; Somlyo et al., 1971), and extrude calcium from cellular compartments (Dambach and Friedmann, 1974; Borle, 1974).


Angiotensin, an agent which depolarizes cell membranes and increases cytoplasmic calcium (Ha-mon and Worcel, 1979; Bolton, 1979; Natke and Kabela, 1979), also inhibits renin secretion by acting specifically on the juxtaglomerular cells (Naftilan and Oparil, 1978; Davis and Freeman, 1976). The magnitude of the angiotensin-induced inhibition of renin secretion depends very strikingly on the cal-cium concentration in the extracellular fluid, the inhibition being greatest when extracellular calcium concentration is largest (Vandongen and Peart, 1974). This suggests that at least one of the mech-anisms whereby angiotensin inhibits renin secretion is dependent on extracellular calcium and possibly on the influx of extracellular calcium, but direct evidence has not been provided. It is interesting to note that the mechanism by which angiotensin stimulates aldosterone secretion from the adrenal cortex also involves depolarization of the glomeru-losa cells (Natke and Kabela, 1979).

Calcium, Magnesium, and Ionophores

Calcium ion concentration in the extracellular fluid plays a key role in the mechanisms controlling renin secretion. Lowering extracellular calcium stimulates renin secretion powerfully (Vandongen and Peart, 1974; Fray, 1977; Fray and Park, 1979; Baumbach and Leyssac, 1977; Logan et al., 1977; Harada and Rubin, 1978), whereas raising calcium inhibits secretion (Kotchen et al., 1977; 1974; Kisch et al., 1976; Watkins et al., 1976). Recently it was shown that lowering extracellular calcium hyper-polarized the membrane potential of parathyroid cells (Bruce and Anderson, 1979). Depolarizing con-centrations of extracellular potassium (50 HIM) par-tially inhibit the renin stimulatory effect of low calcium (Fray and Park, 1979), which suggests that at least one of the mechanisms by which lowering extracellular calcium stimulates renin secretion in-volves membrane hyperpolarization. Whether renal prostaglandins are involved in the stimulatory ef-fect of calcium deprivation is unclear, but this might be possible, especially since renal prostaglandin pro-duction is dependent on calcium transport (Zenser and Davis, 1978).

As with lowering extracellular calcium, raising extracellular concentrations of magnesium stimu-lates renin secretion (Churchill and Lyons, 1976; Fray, 1977; Wilcox, 1978; Ettienne and Fray, 1979). High magnesium concentrations hyperpolarize cell membranes and inhibit net calcium influx (Sigurds-son and Uvelius, 1977; Altura and Altura, 1971; 1974; Woods et al., 1979). Recently it has been shown that depolarizing concentrations of extracel-lular potassium inhibited the stimulatory effect of high magnesium (Ettienne and Fray, 1979).


490 CIRCULATION RESEARCH VOL. 47, No. 4, OCTOBER 1980 The calcium ionophore A23187, which promotes

calcium entry into cells (Pressman, 1973), inhibits renin secretion in the presence of extracellular cal-cium, presumably by increasing net calcium influx and cytoplasmic calcium (Fynn et al., 1977; Baum-bach and Leyssac, 1977); the ionophore stimulates renin secretion in the absence of extracellular cal-cium, presumably by removing calcium from the cytoplasm. A23187 also depolarizes some cell mem-branes when calcium is present but not when it is absent from the extracellular fluid (Poulsen and Williams, 1977; Cochrane and Douglas, 1975).

Calcium ionophores have exactly the opposite effect on most other secretory systems; that is, they stimulate hormone and transmitter release in the presence of calcium but not in its absence (Nord-mann and Dyball, 1978; Kita and Van der Kloot, 1974). Since calcium ionophores may also break down the integrity of the cell membrane (Williams, 1978) and may release calcium from intracellular storage sites (Desmedt and Hainaut, 1976; Chandler and Williams, 1978), the foregoing results must be interpreted with extreme caution. This last point is particularly important since some workers have shown that calcium ionophores stimulate renin se-cretion in the presence of extracellular calcium

(Worley et al., 1978; Harada et al., 1979).

In summary, renal arterial hypotension, renal vasoconstriction, and intrarenal tissue pressure el-evation stimulate renin secretion by hyperpolariz-ing the juxtaglomerular cell membrane and decreas-ing the permeability to calcium. Conversely, hyper-tension and vasodilation inhibit secretion by depo-larizing the cell and increasing the calcium perme-ability. Movement of calcium then, is, critically dependent on the calcium concentration of the ex-tracellular fluid. During inhibition of renin secre-tion, for example, if the calcium concentration out-side the cell is greater than inout-side and the calcium electrochemical gradient favors movement into the cell, then when the cell is stretched, as by raising perfusion pressure, calcium will enter and increase cytoplasmic calcium. Humoral factors such as /?-adrenergic agonists also may hyperpolarize the jux-taglomerular cell membrane and impede the influx of extracellular calcium. However, such agonists also may stimulate net calcium efflux through a cascade of events beginning with the sodium-potas-sium pump linked to a sodium-calcium exchange mechanism. The net effect of these factors is a reduction of cytoplasmic calcium. Thus, humoral agents such as parathyroid hormone, glucagon, methylxanthines, adenosine compounds, and cal-cium ionophores that have profound effects on membrane potential and calcium movements in cells might be expected to regulate renin secretion in an ordered and predictable fashion.


I gratefully acknowledge discussions with Drs. A.J. Cohen, C.S. Park, T.W. Honeyman, C.R. Scheid, Ms L.E. Whitaker, and

Ms N.J. Laurens. I am indebted to Debra George for expert secretarial assistance.


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