Circulation Research
OCTOBER
1980
VOL. 47
NO. 4
An Official 'Journal of the American Heart Association
BRIEF REVIEWS
Stimulus-Secretion Coupling of Renin
Role of Hemodynamic and Other Factors
JOHN C.S. FRAY
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IT IS generally agreed that three intrarenal receptors control renin secretion. The macula densa receptor 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 juxtaglomerular cell membrane, stimulates renin secretion by a
/?-adrenergic mechanism and inhibits by an a mechanism (Ganong, 1972; Vandongen et al., 1973; Capponi and Valloton, 1976). The vascular stretch receptor, 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 receptor and the stretch receptor can function independently of the macula densa (Davis and Freeman,
1976), several investigators have sought to determine the chemical or physical events connecting
the receptors to the secretory process. If we accept
the proposition that decreased stretch and jS-adrenergic stimulation increase renin secretion, then it
is natural to enquire about the hemodynamic factors that affect the stretch and about the cellular
mechanism by which 0 stimulation leads to increased secretion.
In one approach to seek answers to these enquiries, a mathematical formula has been developed to
account for the hemodynamic factors and to point
to possible mechanisms by which these factors activate 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 coupling 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 approach has been particularly useful, for it has alFrom 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 secretory 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 secretion. Douglas and Rubin (1961) suggested that acetylcholine interacts with the chromaffin cell to depolarize the cell membrane and to increase the
calcium permeability of the cell; since calcium concentration usually is higher outside the cell than
inside, it enters the cell and this initiates the secretion process. When calcium is removed from the
perfusion fluid, acetylcholine still induces depolarization but not catecholamine secretion. When calcium 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 calcium is present in the perfusion fluid. This general
scheme, stimulus —* membrane depolarization —»
increased calcium permeability —» increased calcium influx and cytoplasmic calcium —» 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 secretion 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
CIRCULATION RESEARCH
486
release. The process of renin secretion under normal
physiological conditions may be initiated by hyperpolarization 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 hemodynamic and other factors control renin secretion by this process. Because the theoretical analysis used to identify the hemodynamic factors is
fairly new, it will be discussed briefly.
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Hemodynamic Control of Renin Secretion
Tobian (1960) postulated that renin secretion is
inversely related to the stretch of the afferent arteriole. 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-(ri/r) 2
(ri/r) 2 Pi-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 P o is the mean extravascular or intrarenal tissue hydrostatic pressure.
Figure 1 represents a graph of renin secretion as
a function of each independent variable, and illustrates three distinct effects of hemodynamic variables 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 proportional 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 - P o .
An important observation emerges when two of
the variables change simultaneously. Increasing P o
stimulates renin secretion (Fig. IB), whereas increasing 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 P o
is twice as effective as Pi for the same magnitude of
change (Fray, 1976), implying that in the formula
VOL.47, No.4, OCTOBER 1980
(ri/ro)2 Pi — Po, (ri/ro)2 may be 0.5 in some circumstances. A similar phenomenon can be demonstrated by changing ri/ro and Pi simultaneously.
Thus the renin secretion induced by vasoconstriction (lowering ri/ro) can be counteracted by raising
Pi, and the secretion induced by lowering Pi can be
counteracted by vasodilation (raising ri/r o ). In certain 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 measured carefully.
The mathematical analysis has indicated that
tissue elasticity, extravascular and intravascular
pressures, and afferent arteriolar radii modulate
renin secretion. Some experimental evidence supports this indication. Raising the modulus of the
elasticity (E) of the afferent arteriole increases
renin secretion. Although direct demonstration relating afferent arteriolar elasticity to renin secretion
is difficult to obtain, indirect evidence supports the
concept. For example, vasopressin reduces the elasticity of arteries in vitro (Monos et al., 1978) and
reduces renin secretion. An intact tubular organization 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 stimulation also increases tissue elastic modulus (Somlyo and Somlyo, 1968) and renin secretion. Therefore, at least one of the mechanisms whereby vasopressin 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 independent 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 returned toward control when perfusion pressure was
raised by 70 mm Hg. This suggests that the effective
pressure is not a straightforward transmural pressure (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
487
STIMULUS-SECRETION COUPLING OF RENIN/Fray
I 1
HEMOOTNAMIC FACTORS CONTROUMG RENM SECRETION(RS) AS PLOTTED FROM THE EQUATION: RS = K - '
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P, (mmHB)
PjmmHg)
I
('
|/
\
'°
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 elevation increase renal tissue pressure and renin secretion (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 induced by ureteral occlusion, mannitol and other
diuretic infusion, and renal encapsulation may involve a rise in intrarenal tissue pressure.
Perfusion Pressure and Vascular Resistance
It is difficult to discuss the effect of renal perfusion 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 experimentally (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 vasodilation, although this occurred below the autoregulatory range. On the other hand, vasodilation inhibited renin secretion when renal perfusion pressure 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 secretion 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 stimulus activating the stretch receptor to secrete renin
(Eide et al., 1973, 1975, 1977; Kiil, 1975). There are,
however, at least four reasons why afferent arteriolar dilation itself may not be a stimulus that
488
CIRCULATION RESEARCH
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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 vasodilation 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 stimulate 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 norepinephrine release by modifying calcium channels.
If this proposition is applicable to the juxtaglomerular cell, it suggests that prostaglandins stimulate
renin secretion either by preventing influx of calcium into the cell or by promoting its efflux from
the cell. Furthermore, prostaglandins hyperpolarize
cells in the pulmonary artery and portal vein (Kitamura 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 vasodilation (Davis and Freeman, 1976). In fact, in most
of such instances, vasodilation inhibits renin secretion (Davis and Freeman, 1976). The third reason
is that the vasodilation-induced renin secretion hypothesis 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 powerful 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 vasculature 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 support the concept that low perfusion pressure and
renal vasoconstriction stimulate renin secretion,
whereas vasodilation inhibits secretion; and though,
in certain circumstances, vasodilation may be associated with a rise in renin secretion, this association may not be causal.
Low perfusion pressure, which hyperpolarizes
vascular smooth muscles (Anderson, 1976), and vasoconstriction stimulate renin secretion by hyperpolarizing the juxtaglomerular cell membrane and
VOL. 47, No. 4, OCTOBER
1980
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 juxtaglomerular cell completely abolish the stimulatory effects of renal hypotension and renal vasoconstriction (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 calcium is present in the extracellular fluid, but stimulates 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), presumably by promoting a greater net influx of calcium.
Verapamil, which blocks inward movement of calcium in other secretory cells (Eto et al., 1974; Wollheim et al., 1978), prevents the renin inhibitory
effect of high pressure (Fray, in press). One interesting finding is that high concentrations of extracellular potassium, which depolarize the juxtaglomerular cell membrane (Fishman, 1976), mimic
high perfusion pressure in its calcium dependence
and in its inhibitory effect on renal vasoconstrictorand /?-adrenergic-induced renin secretion (Park 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 increases calcium permeability in the juxtaglomerular
cell (Fray and Park, 1979). Supporting this view is
the observation that changing calcium concentration 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 pressure controls renin secretion (Berl et al., 1979; Oates
et al., 1979), it is quite possible that renal prostaglandins may play some intermediate role between
changes in perfusion pressure and changes in calcium permeability.
Humoral Control of Renin Secretion
Several lines of evidence suggest that humoral
agents which stimulate renin secretion hyperpolar-
STIMULUS-SECRETION COUPLING OF
BENIN/Fray
489
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ize cell membranes and lower cytoplasmic calcium
and those which inhibit secretion depolarize cell
membranes and raise calcium.
Friedmann, 1974; Somlyo et al., 1971), and extrude
calcium from cellular compartments (Dambach and
Friedmann, 1974; Borle, 1974).
Catecholamines
Catecholamines that stimulate renin secretion
(Ganong, 1972; Vandongen et al., 1973; Davis and
Freeman, 1976) also hyperpolarize the juxtaglomerular 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 membrane (Fishman, 1976; Fray, 1978a) and by lanthanum, 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 deprivation 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 juxtaglomerular cell (Fray, in press). That is, catecholamines
stimulate renin secretion by hyperpolarizing the
juxtaglomerular cell membrane and thereby prevent the influx of extracellular calcium and by extruding 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 angiotensin (Vandongen and Peart, 1974). This suggests that
factors which inhibit renin secretion by raising cytoplasmic calcium are more potent than those
which stimulate by lowering calcium.
Angiotensin
Parathyroid Hormone and Glucagon
Parathyroid hormone and glucagon, which have
no known adrenergic activity, stimulate renin secretion (Powell et al., 1978; Smith et al., 1979; Vandongen et al., 1973; Lester and Rubin, 1977). Parathyroid hormone also extrudes calcium from kidney
cells and, presumably, from juxtaglomerular cells
(Borle, 1973), whereas glucagon hyperpolarizes
some cell membranes (Somlyo et al., 1971; Dambach 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 secretion. Cyclic AMP and dibutyryl-cyclic AMP stimulate renin secretion (Davis and Freeman, 1976),
hyperpolarize cell membranes (Dambach and
Angiotensin, an agent which depolarizes cell
membranes and increases cytoplasmic calcium (Hamon 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 calcium 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 mechanisms 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 glomerulosa 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 hyperpolarized the membrane potential of parathyroid
cells (Bruce and Anderson, 1979). Depolarizing concentrations of extracellular potassium (50 HIM) partially 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 involves membrane hyperpolarization. Whether renal
prostaglandins are involved in the stimulatory effect of calcium deprivation is unclear, but this might
be possible, especially since renal prostaglandin production is dependent on calcium transport (Zenser
and Davis, 1978).
As with lowering extracellular calcium, raising
extracellular concentrations of magnesium stimulates 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 (Sigurdsson and Uvelius, 1977; Altura and Altura, 1971;
1974; Woods et al., 1979). Recently it has been
shown that depolarizing concentrations of extracellular potassium inhibited the stimulatory effect of
high magnesium (Ettienne and Fray, 1979).
CIRCULATION RESEARCH
490
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The calcium ionophore A23187, which promotes
calcium entry into cells (Pressman, 1973), inhibits
renin secretion in the presence of extracellular calcium, presumably by increasing net calcium influx
and cytoplasmic calcium (Fynn et al., 1977; Baumbach and Leyssac, 1977); the ionophore stimulates
renin secretion in the absence of extracellular calcium, presumably by removing calcium from the
cytoplasm. A23187 also depolarizes some cell membranes 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 (Nordmann 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 secretion 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 elevation stimulate renin secretion by hyperpolarizing the juxtaglomerular cell membrane and decreasing the permeability to calcium. Conversely, hypertension and vasodilation inhibit secretion by depolarizing the cell and increasing the calcium permeability. Movement of calcium then, is, critically
dependent on the calcium concentration of the extracellular fluid. During inhibition of renin secretion, for example, if the calcium concentration outside the cell is greater than inside 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 juxtaglomerular 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-potassium 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 calcium 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.
Acknowledgments
I gratefully acknowledge discussions with Drs. A.J. Cohen,
C.S. Park, T.W. Honeyman, C.R. Scheid, Ms L.E. Whitaker, and
VOL. 47, No. 4, OCTOBER 1980
Ms N.J. Laurens. I am indebted to Debra George for expert
secretarial assistance.
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Circ Res. 1980;47:485-492
doi: 10.1161/01.RES.47.4.485
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