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Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Studies of thapsigargin, cyclopiazonic acid, and ryanodine in isolated pulmonary arteries and smooth muscle cells suggest that release of Ca2+ from inositol 1,4,5-trisphosphate (IP3)- and/or ryanodine-sensitive sarcoplasmic reticulum Ca2+ stores is a component of the mechanism of acute hypoxic pulmonary vasoconstriction (HPV). However, the actions of these agents on HPV in perfused lungs have not been reported. Thus we tested effects of thapsigargin and cyclopiazonic acid, inhibitors of sarcoplasmic reticulum Ca2+-ATPase, and of ryanodine, an agent that either locks the ryanodine receptor open or blocks it, on HPV in salt solution-perfused rat lungs. After inhibition of cyclooxygenase and nitric oxide synthase, thapsigargin (10 nM) and cyclopiazonic acid (5 µM) augmented the vasoconstriction to 0% but not to 3% inspired O2. Relatively high concentrations of ryanodine (100 and 300 µM) blunted HPV in nitric oxide synthase-inhibited lungs. The results indicate that release of Ca2+ from the ryanodine-sensitive, but not the IP3-sensitive, store, contributes to the mechanism of HPV in perfused rat lungs and that Ca2+-ATPase-dependent Ca2+ buffering moderates the response to severe hypoxia.
pulmonary circulation; pulmonary vasoregulation; hypoxia; intracellular calcium
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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STUDIES IN PERFUSED LUNGS (2, 11, 23, 40), catheterized animals (27, 31, 39, 44, 55), and human subjects (26, 38) show inhibition of acute hypoxic pulmonary vasoconstriction (HPV) by voltage-gated Ca2+ channel blockers, such as verapamil and nifedipine. In addition, HPV is potentiated by the voltage-gated Ca2+ channel facilitator BAY K 8644 (22, 43) and the voltage-gated and Ca2+-activated K+ channel blockers 4-aminopyridine and tetraethylammonium chloride (2, 11, 12) and inhibited by ATP-sensitive K+ channel activators (2, 11, 12, 27, 36, 53). These pharmacological observations indicate that vascular smooth muscle membrane depolarization and Ca2+ influx through L-type Ca2+ channels are important components of the mechanism of HPV. This idea is supported by electrophysiological studies of isolated pulmonary arteries and pulmonary artery smooth muscle cells (PASMC) that show that hypoxia can cause inhibition of voltage-gated K+ channels, membrane depolarization, and Ca2+ influx (for recent reviews, see Refs. 1, 5, 19, 21, 41, 51). Collectively, these studies lead to the concept that the mechanism of HPV comprises hypoxic inhibition of a vascular smooth muscle voltage-gated K+ channel, membrane depolarization, opening of L-type Ca2+ channels, Ca2+ influx, and contraction.
In contrast, another body of work in isolated pulmonary arteries and PASMC suggests that hypoxia-induced release of Ca2+ from intracellular sarcoplasmic reticulum (SR) stores, such as the ryanodine receptor-sensitive, or Ca2+-induced Ca2+-release (CICR) store, and the inositol 1,4,5-trisphosphate (IP3) receptor-sensitive Ca2+ store, is a component of the mechanism of HPV. Thus caffeine, an agent that activates and depletes ryanodine-sensitive Ca2+ stores (16), inhibited hypoxia-induced increases in intracellular Ca2+ in rat PASMC (34) and hypoxic suppression of K+ currents in dog PASMC (29). In addition, ryanodine, an agent that depending on concentration either locks the ryanodine receptor open or blocks it (16), inhibited hypoxia-induced increases in cytoplasmic Ca2+ in cat (45), rat (10), and lamb (6) PASMC. Ryanodine also blunted hypoxic contraction of dog pulmonary arteries (13) and blocked the hypoxic response of pig pulmonary arteries (18). Whereas one study of rat pulmonary arteries found blockade of hypoxic contraction by ryanodine (10), two other studies did not (15, 33). The combination of caffeine and ryanodine inhibited hypoxia-induced increases in intracellular Ca2+ in rabbit PASMC (9) and abolished both the initial transient and secondary sustained phases of the biphasic hypoxic contraction of rat and rabbit pulmonary arteries (8, 9). Similarly, although thapsigargin and cyclopiazonic acid, inhibitors of SR Ca2+-ATPase and the uptake of Ca2+ into IP3-sensitive Ca2+ stores (16), inhibited hypoxic increases in cytoplasmic Ca2+ in rat PASMC (10, 34) and the initial hypoxic contractions of rat pulmonary arteries (8, 10, 33), these agents potentiated sustained hypoxic contractions of dog pulmonary arteries (13). Although these observations are somewhat discordant, they indicate collectively that release of Ca2+ from ryanodine- and/or IP3-sensitive SR Ca2+ stores plays a role in the responses of isolated pulmonary arteries and PASMC to hypoxia. Further support for this idea is provided by recent reports that hypoxia increases PASMC levels of the endogenous ryanodine receptor agonist cADP-ribose (54) and that the cADP-ribose antagonist, 8-bromo-cADP-ribose, blocks the sustained hypoxic contractions of rabbit (54) and rat (8) pulmonary arteries and the hypoxic vasoconstriction of perfused rat lungs (8). Thus it has been suggested that HPV is initiated and sustained by release of SR Ca2+ without a significant role for membrane depolarization and voltage-gated Ca2+ influx (8, 9, 33).
With the exception of the recent finding by Dipp and Evans (8) that 8-bromo-cADP-ribose inhibits hypoxic vasoconstriction in rat lungs, the role of Ca2+ release from intracellular SR stores in the mechanism of HPV in perfused lungs has not been reported. Because much of the evidence for involvement of release of SR Ca2+ comes from studies of the effects of thapsigargin, cyclopiazonic acid, and ryanodine in PASMC and isolated pulmonary arteries, and because physiological and pharmacological disparity is often observed between isolated arteries and whole lungs (47), we believe it important to examine the effects of these agents on HPV in the more intact pulmonary vascular bed of the isolated, physiological salt solution (PSS)-perfused rat lung.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Experiments were performed with adult male Sprague-Dawley rats (300-400 g) that were kept at Denver's altitude of 5,280 ft (barometric pressure ~630 mmHg, inspired O2 tension ~122 Torr). The rats were housed under a 12:12-h light-dark cycle and allowed free access to standard rat food and water. All experimental procedures were approved by the Animal Care and Use Committee of the University of Colorado Health Sciences Center.
Isolated perfused lungs.
Lungs were isolated from rats after anesthesia with intraperitoneal
pentobarbital sodium (30 mg) and an intracardiac injection of 100 IU of
heparin as previously described (11, 12, 25, 36, 37).
Isolated lungs were ventilated with a humid mixture of 21%
O2-5% CO2-74% N2 at 60 breaths/min, an inspiratory pressure of 9 cmH2O, and an
end-expiratory pressure of 2.5 cmH2O. They were perfused
through a main pulmonary artery cannula with peristaltic pump at a
constant flow of 0.04 ml · g body
wt
1 · min1. Mean perfusion pressure
was continuously measured with a transducer and pen recorder. The
perfusate was a PSS containing (in mM) 116.3 NaCl, 5.4 KCl, 0.83 MgSO4, 19.0 NaHCO3, 1.04 NaH2PO4, 1.8 CaCl2 · 2H2O, and 5.5 D-glucose (Earle's balanced salt solution; Sigma Chemical). Ficoll (4 g/100 ml, type 70; Sigma Chemical) was included as
a colloid, and 3.1 µM sodium meclofenamate (Sigma Chemical) was
added to inhibit synthesis of vasodilator prostaglandins (27, 36). After lungs were flushed of blood with 20 ml of PSS, they were perfused with a recirculated volume of 30 ml. Effluent perfusate drained from a left ventricular cannula into a perfusate reservoir located below the level of the lung. The perfusate reservoir
volume was continuously monitored, and any lung preparation that leaked perfusate or became overtly edematous was excluded from the study. Lung
and perfusate temperatures were maintained at 37°C, and
perfusate pH was kept between 7.3 and 7.4.
Experimental protocols. Because thapsigargin and cyclopiazonic acid stimulate endothelial NO synthesis (24, 25, 56), the first set of experiments compared the separate effects of the two inhibitors of SR Ca2+-ATPase on HPV in PSS-perfused rat lungs either pretreated or not with the inhibitor of NO synthase nitro-L-arginine (L-NNA) (Aldrich). After equilibration and two initial challenges with 0% O2, lungs were treated by adding either 60 µl saline (vehicle control) or 200 µM L-NNA (25, 36) to the perfusate. Fifteen minutes later, a third hypoxic challenge was given, and then either DMSO (vehicle; 30 µl), thapsigargin (Calbiochem; 10 nM) (4, 25), or cyclopiazonic acid (Calbiochem; 5 µM) (8, 10, 13, 16) was added to the perfusate. After an additional 15 min, the lungs were again challenged twice with 0% O2 ventilation for 15 min, with 10 min of normoxic ventilation between the two challenges.
Although there is no clear evidence that ryanodine stimulates NO synthesis, the second experiment compared effects of the ryanodine-receptor inhibitor on the response to 0% O2 in lungs either pretreated or not with L-NNA to control for any possible interaction between NO and ryanodine-sensitive Ca2+ stores (28, 35). The protocol was identical to that described above for the Ca2+-ATPase inhibitors except either 30 µl distilled H2O (vehicle) or 10 µM ryanodine (10, 13, 15, 18, 33, 45) was added to the perfusate of untreated and L-NNA-pretreated lungs 15 min before the final two hypoxic challenges. The effects of a fivefold higher concentration of ryanodine (50 µM) (30, 35) were also examined in additional L-NNA-pretreated lungs. To test whether a possible role of release of intracellular Ca2+ in HPV might depend on the severity of hypoxia, a third experiment examined the separate effects of thapsigargin and ryanodine in L-NNA-pretreated lungs challenged with 3% O2 instead of 0% O2. The protocol was as described in the preceding paragraphs except lungs were challenged with 3% O2 instead of 0% O2 before and after addition of 200 µM L-NNA and either 30 µl DMSO or distilled H2O (vehicles), 10 nM thapsigargin, or 10 µM ryanodine to the perfusate. In view of the recent report that the cADP-ribose antagonist 8-bromo-cADP-ribose blocks HPV in rat lungs (8), and to enhance our confidence that a sufficiently high concentration of ryanodine was used (14), the effects of 100 and 300 µM ryanodine were tested in additional L-NNA-pretreated lungs challenged with 3% O2. Also, 0.1 µM nifedipine (11, 16) was added to the perfusate at the peak of a third posttreatment hypoxic response to test for involvement of voltage-gated Ca2+ influx in the ongoing HPV in lungs treated with either vehicle or 100 µM ryanodine.Statistics. Data are expressed as means ± SE. Statistical analysis was done by either unpaired t-test or repeated-measures ANOVA followed by Dunn-type multiple comparisons. Differences were considered significant at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the first experiment, cyclopiazonic acid, but
not thapsigargin, caused a slight increase in baseline (normoxic)
perfusion pressure in lungs either pretreated or not with
L-NNA (Table 1). Whereas both
agents reduced the peak of the pressor response to 0% O2
in lungs not pretreated with L-NNA, they augmented the
response in lungs pretreated with the NO synthase inhibitor (Fig.
1). Representative perfusion pressure
tracings in L-NNA-pretreated lungs are shown in Fig.
2. Although both thapsigargin and
cyclopiazonic acid augmented the peak of the hypoxic response, neither
agent prevented the marked spontaneous reversal (dilation) of the
vasoconstriction (Fig. 2 and Table 2).
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In the second experiment, neither 10 nor 50 µM ryanodine had any
effect on either baseline perfusion pressure (Table 1) or the pressor
response to 0% O2 in lungs either pretreated or not with
L-NNA (Fig. 3). Ryanodine
also did not affect the spontaneous reversal of hypoxic
vasoconstriction in L-NNA-pretreated lungs (Fig. 2 and
Table 2).
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In the third experiment with L-NNA-pretreated lungs
challenged with 3% O2 instead of 0% O2, 10 nM
thapsigargin neither increased baseline perfusion pressure (Table 1)
nor affected either the peak (Fig. 4) or
the spontaneous reversal (Fig. 2 and Table 2) of the hypoxic pressor
response. Whereas neither 10, 100, nor 300 µM ryanodine affected
baseline perfusion pressure (Table 1), 100 µM ryanodine tended to
blunt the peak hypoxic vasoconstriction, and the inhibition by 300 µM
was statistically significant (Fig. 5).
The percent spontaneous reversal of hypoxic vasoconstriction was
increased in lungs treated with 300 µM but not with 100 µM, ryanodine (Table 2). Representative perfusion pressure tracings of
effects of 300 µM ryanodine on HPV are shown in Fig. 2. In lungs
treated with 100 µM ryanodine, 0.1 µM nifedipine caused immediate
and marked inhibition of the residual, ongoing hypoxic vasoconstriction
(Fig. 6).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study showed that the effects of thapsigargin and cyclopiazonic acid on HPV in PSS-perfused rat lungs depended on whether lungs had been pretreated with an inhibitor of NO synthase and on the severity of hypoxic challenge. Whereas both inhibitors of SR Ca2+-ATPase blunted the pressor response to 0% O2 in the absence of L-NNA, they augmented the response after inhibition of NO synthesis. However, thapsigargin did not augment the pressor response to 3% O2 in L-NNA-pretreated lungs. Because blunting of HPV by thapsigargin and cyclopiazonic acid in the absence of L-NNA was apparently due to increased synthesis of the vasodilator NO (24, 25, 56), these results provide no evidence that release of Ca2+ from IP3-sensitive SR stores is an important component of the mechanism of HPV in perfused rat lungs. In contrast, relatively high concentrations of ryanodine blunted HPV in L-NNA-pretreated lungs, a finding consistent with the possibility that release of Ca2+ from the ryanodine-sensitive, CICR SR store contributes to the overall mechanism of HPV.
A limitation of this study is that we had no independent measure of the effects of thapsigargin and cyclopiazonic acid or of ryanodine on release of SR Ca2+ in the PASMC of the perfused lung. The 5 µM concentration of cyclopiazonic acid used in our study was similar to that used to inhibit Ca2+-ATPase and deplete IP3-sensitive Ca2+ stores in isolated arteries and smooth muscle cells (8, 10, 13, 16). Because concentrations of thapsigargin >30 nM caused edema in PSS-perfused rat lungs (4), we limited its concentration to 10 nM, which was lower than the 1-5 µM generally used in vitro (10, 13, 16). However, our laboratory has previously observed that 10 nM thapsigargin causes contraction of isolated rat pulmonary arteries (25), which suggests that this concentration is sufficient to inhibit Ca2+-ATPase in rat conduit PASMC. Despite the different concentrations, the two inhibitors of Ca2+- ATPase had very similar effects on pulmonary vasoreactivity. Only cyclopiazonic acid caused a slight increase in baseline perfusion pressure, but both agents blunted the pressor response to 0% O2 in the absence of L-NNA and augmented the response in the presence of L-NNA. Although the 10 µM concentration of ryanodine used in our initial experiments has been commonly used in studies of isolated arteries and PASMC (6, 10, 13, 15, 18, 33, 45) and has been found in some cases to inhibit hypoxic responses (6, 10, 13, 18, 45), it had no effect on HPV in the perfused lungs. Because some reports indicate that concentrations as high as 300 µM are required to inhibit release of Ca2+ from the CICR store (14), we also examined the effects of 100 and 300 µM ryanodine and observed significant blunting of HPV by the highest concentration. We attempted in preliminary experiments to use caffeine-induced vasoconstriction to test for the effectiveness of ryanodine blockade of CICR (13, 14, 33) but found that 10 mM caffeine caused vasodilation rather than vasoconstriction in meclofenamate- and L-NNA-pretreated rat lungs (unpublished observations).
Our observation that thapsigargin and cyclopiazonic acid augmented the pressor response to 0% O2 is similar to that of Jabr et al. (13), who observed potentiation of hypoxic (0% O2) contraction of dog pulmonary arteries by these inhibitors of SR Ca2+-ATPase. A difference between the studies is that we found potentiation of the hypoxic response only after inhibition of NO synthesis, whereas a NO synthase inhibitor was not used in the isolated pulmonary arteries. The arteries were isolated with functional endothelium (13), and it is unclear why endothelial NO production in response to the Ca2+-ATPase inhibitors (24, 25, 56) was apparently not an issue. Because the larger hypoxic contractions of isolated arteries after thapsigargin or cyclopiazonic acid were less sensitive to inhibition by L-type Ca2+ channel blockers than were the control responses, Jabr et al. (13) speculated that additional Ca2+ influx through a dihydropyridine-insensitive pathway contributed to the potentiation. We did not examine this possibility in the perfused lungs, and the potentiation of HPV might have been due to a similar mechanism and/or to a reduction in the ability of SR Ca2+-ATPase to buffer an increase in cytosolic Ca2+ (46). We do not know why we and Jabr et al. observed potentiation of hypoxic responses, whereas Dipp and Evans (8), Gelband and Gelband (10), and Robertson et al. (33) found inhibition of hypoxic contraction of isolated rat pulmonary arteries by thapsigargin and/or cyclopiazonic acid.
We are also uncertain why thapsigargin potentiated HPV to 0% O2 but not to 3% O2 in L-NNA-pretreated lungs. It can be speculated that if potentiation of the peak response to 0% O2 by thapsigargin were due to inhibition of Ca2+ buffering by SR Ca2+-ATPase (46), then possibly the buffering was greater during the response to 0% O2 than during that to 3% O2. In view of evidence that severe hypoxia stimulates Ca2+- ATPase-dependent Ca2+ uptake in rabbit pulmonary arteries (49), such a difference is feasible. In contrast, potentiation of the peak response to 0% O2 by the inhibitors of Ca2+-ATPase was apparently not due to attenuation of the spontaneous reversal (dilation) of the response, because the dilation was not reduced by either thapsigargin or cyclopiazonic acid. This agrees with evidence that the spontaneous reversal of vasoconstriction to severe hypoxia in perfused lungs is due largely to stimulation of ATP-sensitive and Ca2+-activated K+ channels and the resulting membrane hyperpolarization and inhibition of voltage-gated Ca2+ influx (11, 12, 53).
Previous studies of effects of ryanodine on hypoxic contraction of isolated arteries have produced mixed results. Gelband and Gelband (10) and Liu et al. (18) found complete blockade of hypoxic contraction of rat and pig pulmonary arteries by 5 and 10 µM ryanodine, respectively, and Jabr et al. (13) observed blunting of hypoxic contraction of dog pulmonary arteries. In contrast, Jin et al. (15) reported no effect of 10 µM ryanodine on hypoxic contraction of rat pulmonary arteries. Saqueton et al. (35) infused ryanodine into the pulmonary artery of fetal lambs and observed that although it inhibited inhaled NO-induced pulmonary vasodilation, it had no effect on hypoxic pulmonary vascular tone. Whereas Dipp and Evans (8) reported complete blockade of hypoxic contraction of rat pulmonary arteries by 10 µM ryanodine plus 10 mM caffeine, this combination caused only slight inhibition in the study of Robertson et al. (33). There is no evident explanation for these disparate findings. In our study of perfused rat lungs, 10 µM ryanodine had no effect on HPV, 100 µM tended to reduce the response, and 300 µM caused significant blunting. Interpreting this finding to mean that CICR contributes to the mechanism of HPV assumes that the relatively high concentration of ryanodine was required to inhibit Ca2+ release and was not having a nonspecific effect. The lack of effect of ryanodine on baseline perfusion pressure in the isolated rat lungs suggests that ryanodine-sensitive, Ca2+ spark-induced stimulation of Ca2+-activated K+ channels (14, 30, 35, 48) plays no role in regulating the low resting vascular tone of this preparation.
Our finding of blunting instead of blockade of HPV by a high concentration of ryanodine differs somewhat from the recent observation that HPV in rat lungs is both completely prevented and reversed by the cADP-ribose antagonist 8-bromo-cADP-ribose (8). Because hypoxia increases cADP-ribose in pulmonary artery smooth muscle (54), cADP-ribose induces Ca2+ release from ryanodine-sensitive stores (54), and 8-bromo-cADP-ribose blocks sustained hypoxic contraction of isolated pulmonary arteries and hypoxic vasoconstriction of perfused lungs (8, 54), Dipp and Evans (8) have proposed that cADP-ribose-induced release of SR Ca2+ initiates and sustains HPV without a significant role for membrane depolarization and voltage-gated Ca2+ influx. Although these investigators present a strong case that 8-bromo-cADP-ribose-induced inhibition of HPV is due to inhibition of release of SR Ca2+, our findings that high concentrations of ryanodine failed to abolish the hypoxic response and that the residual hypoxic vasoconstriction was immediately and markedly reversed by the voltage-gated Ca2+ channel blocker nifedipine raise a note of caution. It would seem either that ryanodine failed to completely block CICR in our study or that 8-bromo-cADP-ribose had effects other than or in addition to inhibition of Ca2+ release in the study of Dipp and Evans. With respect to the latter, one possibility that could be considered is that 8-bromo-cADP-ribose reversed a cADP-ribose-mediated inhibition of a hyperpolarizing K+ current. For example, cADP-ribose has been reported to inhibit Ca2+-activated K+ channels in coronary arterial smooth muscle (17) and the activation of a voltage-sensitive K+ current in neuroblastoma/glioma hybrid cells (3). Thus we suggest that further work is necessary to test whether 8-bromo-cADP-ribose-induced blockade of HPV in perfused rat lungs is due partly to activation of a hyperpolarizing K+ current and inhibition of Ca2+ influx rather than solely to inhibition of release of SR Ca2+. Such a mechanism would be similar to the inhibition of HPV by blockade of the endothelin-1 ETA receptor that appears to be mediated through derepression of the ATP-sensitive K+ channel (36).
If, as our results suggest, both CICR and voltage-gated Ca2+ influx contribute to the intracellular Ca2+ signal mediating HPV in PSS-perfused rat lungs, then the question arises as to which comes first. Some studies of PASMC indicate that hypoxia-induced release of intracellular Ca2+ is the initiating event (10, 29, 34, 45). However, voltage-gated Ca2+ influx is a physiological trigger for ryanodine receptor-mediated CICR in vascular smooth muscle (7), and Cornfield et al. (6) have proposed that hypoxia-induced membrane depolarization and Ca2+ influx trigger CICR in fetal PASMC.
In summary, our results in PSS-perfused rat lungs do not support evidence from studies of effects of thapsigargin and cyclopiazonic acid in PASMC and isolated pulmonary arteries (8, 10, 33, 34) that Ca2+ release from an IP3-sensitive SR Ca2+ store is an important component of the mechanism of HPV. However, our finding that relatively high concentrations of ryanodine blunt HPV agrees in principle with some studies of PASMC and isolated arteries (6, 8-10, 13, 18, 29, 45) and is consistent with the idea that Ca2+ release from a ryanodine-sensitive SR Ca2+ store contributes to the hypoxia-induced Ca2+ signaling and vasoconstriction. What remains unclear are the relative roles and temporal relationships of voltage-gated Ca2+ influx, CICR, voltage-independent Ca2+ entry (33, 50), and increased Ca2+ sensitivity of contractile myofilaments (20, 32) in the overall mechanism of HPV, and to what extent the contribution of these various components is species and/or experimental preparation dependent. As emphasized in recent editorials by Sylvester (42) and Weissmann et al. (52), many questions concerning the exact sequence of inter- and intracellular events underlying the mechanism of HPV remain to be definitively answered.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-14985 to I. F. McMurtry.
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FOOTNOTES |
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Address for reprint requests and other correspondence: Y. Morio, CVP Research Laboratory, B133, UCHSC, 4200 East Ninth Ave., Denver, CO 80262 (E-mail: yoshiteru.morio{at}uchsc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 18 June 2001; accepted in final form 19 September 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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L-NNA) but augmented the larger HPR in lungs pretreated
with 200 µM L-NNA (+L-NNA). DMSO (30 µl)
was added to perfusate of vehicle control lungs. Time after treatment
is minutes after addition of either vehicle, TG, or CPA to lung
perfusate. Values are means ± SE; nos. in parentheses, no. of
lungs. *P < 0.05 for both TG and CPA groups vs.
vehicle control group by ANOVA. 
P < 0.05 for TG group vs. vehicle control group by ANOVA.
