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EDITORIAL FOCUS
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Submitted 20 January 2005 ; accepted in final form 12 February 2005
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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isolated rat lung; pulmonary vascular resistance; angiotensin II; calcium signaling; vascular smooth muscle; calcium channels
Other findings suggest that Ca2+ release from sarcoplasmic reticulum (SR) and influx through pathways other than VOCC may also be important in HPV. For example, ryanodine, which blocks SR Ca2+ release, inhibited hypoxic responses in PASMC (59), PA (9, 19, 26), and isolated lungs (31). VOCC antagonists inhibited, but did not completely block, [Ca2+]i responses to hypoxia in PASMC (7, 45) and HPV in isolated lungs (30). Depolarization with KCl plus inhibition of L-type VOCC with nifedipine or verapamil did not prevent contractile or [Ca2+]i responses to hypoxia in isolated PA (43). One possible explanation for these findings is that hypoxia caused release of Ca2+ from SR in PASMC, leading to SR depletion, activation of store-operated Ca2+ channels (SOCC), and capacitative Ca2+ entry (CCE).
Recently, we reported that several so-called "canonical transient receptor potential (TRPC)" proteins were expressed in smooth muscle of distal PA (60), which are thought to be the major vascular locus of HPV (49). These proteins are homologs of TRP and TRP-like proteins that make up Ca2+ channels in Drosophila photoreceptors and are thought to compose mammalian SOCC, many forms of which may also be permeable to Na+ and other cations and therefore function as nonselective cation channels (NSCC) (34, 37, 51). Consistent with TRPC expression, we and others demonstrated the presence of CCE in distal PA (51, 60). More recently, we found that acute hypoxia increased [Ca2+]i, Ca2+ influx, and CCE in distal PASMC and that these effects were completely blocked by removal of extracellular Ca2+ or SOCC/NSCC antagonists, but not nifedipine (61). These findings are consistent with recent observations from other laboratories (21, 22, 35) and suggest that HPV may require activation of SOCC in PASMC; however, it is well known that cell isolation and culture can alter cell phenotype. Moreover, changes in PASMC [Ca2+]i do not necessarily translate to changes in pulmonary vascular resistance. In the present study, therefore, we assessed the contribution of SOCC and CCE to HPV in isolated lungs, where physiologically relevant pulmonary vasomotor responses can be measured directly.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Our protocol was approved by the Institutional Animal Care and Use Committee of the Johns Hopkins University. Male Wistar rats (200–400 g) were anesthetized with pentobarbital sodium (65 mg/kg ip). A tracheostomy was performed, and the animal was ventilated with room air at a tidal volume of 10 ml/kg and a rate of 30 min–1 (Harvard Rodent Ventilator model 883; Harvard Apparatus, Holliston, MA). A thoracotomy was performed, heparin (100 units) was injected into the right ventricular cavity, and the animal was exsanguinated from the femoral artery. The ventilating gas was changed to 16% O2-5% CO2. Cannulae were inserted into the main PA and left atrium, which drained into a heated reservoir. The lungs were perfused with a peristaltic pump (Ismatec Reglo Analog Pump; Cole Parmer, Vernon Hills, IL) at 40 ml·kg–1·min–1 with Krebs Ringer bicarbonate solution (KRBS) containing (in mM) 118 NaCl, 4.7 KCl, 0.57 MgSO4, 1.18 KH2PO4, 25 NaHCO3, and 10 glucose. Ficoll (4 g/dl) and sodium meclofenamate (3.1 µM) were added to provide oncotic pressure and prevent release of vasodilator prostaglandins. After the vasculature was flushed free of residual blood, the perfusate was recirculated. Lungs treated with LaCl3 were perfused with bicarbonate- and phosphate-free HEPES-buffered salt solution (HBSS) to prevent precipitation of the antagonist (43, 51, 60) and ventilated without CO2. HBSS contained (in mM) 130 NaCl, 5 KCl, 1.2 MgCl2, 2.5 CaCl2, 10 HEPES, and 10 glucose, as well as Ficoll (4 g/dl) and sodium meclofenamate (3.1 µM). To mitigate edema formation caused by high perfusion pressures, lungs exposed to KCl were perfused with a 70:30 mixture of KRBS or HBSS and the animal’s own blood. Perfusate temperature was monitored with a thermistor in the left atrial effluent and maintained at 37°C with a heat exchanger. Pulmonary arterial, left atrial, and tracheal pressures were measured at end expiration relative to the bottom of the lung with pressure transducers (model P10EZ; Spectramed, Oxnard, CA) and recorded with a computer-linked recording system (Powerlab; ADInstruments, Colorado Springs, CO). End-expiratory tracheal and left atrial pressures were maintained at 3–4 and <0mmHg, respectively. Because perfusate flow was also constant, increases in pulmonary arterial pressure (Ppa) were assumed to result from pulmonary vasoconstriction.
Experimental Protocols
Prevention of pressor responses to hypoxia and angiotensin II. After a 20-min stabilization period of perfusion and ventilation with 16% O2, lungs were alternately exposed four times to angiotensin II (ANG II; 0.05 µg bolus into the main PA) and hypoxia (ventilation with 2% O2 for 5 min) at 5- to 10-min intervals. Perfusate PO2 measured with an oxygen microelectrode (Microelectrodes, Londonderry, NH) in the left atrial effluent of eight lungs averaged 112 (SD 4.6) mmHg during steady-state ventilation with 16% O2 and 15.1 (SD 3.7) mmHg after 5 min of ventilation with 2% O2. The CCE antagonists SKF-96365 (5, 16, or 50 µM; n = 3, 4, and 5, respectively), NiCl2 (100, 200, or 500 µM; n = 3, 4, and 5, respectively), and LaCl3 (1, 10, 30, or 100 µM; n = 6, 6, 4, and 3, respectively) were added to perfusate after the second hypoxic exposure. Additional lungs were exposed similarly to the L-type VOCC antagonist nifedipine (0.05, 0.5, or 5 µM; n = 4, 3, and 3, respectively) or Ca2+-free KRBS perfusate containing 1 mM EGTA (n = 4). Untreated lungs perfused with KRBS (n = 10) or HBSS (n = 6) served as controls.
Reversal of HPV. After the 20-min normoxic stabilization period, lungs were exposed to ANG II (0.05 µg bolus injected into main PA) and hypoxia (ventilation with 2% O2 for 5 min). After 10 min of normoxic recovery, lungs were then ventilated with 2% O2 for 45 min. To assess the ability of CCE antagonists to reverse established HPV, SKF-96365 (50 µM; n = 4), NiCl2 (500 µM; n = 4), or LaCl3 (10 µM; n = 4) was added to the perfusate during the last 15 min of the 45-min hypoxic exposure. Additional lungs were exposed similarly to nifedipine (5 µM; n = 4) or perfusion with Ca2+-free KRBS containing 1 mM EGTA (n = 4). Untreated lungs perfused with KRBS (n = 5) or HBSS (n = 5) and subjected to the same protocol served as controls. Experiments were not accepted for analysis if Ppa after 30 min of hypoxia was not at least 3 mmHg higher than Ppa at the onset of exposure. On this basis, one lung was excluded from each of the KRBS control, SKF-96365, and Ca2+-free perfusate groups, four from the HBSS control group, and two from the LaCl3 group.
Prevention of pressor responses to KCl. After the 20-min stabilization period, 4 M KCl was added to the reservoir in amounts adequate to increase perfusate [KCl] initially by 5 and subsequently by 10 mM increments. After each increment, sufficient time was allowed for Ppa to stabilize. KCl was administered in this manner until Ppa achieved a maximum or the lungs developed edema, as indicated by sudden loss of reservoir volume and increases in Ppa and end-inspiratory tracheal pressure. To examine the effects of CCE antagonists on the pressor response to KCl, SKF-96365 (50 µM; n = 6), NiCl2 (500 µM; n = 6), or LaCl3 (10 µM, n = 4) was administered 10 min before KCl. Additional experiments were performed in lungs exposed to nifedipine (5 µM; n = 6) or Ca2+-free perfusate (n = 3) in a similar manner. Untreated lungs perfused with KRBS (n = 11) or HBSS (n = 4) served as controls.
Drugs and Materials
Stock solutions of SKF-96365 (10 mM) and KCl (4 M) were made up in water and stored at 4°C for 
7 days before use. Stock solutions of NiCl2 (10 mM) and LaCl3 (1 and 10 mM) were made up in water on the day of the experiment. Nifedipine was dissolved in dimethyl sulfoxide to make a 30 mM stock solution and stored at –4°C until use. All agents were obtained from Sigma Chemical (St. Louis, MO).
Statistical Analysis
Data are expressed as means (SD). Statistical analysis was performed using Student’s t-test or analysis of variance. If a significant interaction F-ratio was obtained with the latter, pairwise comparison of individual means was performed by calculating the least significant difference. Comparison of group means with control was performed using Dunnett’s test. Differences were considered significant when P < 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Figure 1 shows representative recordings of four exposures to ANG II and hypoxia in control lungs (Fig. 1A) and lungs perfused with Ca2+-free KRBS after exposure 2 (Fig. 1B). Average Ppa at baseline and peak response to ANG II and hypoxia for each of the four exposures in these groups are shown in Fig. 1, C and D. Both ANG II and hypoxia caused rapid reversible increases in Ppa at constant flow, left atrial pressure, and end-expiratory tracheal pressure, indicating vasoconstriction. In control lungs, Ppa at baseline and peak response to ANG II and hypoxia increased slightly over time. Perfusion with Ca2+-free KRBS abolished the increase in baseline Ppa as well as the pressor responses to hypoxia and ANG II.
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Ppa) caused by ANG II or hypoxia during exposure 2 for each group. Values measured in lungs subsequently treated with SKF-96365, NiCl2, nifedipine, or Ca2+-free perfusate did not differ from values measured in KRBS-perfused control lungs. Baseline values of Ppa measured during exposure 2 in HBSS-perfused control lungs and HBSS-perfused lungs subsequently treated with LaCl3 were slightly higher than values measured in KRBS-perfused control lungs; however, baseline responses to angiotensin and hypoxia were not different.
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In KRBS-perfused control lungs exposed to hypoxia for 45 min (Fig. 6, A and B), Ppa increased initially to a peak [Ppa = 8.2 (SD 2.0) mmHg at 4 min] before stabilizing at a lower value for the remainder of the exposure [Ppa = 5.6 (SD 1.7) mmHg at 30 min and 5.0 (SD 1.3) mmHg at 45 min]. The minimum Ppa between 30 and 45 min, expressed as a percentage of Ppa at 30 min, averaged 91.3% (SD 8.2) in KRBS-perfused control lungs (Fig. 6C). SKF-96365 (50 µM), NiCl2 (500 µM), nifedipine (5 µM), or perfusion with Ca2+-free KRBS abolished this sustained HPV (Fig. 6, B and C). In HBSS-perfused lungs, 10 µM LaCl3, which inhibited initial HPV by 31% (Fig. 4), did not alter sustained HPV; i.e., minimum Ppa between 30 and 45 min, expressed as a percentage of Ppa at 30 min, averaged 60.1% (SD 33.8) in control lungs and 79.1% (SD 25.3) in lungs treated with 10 µM LaCl3 (P = 0.382).
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In KRBS-perfused control lungs, increases in perfusate [KCl] caused progressive increases in Ppa from 10.7 (SD 1.3) mmHg at 5 mM to 34.7 (SD 9.9) mmHg at 40 mM, the highest concentration achieved by all lungs in this group (Fig. 7, A and B). The same maximum [KCl] was achieved by all lungs treated with SKF-96365 (50 µM) or NiCl2 (500 µM). Neither agent altered the Ppa-[KCl] relationship (Fig. 6B). LaCl3 (10 µM), which caused some prevention of HPV (Fig. 4), did not prevent vasoconstriction to KCl (Fig. 7C). In contrast, nifedipine (5 µM) or Ca2+-free perfusate almost abolished vasoconstrictor responses to KCl and allowed all lungs to achieve maximum KCl concentrations of 80 and 70 mM, respectively (Fig. 7, A and B).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The validity of this suggestion depends on the specificity of the antagonists. Inhibition of HPV by SKF-96365 (50 µM) and NiCl2 (500 µM) did not result from nonspecific alterations of baseline vasomotor tone or toxic effects on contractile machinery because baseline Ppa (Fig. 2) and pressor responses to KCl (Fig. 7) in lungs exposed to these antagonists were not different from those in control lungs. Their lack of effect on KCl-induced vasoconstriction also indicates that SKF-96365 and NiCl2 did not inhibit VOCC, confirming previous results in PASMC (60). Although structurally dissimilar, SKF-96365 and NiCl2 clearly shared the intended action in rat distal PASMC, where IC50 against CCE were estimated to equal 6.3 and 191 µM, respectively (60). These values were within ranges of potency previously reported for inhibition of CCE in pulmonary arterial and other smooth muscles (10, 14, 15, 19, 29, 34, 43, 56, 64, 68). Furthermore, the concentrations of SKF-96365 and NiCl2 that blocked CCE in PASMC were similar to those that blocked HPV in isolated lungs (IC50 = 19 and 173 µM, respectively; Fig. 5) and [Ca2+]i responses to hypoxia in PASMC (IC50 = 3.2 and 36.7 µM, respectively) (61), suggesting a common mode of action.
Although these observations are consistent with the possibility that SKF-96365 and NiCl2 blocked HPV by inhibiting CCE, other actions have been described in other tissues. For example, SKF-96365 was found to prevent Ca2+ influx through receptor-operated Ca2+ channels, promote Ca2+ influx through nonspecific cation channels, and inhibit SR Ca2+ pumps (25). NiCl2 is thought to be a nonspecific blocker of Ca2+ entry (25) and has been shown to inhibit sarcolemmal Na+-Ca2+ exchange (5). It seems unlikely that enhanced Ca2+ entry, reduced SR Ca2+ uptake, or blockade of Na+-Ca2+ exchange could explain the inhibitory effects of SKF-96365 and NiCl2 on HPV; however, it remains possible that these agents blocked Ca2+ influx through channels other than SOCC and VOCC, such as the voltage- and store-independent channels hypothesized by Robertson et al. (43).
The effects of LaCl3 are more difficult to interpret. In some previous studies (34, 35), chelation or precipitation of La3+ may have limited bioavailability. To avoid this problem, we used an HBSS perfusate that contained neither bicarbonate nor phosphate (43, 51, 60). In our studies, LaCl3 increased [Ca2+]i in PASMC perfused with HBSS under baseline normoxic conditions (61) and caused concentration-dependent vasoconstriction in normoxic HBSS-perfused lungs (Fig. 2, B and C). These findings suggest that LaCl3 had actions other than inhibition of SOCC, such as inhibition of Na+-Ca2+ exchange and Ca2+ pumps at the plasma membrane (5, 48). They also suggest that effects of LaCl3 on HPV could be the nonspecific result of increased baseline tone. At 10 µM, however, LaCl3 altered neither baseline tone (Fig. 2C) nor the pressor response to KCl (Fig. 7C) but inhibited HPV by 31% (Fig. 4). Because IC50 for LaCl3 against CCE in distal PASMC was 40.4 µM (60), these results are consistent with the hypothesis that HPV requires CCE. At 100 µM, however, LaCl3 increased baseline tone (Fig. 2, B and C) and potentiated HPV (Fig. 3). Because 100 µM LaCl3 increased basal [Ca2+]i, abolished CCE, and blocked [Ca2+]i responses to hypoxia in PASMC (60, 61), potentiation of HPV in isolated lungs may have been due to an increase in myofilament Ca2+ sensitivity occurring in the face of increased basal [Ca2+]i. Several findings support this possibility. In PA exposed to sustained hypoxia, progressive contraction occurred at slightly elevated but constant [Ca2+]i (41), and this response was enhanced by raising basal tone with vasoactive agonists (36). HPV in both isolated lungs and PA was blocked by antagonists of Rho kinase (11, 42, 62), which is thought to increase Ca2+ sensitivity by inhibiting myosin light chain phosphatase, thereby increasing phosphorylated myosin light chain concentration and vasomotor tone at constant levels of [Ca2+]i and myosin light chain kinase activity (54, 62, 63). Further studies will be required to clarify the effects of high [LaCl3] on HPV.
As with hypoxia, the mechanisms by which ANG II changes vasomotor tone are complex and may vary among vessels (44). In PASMC, ANG II caused oscillations of [Ca2+]i that appeared to result from cycling of inositol trisphosphate-dependent SR Ca2+ release (16). These [Ca2+]i oscillations were thought to evoke oscillatory activation of Ca2+-dependent Cl– (ClCa) channels, leading to depolarization, Ca2+ influx through VOCC, and contraction (17); however, nifedipine only partially inhibited ANG II-induced contractions in PA, suggesting contributions by SR Ca2+ release and/or CCE (17). Consistent with these possibilities, we found that SKF-96365 and NiCl2 inhibited pressor responses to ANG II in a concentration-dependent manner, similar to their effects on HPV (Figs. 3 and 5). Indeed, IC50 for SKF-96365 and NiCl2 against ANG II (24 and 173 µM, respectively) were almost identical to IC50 against hypoxia (19 and 173, respectively). Nifedipine was less potent against ANG II than HPV (IC50 = 0.96 and 0.034 µM, respectively), perhaps reflecting a greater contribution of SR Ca2+ release to the ANG II response due to the short duration of stimulation with ANG II, which was delivered as a bolus into the main PA.
In isolated PA, the response to hypoxia of more than a 30-min duration was usually biphasic, consisting of early transient contraction followed by late sustained contraction (4, 9, 23, 24). Similar temporal characteristics have been described for HPV in isolated lungs (65–67). Because the mechanisms responsible for the early and late phases of HPV might be different (55), we determined whether Ca2+-free perfusate, nifedipine, and SOCC/NSCC antagonists could inhibit sustained HPV. Consistent with previous results (20, 24), Ca2+-free perfusate or nifedipine reversed HPV after 30 min of hypoxia (Fig. 6). SKF-96365 (50 µM) and NiCl2 (500 µM) had similar effects. These findings suggest that influx of extracellular Ca2+ through SOCC and VOCC was required not only to initiate but also to sustain HPV. In contrast, Dipp et al. (9) reported that late hypoxic contraction in rat PA was blocked by ryanodine plus caffeine, but not by Ca2+-free conditions, suggesting that HPV was sustained by Ca2+ release from SR rather than Ca2+ influx. We cannot explain this discrepancy.
Our conclusion that HPV requires both CCE and voltage-gated Ca2+ influx is based on our observations that 50 µM SKF-96365 and 500 µM NiCl2 (which blocked CCE but not responses to KCl) or 5 µM nifedipine (which blocked responses to KCl but not CCE) were all quite effective at preventing and reversing HPV (Figs. 1, 3, 5, and 6). In complex preparations like isolated lungs, one possible explanation for this dual requirement is that cells other than PASMC were involved in HPV. For example, endothelin-1, which is derived from endothelial cells and thought to be required for full expression of HPV in vivo (26, 46, 47), can activate SOCC (71); however, this possibility would not explain why [Ca2+]i responses to hypoxia were SOCC dependent in isolated PASMC (35, 61). Another possibility is that SOCC and VOCC provided parallel pathways for influx of Ca2+ into PASMC during hypoxia, but neither pathway on its own was capable of increasing [Ca2+]i by amounts sufficient to trigger contraction. This might occur if CCE and voltage-gated Ca2+ influx occurred in noncontractile and contractile intracellular compartments, respectively, which had limited access to one another (13, 51, 56). Alternatively, primary activation of SOCC by hypoxia could cause secondary activation of VOCC. For example, hypoxia-induced release of Ca2+ from SR (9, 19, 26, 31, 35, 59) could deplete SR Ca2+ stores, leading to SOCC activation and CCE. Increases in [Ca2+]i due to CCE and/or SR Ca2+ release could then inhibit voltage-dependent K+ channels and/or activate ClCa channels (6, 38), leading to PASMC depolarization and Ca2+ influx through VOCC. The opposite sequence has also been suggested (7, 31); namely, that voltage-gated Ca2+ influx might cause secondary release of Ca2+ from SR. Previous findings that [Ca2+]i responses to hypoxia were abolished by SOCC/NSCC antagonists but were inhibited only 50% by VOCC antagonists would seem to argue against this possibility (35, 61). Because SOCC/NSCC are thought to have reversal potentials near 0 mV (34, 37, 51), it is also possible that hypoxic activation of these channels depolarized PASMC directly, again leading to secondary VOCC activation and voltage-dependent Ca2+ influx. Moreover, if activated SOCC/NSCC were sufficiently permeable to Na+, depolarization and increased [Na+]i could promote Ca2+ influx via reverse-mode Na+-Ca2+ exchange (5). More investigation is needed to evaluate these possibilities.
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FOOTNOTES |
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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.
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