There is controversy on the role of endothelin (ET)-1 in the mechanism of hypoxic pulmonary vasoconstriction (HPV). Although HPV is inhibited by ET-1 subtype A (ETA)-receptor antagonists in animals, it has been reported that ETA-receptor blockade does not affect HPV in isolated lungs. Thus we reassessed the role of ET-1 in HPV in both rats and isolated blood- and physiological salt solution (PSS)-perfused rat lungs. In rats, the ETA-receptor antagonist BQ-123 and the nonselective ETA- and ETB-receptor antagonist PD-145065, but not the ETB-receptor antagonist BQ-788, inhibited HPV. Similarly, BQ-123, but not BQ-788, attenuated HPV in blood-perfused lungs. In PSS-perfused lungs, either BQ-123, BQ-788, or the combination of both attenuated HPV equally. Inhibition of HPV by combined BQ-123 and BQ-788 in PSS-perfused lungs was prevented by costimulation with angiotensin II. The ATP-sensitive K+(KATP)-channel blocker glibenclamide also prevented inhibition of HPV by BQ-123 in both lungs and rats. These results suggest that ET-1 contributes to HPV in both isolated lungs and intact animals through ETA receptor-mediated suppression of KATP-channel activity.
- adenosine 5′-triphosphate-sensitive potassium channel
- endothelin-receptor blockers
- pulmonary vascular regulation
the mechanism of acute hypoxic pulmonary vasoconstriction (HPV) has not been fully defined. It is believed that hypoxia acts either directly on peripheral pulmonary arterial smooth muscle cells to inhibit a voltage-sensitive K+ channel and cause membrane depolarization, Ca2+ influx through L-type Ca2+ channels, and contraction (2, 31, 32, 47) or indirectly to stimulate release of vasoconstrictors and/or inhibit release of vasodilators (10, 30, 42). Various endothelium-derived vasoactive factors have been proposed to modulate HPV.
Endothelin (ET)-1 is a potent vasoactive agent that is produced by numerous cell types including pulmonary vascular endothelial cells (23). Two ET-1 receptor subtypes, ETA and ETB, have been identified in the pulmonary vasculature. Both ETAand ETB receptors are on vascular smooth muscle cells and mediate vasoconstriction (13, 22, 36). ETB receptors are also on endothelial cells and cause vasodilation through release of nitric oxide and prostacyclin (8, 14, 20, 27, 36). There is controversy about the role of ET-1 in the mechanism of HPV. Although in vivo studies show that HPV is markedly attenuated by either selective ETA- or nonselective ETA- and ETB-receptor antagonists (4, 5, 9, 30, 41, 46), ETA-receptor blockade has been reported not to inhibit HPV in isolated lungs (17, 40). This apparent disparity suggests that either ETA-receptor blockade has effects in vivo that are not mimicked in vitro or the mechanism of HPV differs between the two preparations.
Thus the purpose of this study was to reassess the role of ET-1 in the mechanism of HPV both in vivo and in vitro. We examined the effects of ET-1 antagonists on HPV in conscious catheterized rats and isolated rat lungs perfused with either blood or physiological salt solution (PSS). Moreover, because increased activity of ATP-sensitive K+ (KATP) channels inhibits HPV (3, 7,11, 29, 45), because ET-1 suppresses KATP-channel activity through activation of ETA receptors (18, 26, 43), and because it has been speculated that HPV is due to ET-1- dependent inhibition of KATP channels (1), we tested whether the KATP-channel blocker glibenclamide prevented inhibition of HPV by ETA-receptor blockade. The results in rats confirmed that a selective ETA- and nonselective ETA- and ETB-receptor antagonists but not a selective ETB-receptor antagonist blocked HPV. HPV was also attenuated only by the ETA-receptor antagonist in isolated blood-perfused rat lungs. In contrast, however, either an ETA- or an ETB-receptor antagonist attenuated HPV in PSS-perfused rat lungs. Furthermore, the inhibition of HPV by ETA-receptor blockade was prevented by pretreatment with glibenclamide in both lungs and rats. These results suggest that ET-1 participates in the mechanism of HPV in both isolated lungs and intact animals through an ETA receptor-mediated inhibition of KATP channels.
Conscious catheterized rats. The first experiment examined the effects of ET-1-receptor antagonists on HPV in catheterized rats. Adult male Sprague-Dawley rats (250–350 g) were anesthetized with ketamine (100 mg/kg im) and rompun (15 mg/kg im), and catheters were implanted in the jugular vein and pulmonary and right carotid arteries as previously described (29). Two days later, conscious rats were placed in a small ventilated plastic box, and pulmonary and systemic arterial pressures were measured with pressure transducers. Cardiac output was determined by a standard dye-dilution method, and total pulmonary and systemic resistances were calculated by dividing mean arterial pressure by cardiac output. The plastic box was flushed continuously with room air except during exposure of the rats to acute hypoxia when it was flushed with a gas mixture of 10% O2-90% N2.
Isolated perfused lungs. The second series of experiments examined the effects of ET-1-receptor antagonists on HPV in isolated blood- and PSS-perfused rat lungs. The lungs were isolated from adult male Sprague-Dawley rats (250–350 g) after anesthesia with intraperitoneal pentobarbital sodium (30 mg) and an intracardiac injection of 100 IU of heparin. 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 arterial cannula with a peristaltic pump at a constant flow of 0.04 ml ⋅ g body wt−1 ⋅ min−1. Effluent perfusate drained from a left ventricular cannula into a perfusate reservoir. Mean perfusion pressure was measured continuously with a transducer and pen recorder. Blood-perfused lungs were perfused in a recirculating manner with 20 ml of heparinized whole blood obtained from methoxyflurane-anesthetized blood donor rats. PSS-perfused lungs were perfused with Earle's balanced salt solution (Sigma) containing Ficoll (4 g/100 ml, type 70; Sigma) as a colloid and 3.1 μM sodium meclofenamate (Sigma) to inhibit synthesis of vasodilator prostaglandins and enhance hypoxic pressor responsiveness. After the lungs were flushed of blood with 20 ml of PSS, they were perfused with a recirculating volume of 30 ml. Blood- and PSS-perfused lungs were equilibrated for 20 min at 38°C before hypoxic pressor responses were elicited. Because the lungs were perfused at a constant flow and ventilated at constant pressures, changes in perfusion pressure reflected changes in vascular resistance.
Experimental protocols. To confirm previously reported inhibition of HPV by ETA-receptor blockade in intact animals (4, 5, 9, 30, 41, 46), we first examined the effects of ET-1 antagonists on HPV in conscious catheterized rats. The rats were pretreated with the selective ETA-receptor antagonist BQ-123 (50 μg ⋅ kg−1 ⋅ min−1iv; Banyu Pharmaceutical) (15) or vehicle (0.9% saline; 24 μl ⋅ kg−1 ⋅ min−1iv) for 45 min before exposure to two successive hypoxic challenges (10% O2 for 5–6 min at 15-min intervals). Preliminary experiments showed that this dose of BQ-123 did not affect the initial transient systemic depressor response to an intravenous bolus of ET-1 (0.22 μg/kg; decrease in mean systemic pressure was −18 ± 4 mmHg in BQ-123-treated rats vs. −25 ± 4 mmHg in control rats;n = 3 each) but did reduce the secondary sustained systemic vasoconstriction (increase in total systemic resistance was 278 ± 48 mmHg ⋅ l−1 ⋅ min in BQ-123-treated rats vs. 1,312 ± 50 mmHg ⋅ l−1 ⋅ min in control rats; n = 3; P = 0.055). To test the effects of the nonselective ETA- and ETB-receptor antagonist PD-145065 (13, 44) and the selective ETB-receptor antagonist BQ-788 (16), the rats were first challenged with hypoxia (10% O2 for 5–6 min) and then treated with PD-145065 (100 μg ⋅ kg−1 ⋅ min−1iv; Parke-Davis), BQ-788 (50 μg ⋅ kg−1 ⋅ min−1iv; Banyu Pharmaceutical), or vehicle [24 μl ⋅ kg−1 ⋅ min−1iv; saline for PD-145065; dimethyl sulfoxide (DMSO; Sigma) for BQ-788] for 45 min before a second exposure to hypoxia. Preliminary experiments showed that this dose of PD-145065 inhibited both the initial systemic depressor response (decrease in mean systemic pressure was −0.4 ± 0.4 mmHg in blocker-treated rats vs. −33 ± 4 mmHg in control rats; P < 0.05; n = 7 and 9, respectively) and the secondary systemic vasoconstriction (increase in total systemic resistance was 78 ± 74 mmHg ⋅ l−1 ⋅ min in blocker-treated rats vs. 771 ± 207 mmHg ⋅ l−1 ⋅ min in control rats; P < 0.05) to the intravenous bolus of ET-1 (0.22 μg/kg). In contrast, BQ-788 inhibited the initial depressor response (decrease in mean systemic pressure was −1 ± 1 mmHg in BQ-788-treated rats vs. −30 ± 4 mmHg in control rats; P< 0.05; n = 4 and 5, respectively) but not the secondary pressor response (increase in mean systemic arterial pressure was 21 ± 7 vs. 23 ± 2 mmHg) to intravenous ET-1.
We next examined effects of selective ETA- and ETB-receptor antagonists on HPV in blood-perfused lungs. After two challenges with hypoxic ventilation (0% O2 for 10 min at 10-min intervals) to elicit hypoxic pressor responses, the lungs were challenged successively with 5, 3, and 0% O2-5% CO2-balance N2 gas mixtures for 10 min each at 10-min intervals. After the last hypoxic response, either BQ-123 (5 μM) plus DMSO (0.05%; vehicle for BQ-788), BQ-788 (5 μM) plus 0.9% saline (vehicle for BQ-123), or vehicle was added to the perfusate, and the lungs were again challenged with 5, 3, and 0% O2. This experiment showed that HPV was attenuated by the ETA- but not by the ETB-receptor antagonist in blood-perfused lungs.
We next examined the effects of ET-1 antagonists on HPV in PSS-perfused lungs. After two initial hypoxic challenges (0% O2 for 10 min at 10-min intervals), the lungs were challenged successively with the 5, 3, and 0% O2 gas mixtures for 10 min each at 10-min intervals. Either BQ-123 (5 μM) plus DMSO, BQ-788 (5 μM) plus saline, the combination of BQ-123 and BQ-788, or the vehicle was then added to the perfusate, and the lungs were again challenged with 5, 3, and 0% O2. After completion of the hypoxic challenges, 10 nM ET-1 (human ET-1, Peptide Institute) was added to the perfusate, and the change in perfusion pressure was measured 10 min later to test for ET-1-receptor blockade.
Because either BQ-123 or BQ-788 alone or a combination of both attenuated HPV in PSS-perfused lungs and because it has been reported that ETA-receptor blockers do not inhibit HPV in PSS-perfused rat lungs costimulated with angiotensin II (17, 40), we tested the effect of combined BQ-123 and BQ-788 on HPV in PSS-perfused lungs challenged alternately with angiotensin II and hypoxia. The protocol was the same as in the preceding experiment except that angiotensin II (0.3 μg, human, acetate salt; Sigma) was injected as a bolus into the pulmonary arterial cannula 5 min before each hypoxic challenge (5, 3, and 0% O2). After the last hypoxic challenge after the addition of BQ-123 and BQ-788, 10 nM ET-1 was added to the perfusate to test for ET-1-receptor blockade.
To test whether the inhibition of HPV by ETA-receptor blockade was associated with activation of KATP channels (18, 26, 43), we examined the effects of BQ-123 on HPV in both PSS- and blood-perfused lungs pretreated with the KATP-channel blocker glibenclamide. After two initial hypoxic challenges (0% O2 for 10 min at 10-min intervals), glibenclamide (Sigma) or vehicle (0.05% DMSO) was added to perfusate. The concentrations of glibenclamide were 20 μM in PSS-perfused lungs and 50 μM in blood-perfused lungs and were determined in preliminary experiments to inhibit the vasodilator response to the K+-channel activator cromakalim (5 μM; Sigma) during an ongoing hypoxic pressor response (data not shown). After either glibenclamide or vehicle, the lungs were again challenged twice with hypoxia (0% O2) before the addition of either BQ-123 (5 μM) or vehicle (saline) to the perfusate and two more challenges with hypoxia.
To examine the effects of glibenclamide in catheterized rats, three groups were studied: rats treated with the vehicle for glibenclamide and then BQ-123, rats treated with glibenclamide and then BQ-123, and rats treated with glibenclamide and then the vehicle for BQ-123. The rats were challenged with hypoxia (10% O2 for 5–6 min) and then treated with either glibenclamide (20 mg/kg iv) or vehicle (0.5 ml DMSO/kg iv) 45 min before a second hypoxic challenge. BQ-123 (50 μg ⋅ kg−1 ⋅ min−1iv) or vehicle (24 μl saline ⋅ kg−1 ⋅ min−1iv) was then infused for 45 min before a final hypoxic exposure. In other rats, this dose of glibenclamide blocked cromakalim (20 μg iv)-induced systemic vasodilation (data not shown).
Statistics. Data are expressed as means ± SE. Statistical analysis was done by Student's t-test or two-way analysis of variance, with Fisher's post hoc test for multiple comparisons. Differences were considered significant at P < 0.05.
Effects of ET-1-receptor antagonists on HPV in intact rats.There were no significant differences in baseline (normoxic) systemic and pulmonary hemodynamics between control and BQ-123-treated rats (Table 1). Whereas acute hypoxia increased pulmonary arterial pressure and total pulmonary resistance, i.e., caused HPV, it had little or no effect on the other hemodynamic parameters. HPV was markedly attenuated in the BQ-123-treated rats (Table 1, Fig. 1). Similarly, the nonselective ETA- and ETB-receptor blocker PD-145065 did not affect systemic or pulmonary hemodynamics during normoxia (Table 2) but blocked HPV (Table2, Fig. 2). In contrast, the selective ETB-receptor antagonist BQ-788 had no effect on HPV (Table3, Fig. 3).
Effects of ET-1-receptor antagonists on HPV in blood- and PSS-perfused rat lungs. There were no differences among the respective control and experimental groups in the pressor responses to 5, 3, and 0% O2 before treatment of either blood- or PSS-perfused lungs with either the vehicle (control), BQ-123, or BQ-788 (data not shown). In addition, baseline (normoxic) perfusion pressures were not affected by the ET-1-receptor antagonists in either blood- or PSS-perfused lungs (data not shown). However, in blood-perfused lungs, the response to hypoxia was inhibited by the ETA- but not by the ETB-receptor antagonist (Fig.4). In contrast, in PSS-perfused lungs, the response to hypoxia was inhibited equally by either BQ-123, BQ-788, or the combination of both (Fig. 5). The pressor response to exogenous ET-1 in the PSS-perfused lungs (17.2 ± 2.4 mmHg in control lungs) was unaffected by BQ-788 (17.8 ± 1.0 mmHg), partially reduced by BQ-123 (10.9 ± 2.0 mmHg), and eliminated by the combination of BQ-123 and BQ-788 (0.3 ± 0.1 mmHg; P< 0.05 vs. control value).
In contrast to the preceding results, the responses to hypoxia were not inhibited by the combined treatment with BQ-123 and BQ-788 in PSS-perfused lungs costimulated with angiotensin II (Fig.6). However, the pressor response to angiotensin II was reduced slightly by the ET-1 antagonists (responses to angiotensin II before and after treatment were 5.5 ± 0.8 and 5.1 ± 0.8 mmHg, respectively, in control lungs and 6.7 ± 1.3 and 4.0 ± 0.4 mmHg, respectively, in BQ-123+BQ-788-treated lungs; P< 0.05), and the response to exogenous ET-1 was blocked (response was 14.1 ± 1.8 mmHg in control lungs and 0.2 ± 0.1 mmHg in BQ-123+BQ-788-treated lungs; P < 0.05).
KATP-channel blocker prevents inhibition of HPV by ETA-receptor antagonist in both isolated lungs and intact rats. Glibenclamide did not affect normoxic perfusion pressure in either PSS- or blood-perfused lungs (data not shown) but potentiated HPV in both preparations [increases in HPV after either glibenclamide or vehicle were 162 ± 32 and 50 ± 12%, respectively, in PSS-perfused lungs (P < 0.05; n = 8 rats/group) and 95 ± 52 and 2 ± 8%, respectively, in blood-perfused lungs (P < 0.05; n = 8 rats/group)]. Furthermore, glibenclamide prevented the inhibition of HPV by BQ-123 in both PSS- and blood-perfused lungs (Figs. 7 and8, respectively).
The effects of glibenclamide on baseline (normoxic) systemic and pulmonary hemodynamics and the responses to acute hypoxia in catheterized rats are shown in Table 4. Glibenclamide increased systemic arterial pressure and total systemic and pulmonary resistances and decreased heart rate but had no effect on HPV. Subsequent treatment with BQ-123 decreased systemic and pulmonary arterial pressures in both vehicle- and glibenclamide-treated rats (Table 5). Although the ETA-receptor antagonist inhibited HPV in control rats, it failed to do so in the glibenclamide-treated animals (Table 5, Fig.9).
The major findings of this study were that HPV was inhibited by an ETA-receptor antagonist in both intact rats and isolated rat lungs and that the inhibition of HPV by ETA-receptor blockade was prevented by pretreatment with the KATP-channel blocker glibenclamide. These results suggest that ET-1 is involved in the mechanism of HPV both in vivo and in vitro through an ETA receptor-mediated suppression of KATP-channel activity.
It has been previously reported (4, 5, 9, 30, 41, 46) that either selective ETA- or nonselective ETA- and ETB-receptor antagonists but not selective ETB-receptor antagonists inhibit HPV in intact animals including rats. In contrast, ETA-receptor antagonists were found not to inhibit HPV in PSS-perfused rat lungs (17, 40). Because this disparity raises the possibility that the mechanism of HPV differs between the in vivo and in vitro preparations, the first aim of our study was to reassess the effects of ET-1 antagonists on HPV in both intact rats and isolated rat lungs. Our results in rats confirmed that either a selective ETA- or a nonselective ETA- or ETB-receptor antagonist but not a selective ETB-receptor antagonist markedly attenuated HPV. Our isolated lung studies also showed that HPV was significantly reduced by only an ETA-receptor antagonist in blood-perfused lungs and by either an ETA- or an ETB-receptor antagonist in PSS-perfused lungs. These results indicate that ETA-receptor activation by endogenous ET-1 is involved in the mechanism of HPV in both intact rats and isolated rat lungs.
On the basis of evidence that activation of KATP channels inhibits HPV (3, 7, 11, 29, 45) and that ET-1 can reduce KATP-channel activity through stimulation of ETA receptors (18, 26, 43), the second aim of our study was to test whether the inhibition of HPV by ETA-receptor blockade could be attributed to increased KATP-channel activity. The results showed that the KATP-channel blocker glibenclamide prevented inhibition of HPV by the ETA-receptor antagonist BQ-123 in intact rats and in both blood- and PSS-perfused lungs. Because glibenclamide did not potentiate HPV in rats and caused only moderate augmentation in perfused lungs, its prevention of the BQ-123-induced inhibition was not due simply to a more vigorous hypoxic response. Instead, we believe that the findings support the idea that ETA-receptor blockade reverses an endogenous ET-1-mediated suppression of vascular smooth muscle KATP-channel activity that, in turn, leads to increased K+ current and inhibition of hypoxia-induced membrane depolarization. Whether the evident ET-1-mediated suppression of KATP-channel activity occurs basally, i.e., during normoxia, or is associated with a hypoxia-induced release of ET-1 is unclear from our results. However, previous studies (12, 38) in isolated rat lungs and intact rats indicated that the levels and duration of hypoxia used in our experiments caused little or no increase in either plasma or lung tissue levels of ET-1. In addition, glibenclamide did not elicit a hypoxia-like pulmonary vasoconstriction during normoxia in either lungs or rats (the increased total pulmonary resistance after glibenclamide in rats was associated with a decrease in cardiac output rather than with an increase in pulmonary arterial pressure). This suggests that HPV is not due simply to inhibition of KATP channels. Thus our speculation is that a basal level of ET-1-mediated suppression of KATP-channel activity “allows” HPV rather than that a hypoxia-induced release of ET-1 inhibits KATP channels and “causes” HPV (1).
A major difference between our isolated rat lung protocol and that of previous investigators who observed no inhibition of HPV by the ETA-receptor antagonists BQ-123 (40) and FR-139317 (17) was that in the earlier studies the PSS-perfused lungs were stimulated with angiotensin II both before and after addition of the blockers. We performed a similar experiment and found that although stimulation with angiotensin II eliminated the blunting of HPV by the combination of BQ-123 and BQ-788, it did not interfere with the inhibition of the vasoconstrictor response to exogenous ET-1; i.e., it did not prevent ET-1-receptor blockade. Angiotensin II has often been used to enhance the hypoxic pressor responsiveness of PSS-perfused rat lungs, and our finding indicates that it modifies reactivity of the preparation so as to render the hypoxic response insensitive to inhibition by ET-1-receptor blockade. Among its many actions, angiotensin II also inhibits vascular smooth muscle K+ channels, including KATP channels (6, 19, 24, 25), and it is possible that it prevents the inhibition of HPV at least partly by suppressing K+-channel activation and membrane hyperpolarization after ET-1-receptor blockade. In other words, adding exogenous angiotensin II to PSS-perfused lungs appears to circumvent the role of endogenous ET-1.
The ETA-receptor antagonist BQ-123 had similar inhibitory effects on HPV in all three preparations, i.e., in catheterized rats and both blood- and PSS-perfused rat lungs, but there was a preparation-dependent difference in the effect of the ETB-receptor antagonist BQ-788. Whereas BQ-788 did not inhibit HPV in either rats or blood-perfused lungs, it was as effective as BQ-123 in reducing HPV in PSS-perfused lungs. Because the equivalent inhibition of HPV by BQ-123 and BQ-788 in PSS-perfused lungs differed from the respective effect of the antagonists on the vasoconstrictor response to exogenous ET-1, i.e., the response to ET-1 was reduced slightly by BQ-123 but unaffected by BQ-788, BQ-788 was apparently not mimicking the effect of BQ-123 by blocking ETA receptors. Whether inhibition of HPV by ETB-receptor blockade was also due to activation of KATP channels or to some other effect cannot be determined from our study. There is evidence for ETB receptor-mediated inhibition of both Ca2+- and voltage-sensitive K+ currents in isolated rat pulmonary arterial smooth muscle cells (21, 35, 37), and perhaps ETB-receptor blockade inhibited HPV in PSS-perfused lungs by increasing the activity of these channels. We have no explanation for why this might have occurred in PSS- but not in blood-perfused lungs. In this regard, it has been previously noted that the nature of the rat lung perfusate, i.e., blood versus PSS, determines whether exogenous ET-1 constricts predominantly pre- or postcapillary vessels (28, 34).
BQ-123 inhibited HPV in both rats and isolated lungs, but the magnitude of inhibition appeared to be greater in rats than in lungs (for example, compare the difference in HPV before and after BQ-123 in rats in Fig. 9 with that in PSS- and blood-perfused lungs in Figs. 7 and 8, respectively). We do not have a definitive explanation for this difference, but one possibility is that the circulating level of an endogenous activator of KATP channels, such as calcitonin gene-related peptide, adenosine, or catecholamines (39), was higher in rats than in isolated lungs. Prostacyclin, another activator of KATP channels (39), is not a likely candidate because there was no apparent difference in the inhibition of HPV by BQ-123 between PSS-perfused lungs that were treated with the cyclooxygenase inhibitor meclofenamate to enhance hypoxic pressor responsiveness and blood-perfused lungs that were not treated.
Our interpretation that endogenous ET-1 promotes HPV by suppressing vascular smooth muscle KATP-channel activity needs to be reconciled with earlier evidence (11) in rat lungs that relatively low doses of exogenous (intraluminal) ET-1 cause at least transient inhibition of HPV by stimulating KATP channels. Although the relative roles of the endothelium-derived vasodilators nitric oxide, prostacyclin, and hyperpolarizing factor remain unclear, subsequent studies in rat lungs and pulmonary arteries have shown that the transient ET-1-induced pulmonary vasodilation is due to ETB-receptor-mediated activation of endothelial cells (8,14, 20, 27, 33, 36). Thus a possible explanation of the apparent paradox is that exogenous ET-1 causes a transient ETBreceptor-mediated increase in release of an endothelium-derived vasodilator that counteracts the endogenous ET-1-induced, ETA receptor-mediated suppression of KATPactivity.
In summary, this study showed that ETA-receptor blockade inhibited HPV in both intact rats and isolated rat lungs and that the inhibition of HPV was, in turn, prevented by inhibition of KATP channels. These results indicate that endogenous ET-1-induced activation of ETA receptors is a component of the mechanism of HPV. Because ETA-receptor blockade inhibited HPV without blocking ET-1-induced vasoconstriction and because the pulmonary vasoconstrictor response to ET-1 is long lasting, whereas that to hypoxia is rapidly reversed (11, 34), we reason that instead of mediating HPV in the classic sense, endogenous ET-1 promotes HPV by suppressing vascular smooth muscle KATP-channel activity and thereby allowing a direct hypoxia-induced inhibition of a voltage-sensitive K+ channel to cause membrane depolarization and activation of L-type Ca2+ channels (2,31, 32, 47). This interpretation reconciles the apparently disparate observations that although hypoxia can act directly on isolated peripheral pulmonary arterial smooth muscle cells to cause membrane depolarization and Ca2+ influx, HPV is inhibited by ETA-receptor blockade in intact animals and isolated lungs.
This study was supported by National Heart, Lung, and Blood Institute Grants HL-14985 (to I. F. McMurtry) and HL-48038 (to D. M. Rodman) and Parke-Davis Pharmaceutical Research (I. F. McMurtry).
Address for reprint requests and other correspondence: I. F. McMurtry, CVP Research Laboratory, B-133, Univ. of Colorado Health Science Center, 4200 East Ninth Ave., Denver, CO 80262 (E-mail:).
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