Journal of Applied Physiology
Vol. 83, No. 2, pp. 569-574, August 1997
PULMONARY CIRCULATION AND LUNG FLUID BALANCE

Pulmonary vasoreactivity to serotonin during hypoxia is modulated by ATP-sensitive potassium channels

Scott A. Barman

Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912

ABSTRACT

INTRODUCTION

METHODS

RESULTS

DISCUSSION

ACKNOWLEDGEMENTS

FOOTNOTES

REFERENCES

ABSTRACT

Barman, Scott A. Pulmonary vasoreactivity to serotonin during hypoxia is modulated by ATP-sensitive potassium channels. J. Appl. Physiol. 83(2): 569-574, 1997.The role of ATP-sensitive K⁺-channel modulation in the canine pulmonary vascular response to serotonin during hypoxia was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured by using vascular occlusion techniques. Under normoxia, serotonin (10⁵ M) significantly increased precapillary and postcapillary resistances and pulmonary capillary pressure and decreased total vascular compliance by decreasing both microvascular and large-vessel compliances. During hypoxia, the effect of serotonin was potentiated on both precapillary and postcapillary resistance and capillary pressure, as well as on microvascular compliance and large-vessel compliance. Under normoxia, the ATP-sensitive K⁺-channel opener cromakalim (10⁵ M) inhibited the serotonergic response on postcapillary resistance and microvascular compliance, whereas during hypoxia cromakalim inhibited the potentiated effect of serotonin on both precapillary and postcapillary resistance, capillary pressure, and both microvascular and large-vessel compliances. These results indicate that canine pulmonary vasoreactivity to serotonin is heightened under hypoxic conditions and that ATP-sensitive K⁺ channels modulate the pressor response to serotonin, an effect that is more pronounced during hypoxia.

adenosine 5-triphosphate; pulmonary vascular resistance; pulmonary vascular compliance; pulmonary capillary pressure; cromakalim

INTRODUCTION

THE MECHANISM OF HYPOXIC pulmonary vasoconstriction first observed by von Euler and Liljestrand (44a) remains unclear. It has been proposed that the hypoxic pulmonary pressor response may be due to the release of vasoactive mediators such as histamine, serotonin, and the prostaglandins (24), or, more recently, through the release of endothelin-1 (23). An alternative explanation is that hypoxic pulmonary vasoconstriction may be elicited through direct activation of the vascular smooth muscle through membrane depolarization (24, 38).

Ion channels, including K⁺ channels, have been identified in pulmonary vascular smooth muscle cells (9, 35, 42) and are reported to be involved in the regulation of vascular tone (10, 18). Several different K⁺ channels are present on vascular smooth muscle, including ATP-sensitive, Ca²⁺-activated, and nonspecific voltage-gated K⁺ channels. Activation of these channels causes an increase in K⁺ efflux, membrane hyperpolarization, inhibition of Ca²⁺ influx, and subsequent vascular smooth muscle relaxation. Recently, Post et al. (38) provided strong evidence for a direct role of K⁺-channel inhibition in hypoxic pulmonary vasoactivity, and hypoxia-induced membrane depolarization has been associated with the inhibition of whole cell K⁺ currents, leading to an increase in pulmonary arterial tension (37). In contrast, ATP-sensitive K⁺-channel openers such as cromakalim, pinacidil, and minoxidil appear to attenuate hypoxia-induced effects through membrane hyperpolarization (8, 33).

In the present study, serotonin (5-hydroxytryptamine) was used to investigate the effect of hypoxia on canine pulmonary vasoreactivity. Serotonin is a vasoactive amine that was originally isolated from the enterochromaffin cell system (14). In the lung, several studies have shown that under normoxia, 5-hydroxytryptamine is a potent vasoconstrictor (16, 20, 21, 40, 41) and, depending on the concentration, can increase both precapillary (Ra) and postcapillary resistances (Rv) (13, 40) and decrease pulmonary vascular compliance; however, little information is available about the effect of serotonin on segmental vascular resistance and compliance during hypoxia or whether K⁺ channels are involved in the hypoxic serotonergic response.

In light of these previous investigations, the present study was done by using vascular occlusion techniques to determine the role of hypoxia in the effect of serotonin on pulmonary vascular resistance and compliance in isolated blood-perfused dog lungs. These occlusion techniques have previously been used to measure the pulmonary vascular resistance-compliance profile in normal lungs and in lungs challenged with many vasoactive compounds including serotonin (40). In addition, the ATP-sensitive K⁺-channel opener cromakalim was used to determine whether ATP-sensitive K⁺ channels modulate the potentiated vasoconstrictor response to serotonin during hypoxia.

The results of this study showed that serotonin increased arterial resistance, venous resistance, and pulmonary capillary pressure and decreased pulmonary vascular compliance, effects that were potentiated during hypoxia. In contrast, cromakalim inhibited the enhanced vasoconstrictor effect of serotonin during hypoxia, indicating that ATP-sensitive K⁺ channels modulate the serotonergic pulmonary vascular response under hypoxic conditions.

METHODS

Adult, heartworm-negative, mongrel dogs of either sex (15-19 kg) were anesthetized with pentobarbital sodium (30 mg/kg), intubated, and ventilated with a Harvard respirator by using room air at a tidal volume of 15 ml/kg. A left thoracotomy was performed through the fifth intercostal space. The left upper and middle lobes of the lung were removed, and the lower left lobe was prepared for isolation by placing loose ligatures around the left main pulmonary artery and lower left bronchus. Each animal was then heparinized (10,000 U iv) and after 5-10 min was rapidly bled through a carotid arterial cannula. Three hundred milliliters of blood were used to prime the perfusion apparatus. After bleeding was completed, the pulmonary artery was ligated, and, with the heart still beating, the lower left lobe with the attached left atrial appendage was rapidly excised and weighed. Plastic cannulas were secured in the lobar artery, lobar vein, and bronchus, and blood perfusion was started within 30 min of lung excision.

The isolated-lung circuit has previously been described in detail (12, 36). Briefly, the lung was perfused at a constant flow by a roller pump (Master Flex-Cole Parmer) that pumped blood from a venous reservoir through a heating coil encased in a water jacket (37.5 ± 0.5 C°) to the rest of the closed circuit. The blood was continuously bubbled with a gas mixture of 95% O₂-5% CO₂ to maintain blood gases in a normal range (arterial PO₂ = 100-110 Torr, arterial PCO₂ = 30-40 Torr) and normal pH. After initial hyperinflation, airway pressure (Paw) was set at 3 cmH₂O.

The perfused lobe was placed on a weighing pan that was counterbalanced by a strain-gauge transducer (Grass FT-10). Pulmonary arterial (Ppa) and venous (Ppv) pressures were measured by inserting catheters into the lobar artery and vein and connecting the catheters to pressure transducers (Statham 23BC) positioned at the openings of the inflow and outflow cannulas. Pressures were zeroed at the level of the lung hilus. Blood flow () was measured by an electromagnetic flow probe (Carolina Medical SF 300A) positioned in the venous outflow line connected to a digital flowmeter (Carolina Medical 701D). Ppa, Ppv, and lung weight were recorded on a Grass polygraph (model 7F). Ppa and Ppv were initially adjusted so that the lung lobe became isogravimetric, i.e., neither gaining nor losing weight in zone III conditions (Ppa > Ppv > Paw).

(1)

(2)

(3)

(4)

(5)

(6)

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RESULTS

Figure 1 shows the effect of ATP-sensitive K⁺ channel modulation on the Ppa response to serotonin during hypoxia. Serotonin significantly increased Ppa, an effect potentiated by hypoxia. Cromakalim inhibited the pressor effect of serotonin under both normoxic conditions and during hypoxia. Figures 2 and 3 show the effects of the treatment groups on pulmonary arterial resistance (Fig. 2) and pulmonary venous resistance (Fig. 3). Figure 2 shows that serotonin significantly increased pulmonary arterial resistance (7.2 ± 1.0 vs. 18.5 ± 0.6 cmH₂O · l¹ · min · 100 g), an effect potentiated by hypoxia (7.7 ± 0.6 vs. 29.7 ± 3.5 cmH₂O · l¹ · min · 100 g). In contrast, cromakalim (9.4 ± 0.9 vs. 11.8 ± 1.6 cmH₂O · l¹ · min · 100 g) inhibited the increase in arterial resistance by serotonin during hypoxia (cromakalim+hypoxia+serotonin) but did not affect the precapillary response to serotonin under normoxia (cromakalim+serotonin).

The effect of serotonin on pulmonary venous resistance is shown in Fig. 3. Serotonin significantly increased Rv approximately two times baseline values (6.9 ± 1.3 vs. 15.9 ± 2.5 cmH₂O · l¹ · min · 100 g), which was inhibited by cromakalim (8.3 ± 1.5 vs. 9.6 ± 0.8 cmH₂O · l¹ · min · 100 g), an effect not present on the arterial vessel segments (Fig. 2). Hypoxia potentiated the venoconstrictor response to serotonin (6.9 ± 1.3 vs. 30.1 ± 5.6 cmH₂O · l¹ · min · 100 g), which again was blocked by cromakalim (6.9 ± 1.3 vs. 8.2 ± 1.5 cmH₂O · l¹ · min · 100 g).

RT is summarized in Fig. 4. Serotonin significantly increased RT in the presence of cromakalim by increasing the pressor response in the venous segments (Fig. 3) but not in the arterial segments (Fig. 2). These data indicate a differential effect of ATP-sensitive K⁺-channel modulation to serotonergic stimulation in pulmonary arteries and veins.

The effect of serotonin on Ppc, which is determined by the distribution of Ra and Rv, is presented in Fig. 5. Serotonin significantly increased capillary pressure (13.1 ± 0.9 to 20.8 ± 2.3 cmH₂O), a phenomenon that was blocked by cromakalim (13.1 ± 0.9 vs. 14.2 ± 0.7 cmH₂O) but amplified during hypoxia (14.1 ± 0.8 vs. 25.5 ± 3.6 cmH₂O). Treatment with cromakalim during hypoxia subsequently blocked the potentiated capillary pressure response to serotonin (13.1 ± 0.8 vs. 15.5 ± 1.6 cmH₂O).

Table 1 summarizes the effect of serotonin on pulmonary segmental vascular compliance. Serotonin significantly decreased total vascular compliance by lowering both Cmc and large-vessel compliance, effects potentiated by hypoxia but subsequently reversed by cromakalim.

Table  1.   Compartmental pulmonary vascular compliances in isolated dog lung Compliance, ml · cmH2O1 · 100 g1 CT Cmc Clv Con 1.26 ± 0.20  0.83 ± 0.19  0.43 ± 0.09  Ser 0.84 ± 0.12* 0.64 ± 0.11* 0.20 ± 0.03* Con 1.26 ± 0.20  0.83 ± 0.19  0.43 ± 0.09  Cro + Ser 1.17 ± 0.14  0.90 ± 0.03  0.27 ± 0.12* Con 1.41 ± 0.18  1.09 ± 0.19  0.32 ± 0.09  Hypox 0.90 ± 0.10* 0.75 ± 0.14* 0.15 ± 0.07* Con 1.41 ± 0.18  1.09 ± 0.19  0.32 ± 0.09  Hypox + Ser 0.53 ± 0.07*, 0.47 ± 0.18*, 0.06 ± 0.03*, Con 1.35 ± 0.17  0.87 ± 0.06  0.48 ± 0.13  Hypox + Cro+ Ser 1.28 ± 0.21  0.85 ± 0.09  0.43 ± 0.14 Values are means ± SE. CT, total pulmonary vascular compliance; Cmc, middle-compartment compliance; Clv, large-vessel compliance; Con, control; Ser, serotonin; Cro, cromakalim; Hypox, hypoxia. * Significantly different from Con, P < 0.05.  Significantly different from Ser, P < 0.05.

DISCUSSION

Results of the present study showed that in isolated blood-perfused canine lungs, serotonin increased pulmonary vascular pressure, a finding observed in other species, including dogs (11, 13, 27, 30, 40, 41). Specifically, serotonin increased Ra, Rv, and Ppc and decreased Cmc and large-vessel compliance, agreeing with previous investigations (20, 40, 41). Hyman (25) originally suggested that serotonin constricted both precapillary and postcapillary pulmonary vessels with preferential vasoconstriction in the arterial segments. It has subsequently been shown that the locus of action of serotonin in the pulmonary vasculature is dose dependent (6, 13, 20). The concentration of serotonin used in the present investigation (10⁵ M) increased both Ra and Rv, a finding agreeing with other studies (20).

In this study, serotonin decreased pulmonary vascular compliance by lowering both Cmc and large-vessel compliance. Rippe et al. (41) observed that serotonin decreased CT by lowering large-vessel compliance and Cmc, and Hofman and Ehrhart (20) reported that pulmonary vascular compliance to serotonin was decreased in the presence of cyclooxygenase inhibition. The decrease in vascular compliance that occurred when vascular pressure was increased reflected the relative indistensibility of the pulmonary vasculature upon stimulation of the serotonin receptors. In addition, there was a tendency for large-vessel compliance (Cpa + Cpv) to comprise a smaller percentage of CT when vascular pressures were increased by serotonin compared with control conditions (24 vs. 34%), which agrees with other studies (41).

In the present investigation, a small but significant hypoxic vasoconstrictor response was observed in indomethacin-treated lung lobes, agreeing with previous studies (22). Specifially, when lung lobes were made hypoxic by ventilation with 95% N₂-5% CO₂, there was a small but significant increase in both Ra and Rv as well as in capillary pressure. Previous studies indicate that alveolar hypoxia causes constriction in the arterial and venous vessels of the dog lung (22), and it has been proposed that the small distensible vessels in the capillary bed region constrict in response to hypoxia (17). In addition, the arterial segments of the cat pulmonary circulation elicit the largest pressor response to hypoxia (31).

In this study, hypoxia potentiated the pulmonary vasoactive response to serotonin. It has been proposed that the pulmonary vascular response to vasoactive agents is PO₂ dependent (44). Reeves et al. (39) observed that the pulmonary pressor response to endotoxin in calf lungs was reduced by 100% oxygen, whereas Lonigro and Dawson (29) reported that there was PO₂ dependency of the pulmonary vascular response to prostaglandin F₂ but not to norepinephrine or serotonin in isolated cat lungs. Specifically, at lower PO₂ values, the pressor effect of prostaglandin F₂ was potentiated, whereas the response to serotonin and norepinephrine was unchanged (29). Also, Boe et al. (5) observed that hypoxia enhanced the contractile effect of histamine in the isolated human pulmonary artery, and Hauge (19) concluded that endogenous histamine in the lung was involved in hypoxic pulmonary hypertension in rats.

Alterations in pulmonary vascular tone independent of changes in PO₂ can also affect pulmonary vasoreactivity to humoral substances. Elevated pulmonary vascular tone attenuates the venoconstrictor effects of histamine (4) and acetylcholine (3) in canine lungs, and endothelin-1 (7) in sheep lungs. Hyman and Kadowitz (26) observed in cats that both phenylephrine and acetylcholine, normally vasoconstrictors, elicited pulmonary vasodilatation, and Neely et al. (32) reported that the pulmonary vascular response to serotonin was both tone and dose dependent, whereby low doses caused vasodilation and higher doses caused vasoconstriction. Thus it cannot be ruled out that the effect of hypoxia on the serotonergic response described in this study is independent of the state of pulmonary vascular tone.

It appears that ATP-sensitive K⁺ channels modulate the pressor effect of serotonin under both normoxic and hypoxic conditions in the dog lung. Specifially, under normoxic conditions, cromakalim inhibited the pressor effect of serotonin on the venous segments, which also leads to the blockade in the increase in capillary pressure. When the lungs were made hypoxic, cromakalim blocked the constrictor effect of serotonin on both the precapillary and postcapillary segments, again inhibiting the increase in Ppc. Evidence indicates that hypoxia blocks voltage-gated K⁺ channels in pulmonary vascular smooth muscle cells (45), and hypoxia-induced membrane depolarization has been associated with inhibition of whole cell K⁺ current, leading to an increase in Ppa (37). In contrast, ATP-sensitive K⁺-channel openers such as cromakalim, pinacidil, and minoxidil appear to attenuate hypoxia-induced effects through membrane hyperpolarization (8, 33). Other types of K⁺ channels may also be modulators of the hypoxic serotonergic pressor response because several different K⁺ channels are present on vascular smooth muscle membranes including Ca²⁺-activated, delayed-rectifier, and other nonspecific voltage-gated K⁺ channels. Activation of these other K⁺ channels also causes an increase in K⁺ efflux, leading to membrane hyperpolarization and subsequent vascular smooth muscle relaxation. Recently, Oka et al. (34) showed that the nonspecific K⁺-channel activator NIP-121 reversed chronic pulmonary hypertension in rats, an effect that was inhibited by the ATP-sensitive K⁺-channel blocker glibenclamide, and Barman (1) reported that inhibition of ATP-sensitive K⁺ channels, Ca²⁺-activated K⁺ channels, and delayed-rectifier K⁺ channels potentiated the endothelin-1 pressor response when pulmonary vascular tone was elevated in the isolated canine lung. In addition, Post et al. (38) provided strong evidence for a direct role of Ca²⁺-activated K⁺-channel inhibition in hypoxic pulmonary vasoactivity,

Although not addressed in this investigation, the possibility exists that L-type voltage-dependent Ca²⁺ channels also modulate the potentiated hypoxic pressor response to serotonin. Under normoxic conditions, it has been shown that the L-type Ca²⁺-channel blocker verapamil inhibits the canine serotonergic pulmonary pressor response (4, 13), and Post et al. (38) observed that the dihydropyridine Ca²⁺-channel blocker nisoldipine prevented hypoxic inhibition of K⁺ currents in pulmonary arterial smooth muscle cells. Therefore, K⁺- channel inhibition may be a key event that links hypoxia to pulmonary vasoconstriction by eliciting membrane depolarization and subsequent Ca²⁺ influx.

In summary, the results of the present study indicate that serotonin increased Ra, Rv, and capillary pressure in the canine pulmonary circulation. Additionally, serotonin decreased CT by lowering both Cmc and large-vessel compliance. During hypoxia, the effect of serotonin was potentiated on both Ra and Rv and on capillary pressure, as well as on Cmc and large-vessel compliance. Under normoxia, the ATP-sensitive K⁺-channel opener cromakalim inhibited the serotonergic response on Rv and Cmc, whereas during hypoxia cromakalim inhibited the effect of serotonin on both Ra and Rv, capillary pressure, and both Cmc and large-vessel compliance. These results indicate that canine pulmonary vasoreactivity to serotonin is potentiated under hypoxic conditions and that ATP-sensitive K⁺-channel modulation plays a role in the pressor response to serotonin that is more pronounced during hypoxia.

ACKNOWLEDGEMENTS

The author thanks Louise Meadows for excellent technical assistance.

FOOTNOTES

Address for reprint requests: S. A. Barman, Dept. of Pharmacology, and Toxicology, Medical College of Georgia, Augusta, GA 30912.

Received 14 November 1996; accepted in final form 4 April 1997.

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