Pulmonary Vasodilator Response to Adenosine Triphosphate-Sensitive Potassium Channel Activation Is Attenuated during Desflurane but Preserved during Sevoflurane Anesthesia Compared with the Conscious State 

All surgical procedures and experimental protocols were approved by the Institutional Animal Care and Use Committee at The Cleveland Clinic Foundation.

Twenty-four conditioned male mongrel dogs (27 +/- 1 kg) were premedicated with morphine sulfate (10 mg intramuscularly) and anesthetized with pentobarbital sodium (20 mg/kg intravenously) and fentanyl citrate (15 micro gram/kg). After tracheal intubation, the lungs were mechanically ventilated. Anesthesia was maintained with halothane ([nearly =] 1.2% end-tidal). With the use of sterile surgical technique, a left lateral thoracotomy was performed via the fifth intercostal space. The pericardium was incised ventral to the phrenic nerve. Heparin-filled Tygon catheters (1.02 mm ID; Norton, Akron, OH) were inserted into the descending thoracic aorta, left and right atria, and main pulmonary artery and were secured with purse-string sutures. After careful dissection and isolation, a hydraulic occluder (18 mm ID; In Vivo Metric, Healdsburg, CA) was positioned loosely around the right main pulmonary artery, and an electromagnetic flow probe (10 mm ID; Zepeda, Seattle, WA) was placed around the left main pulmonary artery. After loose apposition of the pericardial edges, the free ends of the catheters, occluder, and flow probe were threaded through the chest wall and tunneled subcutaneously to a final position between the scapulae. A chest tube placed in the left thorax before closure was removed 1 day after surgery. Morphine sulfate (10 mg) was administered intramuscularly after surgery for pain as required. Ampicillin (1 g), cefazolin (1 g), and gentamicin (80 mg) were administered intravenously during surgery and on a daily basis for 10 days after surgery. The dogs were allowed to recover for >or= to 2 weeks before experimentation.

Vascular pressures were measured by attaching the fluid-filled catheters to strain-gauge manometers (Isotec [registered sign]; Quest Medical, Allen, TX), and were referenced to atmospheric pressure with the transducers positioned at midchest at the level of the spine. Heart rate was calculated from the phasic systemic arterial pressure (SAP) trace. Left pulmonary blood flow (LQ) was measured by connecting the flow probe to an electromagnetic flowmeter (SWF-5RD; Zepeda). The flow probe was calibrated in vivo on a weekly basis via the thermal dilution technique. This was achieved by acutely inserting a 7-French balloon-tipped thermal dilution catheter into the pulmonary artery through a percutaneous jugular puncture after topical anesthesia (lidocaine spray). The catheter was positioned 2–3 cm beyond the pulmonic valve. The implanted perivascular hydraulic occluder was then inflated to occlude the right main pulmonary artery completely, which directed total pulmonary blood flow through the left pulmonary artery (and flow probe). Left pulmonary blood flow was then measured by thermal dilution (HEMOPRO²; Spectramed, Oxnard, CA) with multiple 10-ml sterile injectates of 5% dextrose in water. Values for LQ were referenced to body weight (ml [center dot] min sup -1 [center dot] kg sup -1). The aortic and pulmonary artery catheters were used to obtain blood samples to measure systemic arterial and mixed venous blood gases, respectively. Systemic arterial and mixed venous pH, carbon dioxide tension, and oxygen tension were measured with an ABL-600 (Radiometer, Copenhagen, Denmark). Oxyhemoglobin saturation was measured with a Hemoximeter OSM-3 (Radiometer).

All experiments were performed with each healthy, chronically instrumented dog lying on its right side in a quiet laboratory environment. Conscious dogs were not sedated. Left pulmonary vascular pressure-flow (LPQ) plots were used to assess the effects of the various pharmacologic interventions on the pulmonary circulation. LPQ plots were constructed by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure [PAP]-left atrial pressure [LAP]) and LQ during gradual ([nearly =] 1 min) inflation of the hydraulic occluder implanted around the right main pulmonary artery. This technique to measure the LPQ relationship is highly reproducible and has little or no effect on systemic hemodynamics, blood gases, or the zonal condition of the lung. [7] 

Protocol 1: Effect of Sevoflurane Anesthesia on the Pulmonary Vascular Response to Lemakalim. We investigated the effect of sevoflurane anesthesia on the pulmonary vascular response to cumulative doses of the K sup +^ATPchannel agonist, lemakalim, after preconstriction with the thromboxane analogue 9,11-dideoxy-11^alpha, 9^alpha-epoxymethano-prostaglandin F^2alpha(U46619 [a gift from Cayman Chemical, Ann Arbor, MI]). A baseline LPQ plot was first obtained in each conscious dog (n = 6). U46619 was then administered (0.15 +/- 0.02 micro gram [center dot] kg sup -1 [center dot] min sup -1 intravenously) to preconstrict the pulmonary circulation before the administration of lemakalim. Plots of LPQ were obtained during preconstriction with U46619 alone and then again with each dose of lemakalim (0.1, 0.5, 1.0, and 5.0 micro gram [center dot] kg sup -1 [center dot] min sup -1 intravenously) during its cumulative administration ([nearly =] 15 min at each dose) while the infusion of U46619 was continued. We previously have verified that pulmonary vasoconstriction induced by U46619 is stable during the time course of this protocol. [8]On a different day, this protocol was repeated in the same six dogs during sevoflurane anesthesia. Anesthesia with sevoflurane was induced by mask and was supplemented with a subanesthetic dose of thiopental sodium (3 mg/kg intravenously) to minimize excitatory behavior. The trachea was intubated (with a 9 mm ID tube), and ventilation was controlled with a respirator with zero end-expiratory pressure. Muscle relaxants were not used in this study. Immediately after intubation, sevoflurane was delivered via a vaporizer (Sevotec 3; Ohmeda, Austell, GA) with a fresh gas flow of 100 ml [center dot] min sup -1 [center dot] kg sup -1. Tidal volume was fixed at 15 ml/kg. Systemic arterial blood gas values were matched to values measured in the conscious state by adjusting the respiratory rate to 10–20 breaths/min and by administering supplemental oxygen (fractional inspired oxygen tension = 0.26). End-tidal carbon dioxide tension and concentration of sevoflurane were monitored continuously at the adapter end of the endotracheal tube (Solar 7000; Marquette Electronics, Milwaukee, WI). After induction, sevoflurane was allowed to equilibrate for >or= to 1 h to achieve steady-state conditions. At this time, end-tidal concentrations of sevoflurane were 3.3–3.8%(minimum alveolar concentration, 1.4–1.6). [9]During sevoflurane anesthesia, the dose of U46619 (0.12 +/- 0.01 micro gram [center dot] kg sup -1 [center dot] min sup -1 intravenously) was titrated to achieve the same degree of preconstriction induced in the conscious state. The titration procedure involved administering incremental doses of U46619 and generating LPQ plots until a dose was found that caused the same increase in PAP-LAP (at LQ = 75 ml [center dot] min sup -1 [center dot] kg sup -1) from baseline that was achieved in the conscious state. This allowed assessment of the pulmonary vasodilator response to lemakalim at the same level of vasomotor tone in the conscious and sevoflurane-anesthetized states.

Protocol 2: Effect of Desflurane Anesthesia on the Pulmonary Vascular Response to Lemakalim. We investigated the effect of desflurane anesthesia on the pulmonary vascular response to cumulative doses of lemakalim in the presence of preconstriction with U46619. For each conscious dog (n = 7), LPQ plots were obtained in the baseline condition, during preconstriction with U46619 (0.16 +/- 0.02 micro gram [center dot] kg sup -1 [center dot] min sup -1 intravenously), and during the cumulative administration of lemakalim as described in protocol 1. On a different day, this protocol was repeated in the same seven dogs during desflurane anesthesia. Anesthesia with desflurane was induced as described in protocol 1, and the end-tidal concentration was maintained at 10.1–11.5%(minimum alveolar concentration, 1.4–1.6). [9]Desflurane was delivered via a vaporizer (Tec 6; Ohmeda, Austell, GA). During desflurane anesthesia, the dose of U46619 (0.11 +/- 0.01 micro gram [center dot] kg sup -1 [center dot] min sup -1 intravenously) was titrated to achieve the same degree of preconstriction induced in the conscious state.

Protocol 3: Effect of Sympathetic alpha¹-Adrenoreceptor Block on the Pulmonary Vascular Response to Lemakalim in Desflurane-anesthetized Dogs. We investigated the effect of sympathetic alpha¹-adrenoreceptor inhibition on the magnitude of lemakalim pulmonary vasodilation during desflurane-induced anesthesia. This protocol tested the hypothesis that systemic hypotension during administration of lemakalim in desflurane-anesthetized dogs would result in reflex pulmonary vasoconstriction via sympathetic alpha¹-adrenoreceptor activation, [10]thereby attenuating the magnitude of lemakalim-induced pulmonary vasodilation. Sympathetic alpha¹-adrenoreceptor block was achieved with the intravenous administration of pra-zosin (1 mg/kg). This dose abolishes the pressor response to the bolus intravenous administration of phenylephrine (5 micro gram/kg). [11]The dose-response relationship for lemakalim was obtained in six conscious and desflurane-anesthetized dogs as described in protocol 2. On a different day, this protocol was repeated in the same dogs during desflurane anesthesia after pretreatment with prazosin. Plots of LPQ were obtained at baseline, after administration of prazosin, during preconstriction with U46619, and during the cumulative intravenous administration of lemakalim (0.1, 0.5, and 1.0 micro gram [center dot] kg sup -1 [center dot] min sup -1). The highest dose of lemakalim (5.0 micro gram [center dot] kg sup -1 [center dot] min sup -1) was not administrated during sympathetic alpha¹-adrenoreceptor block because it resulted in circulatory collapse. A second dose of prazosin (0.5 mg/kg) was administered before starting the lemakalim infusion to ensure the efficacy of sympathetic alpha¹-adrenoreceptor block. The doses of U46619 in the desflurane-anesthetized state (0.12 +/- 0.01 micro gram [center dot] kg sup -1 [center dot] min sup -1) and after the administration of prazosin in the desflurane-anesthetized state (0.11 +/- 0.01 micro gram [center dot] kg sup -1 [center dot] min sup -1) were titrated to achieve the same degree of preconstriction induced in the conscious intact state (0.14 +/- 0.01 micro gram [center dot] kg sup -1 [center dot] min sup -1).

Protocol 4: Effect of Indomethacin on the Pulmonary Vascular Response to Lemakalim in Conscious and Desflurane-anesthetized Dogs. We investigated the effect of cyclooxygenase inhibition with indomethacin on the magnitude of lemakalim-induced pulmonary vasodilation. Cyclooxygenase inhibition was achieved via the intravenous administration of indomethacin (5 mg/kg). This dose inhibits prostaglandin synthesis and abolishes the pulmonary pressor response to arachidonic acid. [12]The dose-response relationship for lemakalim was first obtained in five intact conscious dogs as described in protocol 1. On a different day, LPQ plots were obtained in the same conscious dogs at baseline, 45 min after administration of indomethacin, during preconstriction with U46619, and during the cumulative intravenous administration of lemakalim. This protocol was repeated on separate days in the same dogs during desflurane anesthesia with or without pretreatment with indomethacin. Anesthesia with desflurane was induced and maintained as described in protocol 2. The doses of U46619 after the administration of indomethacin in the conscious state (0.11 +/- 0.01 micro gram [center dot] kg sup -1 [center dot] min sup -1) and in the desflurane-anesthetized state (0.10 +/- 0.01 micro gram [center dot] kg sup -1 [center dot] min sup -1) were titrated to achieve the same degree of preconstriction induced in the conscious state (0.13 +/- 0.01 micro gram [center dot] kg sup -1 [center dot] min sup -1).

All solutions were prepared on the day of the experiment. U46619 was diluted in 0.9% saline. Lemakalim and prazosin HCl (Pfizer, Groton, CT) were dissolved in 95% ethanol and then diluted in sterile water. Indo-methacin (Sigma) was dissolved in sterile water with 114 g sodium carbonate.

Phasic and mean vascular pressures and LQ were displayed continuously on an eight-channel strip-chart recorder (2800; Gould, Eastlake, OH). Mean pressures and LQ, measured at end-expiration, were obtained with the use of passive electronic filters with a 2-s time constant. All vascular pressures were referenced to atmospheric pressure before and after each LPQ plot. The analog pressure and LQ signals were digitally converted and multiplexed (PCM-8; Medical Systems, Greenvale, NY) and stored on videotape (videocassette recorder AG-1260; Panasonic, Secaucus, NJ) for later playback and analysis.

The LPQ relationship was linear by inspection over the empirically measured range of LQ. Therefore, linear regression analysis was used to calculate the slope and intercept for PAP-LAP (or PAP-0 if LAP was <or= to 0 mmHg) as a function of LQ in each individual experiment. PAP-LAP intercept values were calculated at the midrange of empirically measured LQ in each protocol. This approach minimized the variance in the PAP-LAP intercept and avoided the use of intercept values outside the range of our empirical measurements; i.e., PAP-LAP was not measured at LQ = 0 ml [center dot] min sup -1 [center dot] kg sup -1. The correlation coefficient for the LPQ relationship in each protocol averaged >or= to 0.98. Multivariate analysis of variance in the form of Hotelling's T²was used to assess the effects of sevoflurane, desflurane, indomethacin, prazosin, U46619, and lemakalim on the regression parameters obtained in each experiment within each specific protocol.

The pulmonary vasodilator response to lemakalim (LQ = 75 ml [center dot] min sup -1 [center dot] kg sup -1) was expressed as the percentage decrease in preconstriction with U46619, which was calculated with the following formula [4,7,13]:Equation 1Thus, a lemakalim-induced decrease in PAP-LAP of 100% represents a complete reversal of U46619 preconstriction and a full return to the baseline LPQ relationship. One-way analysis of variance followed by Student's t test for paired comparisons was used to assess the pulmonary vascular effects of lemakalim within each group. Two-way analysis of variance followed by Student's t test for paired comparisons was used to assess the effects of the volatile anesthetic agents on the magnitude of lemakalim-induced pulmonary vasodilation. Student's t test for paired comparisons was also used to assess changes in steady-state hemodynamics and blood gases. All values are presented as means +/- SE.

Sevoflurane had no net effect on the baseline LPQ relationship compared with the conscious state (Figure 1). Compared with the baseline condition, U46619 caused pulmonary vasoconstriction (P < 0.05) in the conscious and sevoflurane-anesthetized states (Figure 1). A lower (P < 0.05) dose of U46619 was required during sevoflurane administration to match the same degree of preconstriction achieved in the conscious state. After preconstriction with U46619, lemakalim (1.0 micro gram [center dot] kg sup -1 [center dot] min sup -1) resulted in pulmonary vasodilation in the conscious state and during sevoflurane anesthesia (Figure 2). The effect of sevoflurane on the lemakalim dose-response relationship is summarized in Figure 3. Lemakalim resulted in pulmonary vasodilation (P < 0.05) in both conditions. The magnitude of the pulmonary vasodilator response to lemakalim was not significantly altered during sevoflurane anesthesia compared with the conscious state.

Steady-state hemodynamics and blood gases are summarized in Table 1and Table 2, respectively. Baseline SAP was decreased and heart rate was increased during anesthesia with sevoflurane compared with the conscious state. U46619 increased PAP in the conscious and sevoflurane-anesthetized states. Lemakalim decreased SAP and increased heart rate and LQ in both conditions. Baseline blood gases were similar in conscious and sevoflurane-anesthetized dogs (Table 2). U46619 decreased mixed venous pH and oxyhemoglobin saturation in both conditions. Lemakalim increased mixed venous oxygen tension and oxyhemoglobin saturation in both conditions.

Desflurane had no net effect on the baseline LPQ relationship compared with the conscious state (Figure 4). Compared with the baseline condition, U46619 caused pulmonary vasoconstriction (P < 0.05) in the conscious and desflurane-anesthetized states (Figure 4). A lower (P < 0.05) dose of U46619 was required during desflurane anesthesia to match the same degree of preconstriction achieved in the conscious state. After preconstriction with U46619, administration of lemakalim (1.0 micro gram [center dot] kg sup -1 [center dot] min sup -1) resulted in pulmonary vasodilation in the conscious state, but the magnitude of the vasodilator response was attenuated (P < 0.05) during desflurane anesthesia (Figure 5). The effect of desflurane on the lemakalim dose-response relationship is summarized in Figure 6. Lemakalim resulted in dose-dependent pulmonary vasodilation (P < 0.05) in both conditions; however, the magnitude of the pulmonary vasodilator response to lemakalim was attenuated (P < 0.05) during anesthesia with desflurane compared with the conscious state.

Steady-state hemodynamics and blood gases are summarized in Table 3and Table 4, respectively. Baseline SAP was decreased and LAP and heart rate were increased during anesthesia with desflurane compared with the conscious state. U46619 increased PAP in both conditions. Lemakalim decreased SAP and LAP and increased heart rate in both conditions. Lemakalim increased LQ in the conscious state, whereas LQ was unchanged during desflurane anesthesia. Baseline blood gases were similar in conscious and desflurane-anesthetized dogs (Table 4). U46619 decreased systemic arterial and mixed venous pH and oxyhemoglobin saturation in both conditions. Lemakalim decreased mixed venous carbon dioxide tension and increased mixed venous oxygen tension and oxyhemoglobin saturation in both conditions.

The sympathetic alpha¹-adrenoreceptor antagonist, prazosin, had no net effect on the baseline LPQ relationship during desflurane anesthesia (results not shown). The pulmonary vascular dose-response relationships for lemakalim in the conscious state, during desflurane anesthesia and during anesthesia with desflurane after pretreatment with prazosin, are summarized in Figure 7. After preconstriction with U46619, lemakalim resulted in dose-dependent pulmonary vasodilation (P < 0.05) in all three conditions; however, the attenuated (P < 0.05) pulmonary vasodilator response to lemakalim during anesthesia with desflurane was largely reversed by prazosin. Steady-state hemodynamics are summarized in Table 5.

In the conscious and desflurane-anesthetized states, the cyclooxygenase inhibitor, indomethacin, had no net effect on the baseline LPQ relationship (results not shown). The pulmonary vascular dose-response relationships for lemakalim in the conscious and desflurane-anesthetized states with or without pretreatment with indomethacin are summarized in Figure 8. After preconstriction with U46619, lemakalim resulted in dose-dependent pulmonary vasodilation (P <0.05) in all four conditions. Indomethacin did not alter the magnitude of the pulmonary vasodilator response to lemakalim in the conscious state. The attenuated pulmonary vasodilator response to lemakalim during desflurane anesthesia was still apparent after pretreatment with indomethacin. Steady-state hemodynamics are summarized in Table 6.

This study demonstrated that (1) sevoflurane and desflurane anesthesia had no net effect on the baseline LPQ relationship;(2) the pulmonary vasodilator response to the K sup +^ATPchannel agonist, lemakalim, was not altered during sevoflurane anesthesia but was attenuated during desflurane anesthesia compared with the conscious state;(3) the attenuated pulmonary vasodilator response to lemakalim during desflurane anesthesia was largely reversed after sympathetic alpha¹-adrenoreceptor inhibition; and (4) cyclooxygenase inhibition did not modulate the pulmonary vasodilator response to lemakalim in the conscious or desflurane-anesthetized states.

We used chronically instrumented dogs so that the pulmonary vascular effects of K sup +^ATPchannel activation could be assessed in the same dog in the conscious and anesthetized states. This experimental model avoids the use of background anesthetic agents and acute surgical trauma, which can modify neural, [11,13]humoral, [8,14]and local [4,15]mechanisms of pulmonary vascular regulation. Moreover, the use of pressure-flow plots avoids the limitations inherent in the interpretation of single-point calculations of pulmonary vascular resistance. [16]We used lemakalim as a pharmacologic tool to activate K sup +^ATP-mediated pulmonary vasodilation. [3]This is based on previous observations that lemakalim is a potent and selective activator of K sup +^ATPchannels in the pulmonary vasculature. [2,4] 

Sevoflurane and desflurane have been reported to cause systemic vasodilation. [17,18]In contrast, neither anesthetic agent had a net effect on the baseline LPQ relationship compared with the conscious state. Because the normal pulmonary circulation has very little vasomotor tone, an anesthesia-induced vasodilator influence on the LPQ relationship during baseline conditions would not be expected. In contrast, volatile anesthetic agents are known to inhibit endothelium-dependent vasodilation, [15,19]which could result in a net pulmonary vasoconstrictor influence. We have reported, however, that neither nitric oxide synthase inhibition nor cyclooxygenase inhibition have a net effect on the baseline LPQ relationship in conscious dogs. [7,12]Therefore, it was not surprising that sevoflurane and desflurane had no effect on the baseline LPQ relationship in the current study. We should note, however, that sevoflurane and desflurane reduced the concentration of U46619 required to achieve the same degree of preconstriction observed in the conscious state. This could be due to an inhibitory effect of both anesthetic agents on the endothelial production of nitric oxide. In contrast to baseline conditions, preconstriction with U46619 stimulates the endogenous production of nitric oxide, as manifested by a leftward shift in the pulmonary vascular dose-response relationship for U46619 after nitric oxide synthase inhibition. [7] 

Recently, interactions between volatile anesthetic agents and K sup +^ATPchannels in various tissues have been described. [20–25]Several studies have demonstrated that activation of K sup +^ATPchannels plays an important role in coronary vasodilation induced by volatile anesthetic agents. [20–22]In contrast, we have demonstrated previously that halothane and enflurane attenuate lemakalim-induced pulmonary vasodilation in chronically instrumented dogs. [4]In in vitro studies, we also observed that halothane and isoflurane attenuated the endothelium-dependent pulmonary vasorelaxant responses to K sup + sub ATP channel activation. [26,27]In the current study, desflurane, but not sevoflurane, attenuated lemakalim-induced pulmonary vasodilation. To our knowledge, this is the first study to investigate the effects of sevoflurane and desflurane anesthesia on K sup +^ATPchannel activity. Only one study has reported that desflurane inhibits a potassium channel current in human neuronal cells at clinically relevant concentrations. [28] 

The possible mechanisms by which desflurane attenuated K sup +^ATPchannel-mediated pulmonary vasodilation could involve (1) activation of reflex vasoconstrictor mechanisms, (2) inhibition of endothelium-dependent vasodilator mechanisms, or (3) a direct effect of desflurane on vascular smooth muscle K sup +^ATPchannels. Administration of lemakalim resulted in systemic hypotension in the conscious state, and this effect was even more pronounced during anesthesia with desflurane. Systemic hypotension causes reflex pulmonary vasoconstriction mediated by sympathetic alpha¹-adrenoreceptor activation in conscious dogs. [10]We have reported previously that combined neurohumoral block had no effect on the magnitude of lemakalim-induced pulmonary vasodilation in the conscious or halothane-anesthetized state. [4]In this study, however, sympathetic alpha¹-adrenoreceptor inhibition with prazosin reversed the attenuation of lemakalim-induced pulmonary vasodilation during desflurane anesthesia. These results suggest that reflex pulmonary vasoconstriction mediated by sympathetic alpha¹-adrenoreceptors acted to offset the pulmonary vasodilator response to lemakalim during desflurane anesthesia. This is consistent with our previous observation that phenylephrine-induced pulmonary vasoconstriction is potentiated during anesthesia with desflurane compared with the conscious state. [29]Thus, the inhibitory effect of desflurane on K sup +^ATPchannel-mediated pulmonary vasodilation appears to be at least partly a secondary effect caused by activation of sympathetic alpha¹-adrenoreceptors.

Recent evidence indicates that K sup +^ATPchannels are expressed in both vascular smooth muscle and endothelial cells. [30–32]Activation of endothelial K sup +^ATPchannels increases Ca sup 2+ influx, which stimulates the production of endothelium-derived relaxant factors. In in vitro studies, we recently demonstrated that the pulmonary vasorelaxant response to lemakalim involves both an endothelium-dependent and vascular smooth muscle component. [26]The endothelium-dependent component of lemakalim-induced pulmonary vasorelaxation was mediated by cyclooxygenase metabolites and not by nitric oxide. [26]Moreover, halothane attenuated lemakalim-induced pulmonary vasorelaxation via an inhibitory effect on the endothelium-dependent, cyclooxygenase-mediated component of the response. [26]In the current in vivo study, we tested the hypothesis that desflurane inhibited lemakalim-induced pulmonary vasodilation via a similar mechanism. The attenuated response to lemakalim during desflurane anesthesia, however, was still apparent after cyclooxygenase inhibition, which suggests that this mechanism is not involved.

The possibility that desflurane directly interferes with K sup +^ATPchannels cannot be discounted. It has been suggested that inhalational anesthetic agents bind specifically to ion channels and alter their function directly. [33,34]Inhalational anesthetic agents may alter membrane fluidity and lateral membrane pressure, which could inhibit the opening or accelerate the closing of ion channels. Additional studies are required to identify the molecular mechanisms by which inhalational anesthetic agents directly alter K sup +^ATPchannel activity.

In contrast to desflurane, sevoflurane had no effect on lemakalim-induced pulmonary vasodilation. These differential results may partially reflect the different effects of sevoflurane and desflurane on sympathetic alpha¹-adrenoreceptors. We previously reported that, in contrast to desflurane, sevoflurane had no effect on phenylephrine-induced pulmonary vasoconstriction compared with the response measured in the conscious state. [29]Therefore, although the same degree of systemic hypotension was observed during anesthesia with sevoflurane and desflurane, reflex pulmonary vasoconstriction via sympathetic alpha¹-adrenoreceptor activation did not inhibit lemakalim-induced pulmonary vasodilation during sevoflurane anesthesia.

In summary, K sup +^ATPchannel-mediated pulmonary vasodilation is preserved during sevoflurane anesthesia but is attenuated during desflurane anesthesia. This effect of desflurane does not involve the cyclooxygenase pathway but is largely mediated by reflex sympathetic alpha¹-adrenoreceptor vasoconstriction. These results indicate that volatile anesthetic agents can have differential effects on the pulmonary vasodilator response to K sup +^ATPchannel activation.

The authors thank Steve Schomisch, Pantelis Konstantinopoulos, and Mike Trentanelli for technical work, and Ronnie Sanders for secretarial support in preparing the manuscript.