Effects of neostigmine on bronchoconstriction with continuous electrical stimulation in rats.

PURPOSE: When neostigmine is used to reverse muscle relaxants in patients with asthma without signs of airway inflammation, asthma attack is occasionally encountered. It is likely that abnormally increased electrical impulses traveling from the brain through cholinergic nerves to airway smooth muscles may be one of the pathogeneses of asthma attack. We applied continuous electrical field stimulation (c-EFS) or continuous electrical stimulation (c-ES) of low frequency to the vagal nerve of the rat in vitro and in vivo to determine the role of cholinergic nerve activation in inducing airway constriction. METHODS: Fifty-seven male Wistar rats were used. In an in vitro study we examined whether tetrodotoxin (TTX), an Na(+)-channel blocker, 4-DAMP, a muscarinic M(3) receptor antagonist, or neostigmine could affect c-EFS-induced contraction of the tracheal ring. In an in vivo study, we examined whether c-ES of the vagal nerve could increase maximum airway pressure (P (max)) and whether neostigmine could potentiate c-ES-induced P (max). RESULTS: TTX and 4-DAMP completely inhibited c-EFS-induced contraction whereas neostigmine potentiated c-EFS-induced contraction dose-dependently. P (max) was not increased by neostigmine. P (max) was not increased by 2-Hz c-ES, but was increased by the addition of neostigmine. P (max) was increased by 5-Hz c-ES, and further increased by the addition of neostigmine. CONCLUSION: The contractile response of the tracheal ring to c-EFS is potentiated by neostigmine. P (max) is increased by c-ES of the vagal nerve, and is potentiated by neostigmine. These data suggest that increased activity of the cholinergic nerve could be involved in asthma attack.

[Influence of general anesthetics on the incidence of postoperative delirium in the elderly].

BACKGROUND: Postoperative delirium increases the morbidity and mortality in elderly patients. The present study was carried out to evaluate whether the difference of anesthetics has influence on the incidence of postoperative delirium, retrospectively. METHODS: Among the patients undergoing surgical procedure aged above 75 years, in seventy one patients anesthesia was maintained with sevoflurane (group S), and 38 with propofol (group P). The incidence of delirium postoperatively was obtained retrospectively from their medical chart. The delirium was diagnosed with the confusion assessment method diagnostic algorithm. RESULTS: The incidence of postoperative delirium of group P (15.8%) was significantly lower than that of group S (38.0%, P=0.02). CONCLUSIONS: Propofol anesthesia decreases postoperative delirium in elderly patients compared with sevoflurane anesthesia.

Synthetic atrial natriuretic peptide improves systemic and splanchnic circulation and has a lung-protective effect during endotoxemia in pigs.

BACKGROUND: Pharmacological blockade of the renin-angiotensin system is thought to maintain gut perfusion during circulatory stress and thereby avoid later failure of distant organs. In this controlled experimental study, we investigated the effects of carperitide, a synthetic atrial natriuretic peptide that inhibits the renin-angiotensin system, on the systemic and splanchnic circulation during fluid-resuscitated endotoxemia in pigs. METHODS: Sixteen domestic pigs of both sexes were randomly divided into 2 groups. The pigs were anesthetized and their lungs ventilated before receiving either saline (Group A: n = 8) or carperitide (Group B: n = 8). After a baseline measurement was taken, the pigs from both groups received a continuous infusion (1.7 microg x kg(-1) x h(-1)) of endotoxin for 240 min. Group B received a continuous infusion of carperitide (0.05 microg x kg(-1) x min(-1)) starting 30 min before the endotoxin infusion and lasting until the end of the study, whereas Group A received the same volume of saline. Fluid resuscitation was titrated to maintain pulmonary artery wedge pressure between 10 and 12 mm Hg. Systemic and regional hemodynamics, oxygenation variables, and the arterial-to-intestinal PCO(2) gap were measured at baseline and after endotoxin infusion for 240 min. The primary end points were cardiac index, superior mesenteric artery flow index, and PCO(2) gap at the end of this study (T240). RESULTS: Cardiac index and superior mesenteric artery flow index in Group B were significantly higher than those in Group A at T240 (83 +/- 15 vs 135 +/- 23 mL x kg(-1) x min(-1), P < 0.001; 2.6 +/- 1.4 vs 7.9 +/- 4.8, P = 0.01), respectively. Carperitide administration resulted in a significantly better maintenance of intestinal mucosal perfusion assessed by the PCO(2) gap at T240 (33.0 +/- 14.5 vs 11.6 +/- 10.0 mm Hg, P = 0.004). The PaO(2)/FIO(2) ratio in Group B was significantly greater than that in Group A from T60 to T240. CONCLUSIONS: In this porcine fluid-resuscitated endotoxemia model, a low dose of carperitide administered before endotoxemia maintained systemic and splanchnic circulation, and prevented the deterioration of oxygenation. Atrial natriuretic peptide infusion is a potentially beneficial therapy with respect to systemic and splanchnic circulation as well as the respiratory system during sepsis.

Effects of amitriptyline, a tricyclic antidepressant, on smooth muscle reactivity in isolated rat trachea.

PURPOSE: This study was designed to investigate the action of amitriptyline, a tricyclic antidepressant, on airway smooth muscle reactivity and its underlying mechanisms. METHODS: In isolated rat trachea, isometric force was recorded to examine the effects of amitriptyline on the contractile response to acetylcholine (ACh), electrical field stimulation (EFS), calyculin A (a myosin light chain phosphatase inhibitor), and sphingosylphosphorylcholine (SPC; a Rhokinase activator). In addition, inositol monophosphate (IP1) accumulation was measured to examine its effects on inositol 1, 4, 5-trisphosphate (IP(3)) production during stimulation with ACh. RESULTS: Amitriptyline inhibited the contractile responses to ACh, EFS, calyculin A, and SPC, with the concentrations of amitriptyline (mean +/- SD) required to exert 50% inhibition (IC(50)) being 4.3 +/- 1.3 microM, 3.2 +/- 1.6 microM, 256.4 +/- 106.4 microM, and 98.2 +/- 21.8 microM, respectively. In addition, amitriptyline (10 microM) eliminated the ACh (10 microM)-induced IP(1) accumulation. CONCLUSION: The results suggest that amitriptyline does not influence tracheal smooth muscle reactivity at clinical concentrations (<1 microM), but attenuates the reactivity at supraclinical concentrations (> or =1 microM). The attenuated response to ACh brought about by amitriptyline is presumably due, at least in part, to the inhibition of phosphatidylinositol (PI) metabolism. The ability of amitriptyline to inhibit the calyculin Ainduced contraction suggests that amitriptyline also inhibits the Ca(2+)-calmodulin-myosin light chain pathway independently of the inhibition of PI metabolism. Finally, the difference between the IC(50) values for SPC-induced contraction and those for calyculin A-induced contraction suggests that amitriptyline may also inhibit the Rho-kinase pathway.

The effects of fentanyl on the contractile response of ovalbumin-sensitized rat trachea.

BACKGROUND: It is not clear whether fentanyl affects a hyperresponsive airway. We examined the effects of fentanyl on the contractile response of ovalbumin (OA)-sensitized rat tracheas. METHODS: Rats were sensitized with a single intraperitoneal injection of 10 mug of OA mixed with adjuvant. Fourteen days later, the trachea was cut into 3-mm-wide rings. The OA-induced tension was measured, and the effects of fentanyl were studied in the presence of naloxone. Second, the role of cholinergic nerves and serotonin in the contraction and the effects of fentanyl were examined using tetrodotoxin and ketanserin. Third, lungs of sensitized rats were ventilated, and respiratory system resistance was calculated before and after the administration of OA in the presence of fentanyl. RESULTS: Fentanyl dose-dependently attenuated the OA-induced contraction, and naloxone partly reversed it. Both tetrodotoxin and ketanserin attenuated the contraction. Fentanyl had no further effect on the contraction in the presence of tetrodotoxin, whereas the contraction was nearly abolished by fentanyl in the presence of ketanserin. OA increased respiratory system resistance in sensitized rats, and this effect was attenuated by fentanyl. CONCLUSIONS: Fentanyl attenuates the airway hyperresponsiveness of sensitized rat trachea through the inhibition of cholinergic nerves on the smooth muscle.

Propofol attenuates ovalbumin-induced smooth muscle contraction of the sensitized rat trachea: inhibition of serotonergic and cholinergic signaling.

Propofol is considered suitable for induction of anesthesia in patients with bronchial asthma. However, the mechanisms of its action on bronchi are not fully understood. We examined the effects of propofol on ovalbumin (OA)-induced contraction of OA-sensitized rat trachea. Male Wistar rats were sensitized by a single intraperitoneal injection of OA 10 microg mixed with aluminum hydroxide, 10 mg, as adjuvant. Fourteen days later, the experiment was performed using the tracheal rings. We observed the effects of ketanserin, a 5-HT2 receptor antagonist, and atropine on OA-induced contraction. Next, the effects of propofol on OA-, serotonin (5-HT)-, acetylcholine-, or electrical field stimulation-induced contractions were observed. OA-induced contraction was 90% attenuated by the combination of ketanserin and atropine. Propofol significantly attenuated OA-induced contraction in a dose-dependent manner. Propofol abolished 5-HT-induced contraction, attenuated acetylcholine-induced contraction, and also almost completely attenuated the enhancement by 5-HT of electrical field stimulation-induced contraction. These results suggest that the mechanism involved in the attenuation by propofol of OA-induced contraction is inhibition of the actions of 5-HT. Propofol should be a useful anesthetic in patients with immunoglobulin E-related asthma.

Anticholinesterase drugs stimulate smooth muscle contraction of the rat trachea through the Rho-kinase pathway.

We performed this study to determine the effects of Rho-kinase inhibitors, Y-27632 and fasudil, on the anticholinesterase (anti-ChE)-induced contractile and phosphatidylinositol responses of the rat trachea. In vitro measurements of isometric tension and [3H] inositol monophosphate (IP1) that was formed were conducted by using rat tracheal rings or slices. Neostigmine- and pyridostigmine-induced contractions were almost completely inhibited by Y-27632 and fasudil at 30 microM each, whereas acetylcholine-induced contraction was inhibited incompletely, i.e., by 56% by Y-27632 and by 51% by fasudil, at 100 microM for each, respectively. The inhibitory effects of fasudil on neostigmine- and acetylcholine-induced contractions were completely reversed by calyculin-A, a myosin phosphatase inhibitor. Neostigmine-induced IP1 accumulation was attenuated by fasudil at 100 microM. The results suggest that anti-ChEs cause airway smooth muscle contraction, in part, through activation of the Rho-kinase pathway.

Total intravenous anesthesia with propofol is associated with a lower rate of postoperative delirium in comparison with sevoflurane anesthesia in elderly patients.

STUDY OBJECTIVE: Postoperative delirium (POD) is a common complication of anesthesia. The incidence of POD in elderly patients ranges from 37% to 53%, and POD increases the morbidity and mortality of elderly patients. However, the effects of anesthetics on POD are not well known. The present study aimed to compare the incidence of POD resulting from propofol and sevoflurane anesthesia. DESIGN: Double-blind prospective study. SETTING: Operating room and postoperative recovery area. PATIENTS: Thirty patients in the sevoflurane anesthesia group and 29 in the propofol anesthesia group. MEASUREMENTS: Statistical analyses were performed using Microsoft Excel 2010 for Windows 7 (Microsoft Corporation, Redmond, Wash). Statistical analysis was performed using Fisher exact test and Student t test. MAIN RESULTS: The incidence of POD in the propofol anesthesia (6.9%) was significantly less than that observed in the sevoflurane anesthesia (26.7%; 038). CONCLUSION: In comparison with sevoflurane anesthesia, propofol anesthesia is associated with a lower incidence of POD in elderly patients.

Selegiline, an MAO-B inhibitor, attenuates airway smooth muscle contraction in the rat trachea.

Selegiline is widely used for Parkinson's disease and sometimes for Alzheimer's disease. It is reported to affect intracellular Ca(2+) concentration. Since intracellular Ca(2+) is partly regulated by phosphatidylinositol (PI) response and is important for smooth muscle contraction, selegiline may affect airway smooth muscle tension. We examined the effects of selegiline on acetylcholine (ACh)- and KCl-induced contractile and PI responses in rat trachea. The trachea was cut into 3-mm-wide ring segments or 1-mm-wide slices. ACh (3 microM, 50% effective dose) or KCl (40 mM) was added, and ring relaxation was induced by the addition of selegiline. Tracheal slices were incubated with [(3)H]myo-inositol and 3 microM ACh in the presence of selegiline, and [(3)H]inositol monophosphate (IP(1)) was measured. Selegiline dose-dependently attenuated ACh- and KCl-induced tracheal ring contractions. Fifty-percent inhibitory doses (ID50) of selegiline against ACh- and KCl-induced contraction were 120 +/- 30 microM and 80 +/- 20 microM, respectively. Basal and ACh-induced IP(1) accumulation were 2.20 +/- 0.20 Bq and 7.88 +/- 0.23 Bq, respectively, and selegiline at a dose of 1000 microM attenuated ACh-induced IP(1) accumulation (5.44 +/- 0.30 Bq). These results suggest that selegiline inhibits contractile responses through the inhibition of voltage-operated Ca(2+) channels and the PI response.

A new technique for post-pyloric feeding tube placement by palpation in lean critically ill patients.

Various techniques have been described for blind bedside placement of a post-pyloric feeding tube. However, there is no universal method and the technique depends on the local institutional resources and expertise. The purpose of this study was to evaluate a simple new technique for the bedside placement of a post-pyloric feeding tube in an intensive care unit using palpation to confirm tube position. We studied 47 consecutive ventilated patients (mean body mass index 22.4 ± 4.2 kg/m(2)) requiring enteral tube feeding for nutritional support. We monitored the maximum intensity point of injected air 'bubbling' by palpation and estimated tube position. We monitored the movement of the maximum intensity point from the left upper quadrant to the right upper quadrant. If the maximum intensity point on the right upper quadrant diminished or weakened, we considered the tube had proceeded beyond the pylorus. By palpation, we could feel the bubbling of the injected air in all patients, but four patients were excluded because of failure to complete the protocol. The overall success rate including the four excluded cases was 85.1% (40/47) on the first attempt and 91.5% (43/47) when we included the second attempt. The median time for 40 successful tube placements on the first attempt was 10 (7 to 23) minutes. Our new palpation technique can successfully detect the position of a feeding tube in the stomach and help guide the tube to the correct location in the post-pyloric portion of the stomach in lean critically ill patients.

High concentrations of landiolol, a beta(1)-adrenoceptor antagonist, stimulate smooth muscle contraction of the rat trachea through the Rho-kinase pathway.

PURPOSE: Gradually progressing contraction of airway smooth muscle is suggested to be due to the Rho-kinase signaling pathway. In our preliminary study in rat tracheas, landiolol, a beta(1)-adrenoceptor antagonist, at high doses caused gradually progressing contraction, and this contraction reached a plateau after 20 min. Therefore, this study was carried out to clarify whether landiolol could stimulate the Rho-kinase pathway or the phosphatidylinositol (PI) response in the rat trachea. METHODS: Seventy-eight male Wistar rats weighing 250-350 g were used for the experiments. Their tracheas were cut into 3-mm-wide ring segments or 1-mm-wide slices. Measurements of isometric tension and [(3)H] inositol monophosphate (IP(1)) production were conducted, using these tracheal rings or slices. Data values are expressed as means +/- SD, and statistical significance (P < 0.05) was determined using analysis of variance (ANOVA). RESULTS: Landiolol (700 microM)-induced contraction was completely inhibited by fasudil at 30 microM, while the landiolol-induced contraction was not inhibited by 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), ketanserin, or nicardipine. Landiolol did not stimulate IP(1) production. CONCLUSION: These results suggest that high concentrations of landiolol could cause airway smooth muscle contraction through the Rho-kinase pathway, but not through the PI response coupled with muscarinic M(3) receptors, 5-HT receptors or the activation of L-type Ca(2+) channels.

Effects of propofol and ketamine on ATP-induced contraction of the rat trachea.

PURPOSE: ATP causes airway smooth-muscle contraction in patients with asthma and chronic obstructive pulmonary disease. Propofol and ketamine attenuate the airway smooth-muscle contraction induced by histamine and acetylcholine. However, it is not clear whether propofol and ketamine affect the ATP-induced airway smooth-muscle contraction. METHODS: We examined the effects of propofol and ketamine on the ATP-induced contraction and ATP-P(2)-purinoceptor binding. RESULTS: Propofol attenuated the ATP-induced contraction in a dose-dependent manner, with a 50% inhibitory concentration of 54 +/- 22 microM. Ketamine at 300 microM attenuated the ATP-induced contraction. In the binding study, propofol attenuated the binding of the P(2)-purinoceptor with [(3)H]-ATP in a dose-dependent manner, while ketamine did not attenuate this binding. CONCLUSION: Propofol attenuates ATP-induced contraction through the inhibition of ATP-P(2)-purinoceptor binding.

Succinylcholine potentiates acetylcholine-induced contractile and phosphatidylinositol responses of rat trachea.

PURPOSE: Although succinylcholine (SCh) is often used as a muscle relaxant in electroconvulsive therapy, its influence on airway reactivity has not been fully investigated. We examined the effects of SCh on acetylcholine (ACh)-, carbachol (CCh)-, and electrical field stimulation (EFS)-induced contractions, and on the ACh-induced phosphatidylinositol (PI) response of rat trachea. METHODS: Thirty-two male Wistar rats weighing 250-350 g were used. The trachea was rapidly isolated and cut into 3-mm-wide rings. The resting tension was adjusted periodically to 1.0 g during the equilibration period. ACh, 1 microM; carbachol (CCh), 0.05 microM; or neither of them, was added, and SCh was then added at 1-300 microM final concentrations, and ring tension was examined. Contractions were elicited by EFS in the presence or absence of 100 microM SCh. Tracheal slices were incubated with [3H] myo-inositol, 1 microM ACh, and various concentrations of SCh. The accumulation of [3H] inositol monophosphate (IP1) was measured. RESULTS: SCh did not affect the tension by itself without ACh, or with CCh, but SCh potentiated the ACh-induced contraction of rat trachea at concentrations of 10 microM or more (50% effective concentration [EC50]; 43.6 microM). SCh produced a significant increase in the amplitude and duration of EFS-induced contractions. SCh, at concentrations of 10 microM and 100 microM, potentiated ACh-induced IP1 accumulation. CONCLUSION: SCh potentiated ACh-induced, but not CCh-induced, contractile and PI responses, and enhanced EFS-induced contraction of rat trachea, suggesting that competition for butyrylcholinesterase (BChE) in airway smooth muscle could be involved in the potentiation by SCh of ACh-induced airway smooth muscle contraction.

Cardioprotection induced by olprinone, a phosphodiesterase III inhibitor, involves phosphatidylinositol-3-OH kinase-Akt and a mitochondrial permeability transition pore during early reperfusion.

PURPOSE: Ischemic preconditioning is mediated by the activation of phosphatidylinositol-3-OH kinase-Akt (PI3K-Akt) and by the inhibition of the opening of a mitochondrial permeability transition pore (mPTP) during early reperfusion. Preischemic administration of the phosphodiesterase type III inhibitor olprinone protects the myocardium against infarction, but its mechanism has not been fully clarified. We hypothesized that this olprinone-induced cardioprotective effect was mediated by the activation of PI3K-Akt and by the inhibition of mPTP during early reperfusion. METHODS: Pentobarbital-anesthetized rats (n = 42) subjected to 30-min coronary occlusion followed by 2-h reperfusion, received olprinone (20 microg.kg(-1)) or saline (control) in the preischemic phase in the presence or absence of the PI3K-Akt inhibitor wortmannin (0.6 mg.kg(-1)) or the mPTP opener atractyloside (5 mg.kg(-1)) before 5 min of reperfusion. The myocardial infarct size was expressed as a percentage of the area at risk. All values were expressed as means +/- SD. Statistical comparisons within groups were made using repeated-measures analysis of variance (ANOVA), followed by a paired t-test, and comparisons among groups were analyzed using a two-way ANOVA, followed by the Tukey-Kramer test. RESULTS: Mean arterial pressure and heart rate showed no significant differences within or among groups. The preischemic administration of olprinone significantly reduced the infarct size (12 +/- 4%) as compared with that in the control group (43 +/- 4%). Wortmannin or atractyloside abolished the protective effect of olprinone (42 +/- 11% or 41 +/- 10%). CONCLUSION: The olprinone-induced cardioprotective effect could be exerted via the activation of PI3K-Akt and the inhibition of mPTP during early reperfusion.

Milrinone administered before ischemia or just after reperfusion, attenuates myocardial stunning in anesthetized swine.

PURPOSE: We assessed the dose or timing effect of milrinone administered against myocardial stunning in 37 anesthetized open-chest swine. METHODS: All swine were subjected to 12-min ischemia followed by reperfusion to produce myocardial stunning. Group A (n = 12) received saline in place of milrinone both before and after ischemia. Group B (n = 9) and C (n = 9) received intravenous milrinone at a rate of 5 microg/kg/min for 10 min followed by 0.5 microg/kg/min for 10 min and 10 microg/kg/min for 10 min followed by 1 microg/kg/min for 10 min, respectively, until 30 min before coronary occlusion. Group D (n = 7) received the same dose of milrinone as group B starting 1 min after reperfusion. Myocardial contractility was assessed by percentage segment shortening (%SS). RESULTS: Five swine in group A and two swine in groups B and C each had ventricular fibrillation or tachycardia after reperfusion, and were thus excluded from further analysis. The percentage changes of %SS from the baseline 90 min after reperfusion in groups B, C, and D were 78 +/- 9%, 82 +/- 13%, and 79 +/- 7%, respectively, which were significantly higher than those in group A (43 +/- 13%). CONCLUSION: We conclude that milrinone administered before ischemia or just after reperfusion attenuates myocardial stunning.

Negative inotropic action of propofol is enhanced in the acute ischemic myocardium of dogs.

PURPOSE: We investigated the effects of propofol on contractility and oxygen balance in acute ischemic myocardium and compared them with those of normal myocardium using a coronary microembolization model in dogs. METHODS: In open-chest dogs, the left anterior descending coronary artery (LAD) was perfused through an extracorporeal bypass from the carotid artery. Regional myocardial contractility and myocardial oxygen balance were evaluated along with segment shortening (%SS), regional myocardial oxygen consumption (MVO2), and lactate extraction ratio (LER) of the area perfused by the LAD. Acute ischemia was produced by repeated injection of microspheres into the LAD-perfused area until %SS decreased by 50% of baseline. RESULTS: In normal myocardium, intracoronary infusion of propofol at doses of 1.2 and 2.4 mg x kg(-1) x h(-1) caused slight decreases in %SS to 83% +/- 8% and 80% +/- 10%, respectively. In ischemic myocardium, propofol caused greater decreases in %SS (59% +/- 18% and 35% +/- 20%, respectively). The changes in MVO2 after propofol infusion generally paralleled the changes in %SS, but LER was not changed in either ischemic or normal myocardium. CONCLUSION: Propofol causes a greater decrease in the contractility of acute ischemic myocardium as compared with normal myocardium in which myocardial oxygen imbalance is not involved as a mechanism.

Droperidol attenuates contractile and phosphatidylinositol responses of rat trachea.

Droperidol attenuates airway smooth muscle contraction. However, the intracellular mechanisms involved in the droperidol-induced attenuation of airway smooth muscle contraction are not fully understood. We examined the effects of droperidol on contractile and phosphatidylinositol responses of the rat trachea. Droperidol dose dependently attenuated carbachol (CCh) induced tracheal ring contractions. The IC(50) of droperidol on CCh-induced tracheal ring contraction was 13 +/- 2 micromol/l. Droperidol attenuated CCh and aluminum fluoride stimulated inositol monophosphate accumulation. These results suggest that droperidol inhibits G protein coupled phospholipase C, resulting in attenuation of CCh-induced phosphatidylinositol response and subsequent attenuation of contractions of the rat trachea.

JTV-506, a new K(ATP) channel opener, relaxes pulmonary artery isolated from monocrotaline-treated pulmonary hypertensive rats.

PURPOSE: Vasodilators are considered effective in the treatment of pulmonary hypertension if the vascular reactivity remains reversible. This study was designed to investigate the possibility that JTV-506, a new adenosine trisphoshate-sensitive potassium channel opener, may serve as a useful vasodilator in the treatment of pulmonary hypertension. METHODS: After approval by the animal care committee, with the use of the isometric-force recording method, the effects of JTV-506 (1 nM-100 micro M) on the contractile response to norepinephrine (0.1 micro M) were examined in pulmonary arteries isolated from monocrotaline (MCT)-treated (i.e., presumed pulmonary hypertensive) and age-matched control rats. The experiments were performed in the presence of endothelium with or without treatment with N(G)-nitro- l-arginine (L-NAME, 100 micro M), and in its absence. RESULTS: JTV-506 relaxed ( P < 0.05) norepinephrine-preconstricted, endothelium-intact arteries from MCT-treated and control rats. However, the vasorelaxation was greater ( P < 0.05) in the arteries from MCT-treated rats than in controls. L-NAME treatment attenuated ( P < 0.05) vasorelaxation in the arteries from both MCT-treated and control rats. However, endothelial removal attenuated ( P < 0.05) vasorelaxation only in the arteries from MCT-treated rats and not in control arteries. CONCLUSION: JTV-506 may possibly attenuate pulmonary vascular tone through its direct action on vascular smooth muscle cells. In the presence of MCT-induced pulmonary hypertension, JTV-506 may further attenuate pulmonary vascular tone through its direct action on endothelial cells, possibly by stimulating the endothelial release of NO.