Pulmonary Arterial Response Research Articles

Mitochondrial ROS-PKCε signaling axis is uniquely involved in hypoxic increase in [Ca 2+] i in pulmonary artery smooth muscle cells

The molecular mechanisms underlying hypoxic responses in pulmonary and systemic arteries remain obscure. Here we for the first time report that acute hypoxia significantly increased total PKC and PKCε activity in pulmonary, but not mesenteric arteries, while these two tissues showed comparable PKCε protein expression and activation by the PKC activator phorbol 12-myristate 13-acetate. Hypoxia induced an increase in intracellular reactive oxygen species (ROS) generation in isolated pulmonary artery smooth muscle cells (PASMCs), but not in mesenteric artery SMCs. Inhibition of mitochondrial ROS generation with rotenone, myxothiazol, or glutathione peroxidase-1 overexpression prevented hypoxia-induced increases in total PKC and PKCε activity in pulmonary arteries. The inhibitory effects of rotenone were reversed by exogenous hydrogen peroxide. A PKCε translocation peptide inhibitor or PKCε gene deletion decreased hypoxic increase in [Ca 2+] i in PASMCs, whereas the conventional PKC inhibitor GÖ6976 had no effect. These data suggest that acute hypoxia may specifically increase mitochondrial ROS generation, which subsequently activates PKC, particularly PKCε, contributing to hypoxia-induced increase in [Ca 2+] i and contraction in PASMCs.

Superoxide Dismutase Improves Oxygenation and Reduces Oxidation in Neonatal Pulmonary Hypertension

Hyperoxic ventilation in the management of persistent pulmonary hypertension of the newborn (PPHN) can result in the formation of reactive oxygen species, such as superoxide anions, which can inactivate nitric oxide (NO) and cause vasoconstriction and oxidation. To compare the effect of intratracheal recombinant human superoxide dismutase (rhSOD) and/or inhaled NO (iNO) on systemic oxygenation, contractility of pulmonary arteries (PAs), and lung reactive oxygen species (isoprostane, 3-nitrotyrosine) levels in neonatal lambs with PPHN. Six newborn lambs with PPHN (induced by antenatal ductal ligation) were killed at birth. Twenty-six PPHN lambs were ventilated for 24 h with 100% O(2) alone (n = 6) or O(2) combined with rhSOD (5 mg/kg intratracheally) at birth (n = 4), rhSOD at 4 h of age (n = 5), iNO (20 ppm, n = 5), or rhSOD + iNO (n = 6). Contraction responses of fifth-generation PAs to norepinephrine and KCl, lung isoprostane levels, and 3-nitrotyrosine fluorescent intensity were measured. Systemic oxygenation was impaired in PPHN lambs and significantly improved (up to threefold) in both rhSOD groups with or without iNO. Oxygenation improved more rapidly with the combination of rhSOD + iNO compared with either intervention alone. Norepinephrine- and KCl-induced contractions and lung isoprostane levels were significantly increased by 100% O(2) compared with nonventilated newborn lambs with PPHN. Both rhSOD and iNO mitigated the increased PA contraction response and lung isoprostane levels. Intratracheal rhSOD decreased the enhanced lung 3-nitrotyrosine fluorescence observed with iNO therapy. Intratracheal rhSOD and/or iNO rapidly increase oxygenation and reduce both vasoconstriction and oxidation in newborn lambs with PPHN. This has important implications for clinical trials of rhSOD and iNO in newborn infants with PPHN.

Influence of physical preconditioning on the responsiveness of rat pulmonary artery after pulmonary ischemia/reperfusion

The aim of this work was to evaluate the effect of physical preconditioning in the responsiveness of rat pulmonary rings submitted to lung ischemia/reperfusion (IR). Wistar rats were divided into three groups: Sedentary sham-operated (SD/SHAM); sedentary submitted to ischemia/reperfusion (SD/IR) and trained submitted to ischemia/reperfusion (TR/IR) animals. Exercise training consisted in sessions of 60 min/day running sessions, 5 days/week for 8 weeks. Left pulmonary IR was performed by occluding for 90 min and reperfusing for 120 min. After that, pulmonary arteries were isolated and concentration-response curves to acetylcholine (ACh), histamine (HIST), sodium nitroprusside (SNP), phenylephrine and U46619 were obtained. Neither potency (-log EC(50)) nor maximal responses (E(max)) were modified for ACh and HIST in all groups. On the other hand, the potency for SNP was significantly increased in TR/IR group (8.23+/-0.06) compared to SD/IR group (7.85+/-0.04). Contractile responses mediated by a-adrenergic receptor were markedly decreased in IR groups (SD/IR: 6.75+/-0.06 and TR/IR: 6.62+/-0.04) compared to SD/SHAM (7.33+/-0.05). No changes were seen for the U46619 in all groups. In conclusion, the present study shows that exercise training has no protective actions in the local blood vessel where the IR process takes place.

COUNTERPOINT: HYPOXIC PULMONARY VASOCONSTRICTION IS NOT MEDIATED BY INCREASED PRODUCTION OF REACTIVE OXYGEN SPECIES

The acute hypoxic pulmonary vasoconstriction (HPV) that we discuss in this debate involves rapid constriction of small pulmonary arteries in response to physiological levels of alveolar hypoxia. HPV starts within seconds of the onset of hypoxic ventilation and we focus on the early events before

OC38: Preventive collagen plugging of fetal membrane defects following fetoscopic endoluminal tracheal occlusion (FETO)

significant. In 4 fetuses, the hyperoxygenation test was reactive before and remained so after balloon removal. Out of these 4, 3 survived. However in one baby, a reactive test became non-reactive and this baby died of pulmonary hypoplasia. In 2 patients a nonreactive test became reactive, and both babies survived. In 4 patients a non-reactive test remained non-reactive; 1 survived. Conclusion: There is no strict relation between in utero reversal of TO at 34 weeks and the reactivity of the contralateral fetal pulmonary artery to oxygen. Fetuses undergoing FETO who have a reactive test at any stage prior to birth were more likely to survive (5/7). A negative test prior to birth was predictive of neonatal death (3/4 neonatal deaths). Additional data are required certainly in function of prediction of pulmonary hypertension.

OC37: The hyperoxygenation test for fetal pulmonary artery reactivity before and after in utero unplugging in fetuses with severe congenital diaphragmatic hernia that underwent fetoscopic endoluminal tracheal occlusion

OC37: The hyperoxygenation test for fetal pulmonary artery reactivity before and after <i>in utero</i> unplugging in fetuses with severe congenital diaphragmatic hernia that underwent fetoscopic endoluminal tracheal occlusion

Pulmonary Artery Adventitial Fibroblasts Cooperate with Vasa Vasorum Endothelial Cells to Regulate Vasa Vasorum Neovascularization: A Process Mediated by Hypoxia and Endothelin-1

The precise cellular and molecular mechanisms regulating adventitial vasa vasorum neovascularization, which occurs in the pulmonary arterial circulation in response to hypoxia, remain unknown. Here, using a technique to isolate and culture adventitial fibroblasts (AdvFBs) and vasa vasorum endothelial cells (VVECs) from the adventitia of pulmonary arteries, we report that hypoxia-activated pulmonary artery AdvFBs exhibited pro-angiogenic properties and influenced the angiogenic phenotype of VVEC, in a process of cell-cell communication involving endothelin-1 (ET-1). We demonstrated that AdvFBs, either via co-culture or conditioned media, stimulated VVEC proliferation and augmented the self-assembly and integrity of cord-like networks that formed when VVECs where cultured on Matrigel. In addition, hypoxia-activated AdvFBs produced ET-1, suggesting a paracrine role for this pro-angiogenic molecule in these processes. When co-cultured on Matrigel, AdvFBs and VVECs self-assembled into heterotypic cord-like networks, a process augmented by hypoxia but attenuated by either selective endothelin receptor antagonists or oligonucleotides targeting prepro-ET-1 mRNA. From these observations, we propose that hypoxia-activated AdvFBs exhibit pro-angiogenic properties and, as such, communicate with VVECs, in a process involving ET-1, to regulate vasa vasorum neovascularization occurring in the adventitia of pulmonary arteries in response to chronic hypoxia.

Porcine Pulmonary Artery and Bronchial Responses to Endothelin-1 and Norepinephrine on Recovery from Hypoxic Pulmonary Hypertension

Many infants recovering from acute lung disease and pulmonary hypertension still have evidence of reactive airways disease at one year of age, suggesting longer-term airway effects. We hypothesized that parallel changes in smooth muscle would occur in airways and pulmonary arteries from animals with pulmonary hypertension and during normoxic recovery. Thus, two-hour-old piglets were subjected to 3 d chronic hypobaric hypoxia and 3-d-old piglets were subjected to 11 d hypoxia. Some animals were allowed to recover in room air for 3 or 6 d. The amount of smooth muscle and responses of isolated paired bronchial and pulmonary artery rings to endothelin-1 (ET-1) and norepinephrine were studied at the end of hypoxic exposure, on recovery and in age-matched control animals. In all hypoxia induced pulmonary hypertensive animals, smooth muscle area and ET-1 contractile response was increased in the pulmonary arteries and bronchi. Norepinephrine-induced relaxant response was impaired significantly in both bronchi and pulmonary arteries. After 3 d recovery, pulmonary arterial smooth muscle area decreased by 65%, and ET-1-induced contractile responses were normal for age. In the airways, ET-1 contractile response only normalized after six days and bronchial smooth muscle was still increased. After 6 d recovery pulmonary arterial norepinephrine-induced relaxant response had returned to normal, but bronchial response remained impaired. Thus during pulmonary hypertension, both bronchial and pulmonary arterial smooth muscle area and contractile responses are increased. On recovery, regression of bronchial structural and functional abnormalities is slower than in pulmonary arteries.

β-Adrenoceptor mediated responses in rat pulmonary artery: putative role of TASK-1 related K channels

The effect of isoprenaline on tone, cyclic adenosine 3':5' monophosphate (cAMP), and smooth muscle membrane potential (E ( m )) were assessed in rat isolated pulmonary arteries. N(omega)-nitro-L-arginine methyl ester (10.0 microM) or removal of endothelium partially inhibited relaxant responses to isoprenaline, but glibenclamide (10.0 microM) and indomethacin (10.0 microM) did not. While Rp-8-Br-cAMP (30.0 microM), tetraethylammonium (0.3 & 1.0 mM), 4-aminopyridine (100 microM), anandamide (10.0 microM), charybdotoxin (0.1 microM), ouabain (100 microM), and barium chloride (100 microM), incompletely blocked relaxation to isoprenaline, cyclopiazonic acid (1.0 microM), apamin (3.0 microM) and zinc acetate (300 microM) were without effect. Increasing extracellular K(+) ([K(+)](e)) inhibited relaxant responses to isoprenaline, completely abolishing the response at 30 mM [K+](e). Vasorelaxant effects of isoprenaline were significantly attenuated in buffer pH 6.4, and concomitant presence of Rp-8-Br-cAMP (30.0 microM) in pH 6.4 produced significant additive inhibition when compared to pH 6.4 without Rp-8-Br-cAMP. Isoprenaline increased cAMP turnover (1.55+/-0.24 fold; mean +/- SEM), which was inhibited by propranolol (1.0 microM). Resting E ( m ) of smooth muscle cells was -63.0+/-0.50 mV, and isoprenaline (1.0 microM) produced hyperpolarisation (-73.3+/-0.80 mV). While glibenclamide failed to affect isoprenaline-induced hyperpolarisation, ICI 118,551 (1.0 microM), anandamide or buffer pH 6.4 prevented it, and barium chloride and oubain combined caused partial inhibition. Isoprenaline-mediated relaxation seems to arise from several processes, including the generation of nitric oxide, the cAMP-cascade and, more importantly, a hyperpolarisation that is not due to activation of ATP-sensitive K channels but possibly of two-pore domain K channels of the TASK family.

Ovine bronchial-derived relaxing factor: changes with development and hyperoxic ventilation

Recent studies suggest that a bronchial-derived relaxing factor (BrDRF) decreases the contractility of newborn, but not fetal, rat pulmonary arteries (PAs) by a nitric oxide (NO)-mediated mechanism. We studied the effect of an adjacent bronchus on PA contractility to norepinephrine (NE) in late-gestation fetal (n = 7), neonatal (1 day old, n = 9), ventilated neonatal (24-h ventilation from birth with 100% oxygen, n = 9), and adult sheep (n = 6) in the presence and absence of the NO synthase inhibitor N(omega)-nitro-l-arginine (l-NNA). The sheep were anesthetized and killed, and fifth-generation PA rings with and without an attached adjacent bronchus (PA+Br) were contracted in standard tissue baths with NE (10(-8)-10(-6) M). NE contractions were expressed as fraction of KCl (118 mM) contraction and as grams of contraction force. NE contractions were significantly diminished by the presence of an attached bronchus in the neonatal and ventilated neonatal and adult, but not fetal, lambs. Hyperoxic ventilation markedly increased NE contractions in PA and PA+Br. l-NNA significantly enhanced NE contractions in PA+Br in postnatal but not in fetal lambs. Pretreatment with l-NNA abolished the difference between NE contractions in PA and PA+Br in neonatal but not in hyperoxic ventilated neonatal lambs. We conclude that there is a BrDRF that is developmentally regulated and has vascular activity postnatally but not during fetal life. The effect of BrDRF is predominantly mediated by NO in air-breathing neonatal lambs but may involve a second non-NO mediator following hyperoxic ventilation. We speculate that BrDRF may have an important role in postnatal changes in pulmonary arterial reactivity.

Homocysteine-induced changes in vascular reactivity of guinea-pig pulmonary arteries: Role of the oxidative stress and poly (ADP-ribose) polymerase activation

This study was aimed to examine the effects of homocysteine (Hcy) on vascular responsiveness of guinea-pig isolated pulmonary arteries and to investigate possible underlying mechanisms. In order to evaluate vascular reactivity, isometric tension studies were performed in response to potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP). Incubation of pulmonary artery rings with Hcy (10 −3 M, 180 min) resulted in significant inhibition of response to ACh (an endothelium-dependent vasodilator)( E max: 55.3±6.7 vs. 13.1±2.0 *, P<0.05) while SNP (an endothelium-independent vasodilator)-induced relaxation was not changed significantly. Furthermore, Hcy enhanced KCl- and Phe-induced contraction of pulmonary artery rings ( E max: 1568±81 vs. 2101±145 * mg for KCl and 1081±101 vs. 1544±117 * mg for Phe, P<0.05). Pulmonary artery ring contractions induced by stepwise addition to Ca 2+ to high KCl solution with no Ca 2+ were also significantly augmented by Hcy incubation ( E max: 1750±121 vs. 2295±134 * mg, P<0.05). To investigate mechanisms of Hcy action, additional sets of experiments involving rings incubation with Hcy alone or with addition of Tiron (an intracellular superoxide anion scavenger, 10 −2 M), PJ34 (an inhibitor of polyADP-ribose polymerase, 3×10 −6 M), and combination of two antioxidant enzymes superoxide dismutase (SOD, 100 U/ml) and catalase (CAT, 120 U/ml) for 180 min. The findings of our study clearly show that all these co-treatments significantly prevented the development of endothelial dysfunction induced by Hcy. Furthermore, the effect of Hcy on KCl- and Phe-induced contraction was significantly inhibited by the concomitant incubation with either SOD plus CAT, Tiron or PJ34. This study demonstrates that Hcy causes a significant alteration in vascular reactivity of pulmonary arteries, and this alteration seems to be via oxidative stress in pulmonary artery endothelium with subsequent DNA damage and activation of poly(ADP-ribose) polymerase (PARP) pathway.

Effect of propofol and etomidate on normoxic and chronically hypoxic pulmonary artery

BackgroundChronic alveolar hypoxia results in sustained arterial constriction, and increase in pulmonary vascular resistance leading to pulmonary artery hypertension (PAHT). The aim of this study was to investigate the effect of propofol and etomidate on pulmonary artery (PA) reactivity in chronically hypoxic (CH) rats, a model of pulmonary arterial hypertension (PAHT), in normoxic animals, and human PA.MethodsCH rats were maintained 14 days at 380 mmHg pressure in a hypobaric chamber. Human tissue was retrieved from histological lung pieces from patients undergoing resection for carcinoma. Cumulative concentrations of anaesthetics were tested on isolated vascular rings precontracted with phenylephrine (PHE) or 100 mM KCl. Statistical comparisons were done by ANOVA, followed, when needed, by Student t tests with Bonferroni correction as post-hoc tests.ResultsIn normoxic rat PA, maximal relaxation (Rmax) induced by etomidate and propofol was 101.3 ± 0.8% and 94.0 ± 2.3%, respectively, in KCl-precontracted rings, and 63.3 ± 9.7% and 46.1 ± 9.1%, respectively, in PHE-precontracted rings (n = 7). In KCl-precontracted human PA, Rmax was 84.7 ± 8.6 % and 66.5 ± 11.8%, for etomidate and propofol, respectively, and 154.2 ± 22.4 % and 51.6 ± 15.1 %, respectively, in PHE-precontracted human PA (n = 7). In CH rat PA, the relaxant effect of both anaesthetics was increased in PHE-precontracted and, for etomidate only, in KCl-precontracted PA. In aorta, CH induced no change in the relaxant effect of anaesthetics.ConclusionPropofol and etomidate have relaxant properties in PA from human and normoxic rat. The relaxant effect is specifically accentuated in PA from CH rat, mainly via an effect on the pharmacomechanical coupling. Etomidate appears to be more efficient than propofol at identical concentration, but, taking into account clinical concentrations, etomidate is less potent than propofol, which effect was in the range of clinical doses. Although these findings provide experimental support for the preferential use of etomidate for haemodynamic stability in patients suffering from PAHT, the clinical relevance of the observations requires further investigation.

The Acute Responses of Coronary and Pulmonary Arteries to Natural Steroids

The purpose of this study was to characterize the vascular responses of coronary and pulmonary arteries to naturally occurring androgens and to test the hypothesis that the vascular responses will vary depending on the androgen and anatomical source of the artery. Segments of porcine coronary and pulmonary arteries were dissected, mounted in isolated tissue baths, and administered increasing concentrations of androstenedione (ANDRO), dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), or testosterone (TES) following constriction with 10 μM prostaglandin F2α. DHT and TES caused a significant relaxation in coronary and pulmonary arteries. The responses to DHT and TES were significantly greater than the responses to ANDRO and DHEA in coronary arteries. In the pulmonary arteries, all androgens caused a significant relaxation at high concentrations. Pulmonary arteries exhibited greater relaxations to DHEA than coronary arteries. The results of these studies indicate that the vascular responses to androgens vary depending on the androgen and anatomical source of the artery. This study was supported by a Student Summer Scholars grant at Grand Valley State University.

High Flow Attenuates Reactivity of Porcine Pulmonary Arteries to Phenylephrine and U‐46619

A model has been developed in vivo to study the effects of high blood flow on the pulmonary vasculature. Briefly, the branch of the pulmonary artery (PA) of 3-4 week old piglets, which supplies the left lower lobe of the lung is anastamosed end-to-side to the aorta to substantially increases the flow (3 fold) to this lobe. Branches of the PA (1-2 mm diameter) harvested from this lobe can be compared to vessels in the contralateral lobe to determine the effects of flow on signaling pathways. Constriction in response to the thromboxane mimetic, U-46619 (10−7 M, n=8) and phenylephrine (10−5 M, n=8) is blunted (p<.05 for both agonists) in vessels exposed to high flow for 72 hours. Application of the eNOS inhibitor L-NMMA (10−3 M) or two different rho-kinase inhibitors (Y-27632, 10−4 M or HA-1077, 10−5 M) altered contractility but did not significantly alter the difference in reactivity between shunted vessels versus controls. Preliminary results suggest that a combination of inhibitors of arachidonic acid metabolism that block cyclooxygenases (indomethacin, 100 μM), cytochrome P450 enzymes (DDMS, 10 μM) and lipoxygenases (NDGA, 20 μM) eliminate the difference in contractility produced by U46619. Our results demonstrate that high flow reduces reactivity in pulmonary arteries within 48-72 hours, which does not appear to be due to changes in the eNOS or Rho kinase signaling pathways. However, the decrease in contractility induced by high flow may be due to changes in arachidonic acid metabolism. This work is supported by NHLBI 68627, 49294 and 69996.

Influence of pretone agents on calcium release and influx pathways during HPV

Hypoxic pulmonary vasoconstriction (HPV) is the response of small pulmonary arteries to acute moderate hypoxia. Although HPV has been extensively investigated, the underlying mechanisms and their relative contributions are still largely controversial, possibly due to differences in experimental conditions. However, there is wide agreement that Ca2+ release from the SR and influx of extracellular Ca2+ are crucial for the development of HPV. We have therefore investigated the contribution of these pathways to HPV with PGF2α and high K+ as pretone agents in isolated rat small pulmonary arteries mounted on a small vessel myograph. In vessels preconstricted with PGF2αphase 1 of HPV was not significantly altered by inhibition of ryanodine receptors with dantrolene (50 μM) and ryanodine (100 μM) or by the TRPC modulator flufenamic acid (FFA, 2 μM), but blocked by store depletion with low ryanodine (1 μM) and caffeine (10 mM), inhibition of store-operated Ca2+ entry with 2-APB (75 μM) and Ca2+ substitution with 4 mM Sr2+. Combined treatment of 2-APB with diltiazem (10 μM) blocked phase 1 significantly. Phase 2 was greatly inhibited by dantrolene, ryanodine (100 μM), 2-APB, 2-APB + diltiazem and Sr2+, but not altered by low ryanodine or FFA. However, when vessels were preconstricted with K+, dantrolene and 2-APB did not attenuate, Ca2+ substitution with Sr2+ inhibited and FFA (2 μM) increased HPV. We therefore conclude that the pathways involved in the development of HPV are dependent on the pretone agent used. It is highly likely that at least some of the discrepancies of earlier studies may be due to differences in the experimental conditions used. Sponsored by the BHF

The Obese Zucker Rat is Not a Model of Obesity‐Associated Pulmonary Hypertension

Obesity is often associated with the development of pulmonary hypertension and right-heart failure. The increased pulmonary vascular resistance is associated with elevated vasoconstriction and arterial medial thickening. To date, normal lean animals exposed to intermittent bouts of hypoxia, mimicking sleep apnea, have been used as a model of obesity-associated pulmonary hypertension. This model ignores the milieu of metabolic abnormalities associated with obesity, which may play a role in the pulmonary hypertension associated with obesity. The obese Zucker rat exhibits obesity, Type 2 diabetes, and systemic hypertension. Therefore we hypothesized that the obese Zucker rat would be an ideal model of obesity-associated pulmonary hypertension. To this end, small pulmonary arterial vasoconstrictor reactivity, medial hypertrophy, and right ventricular weight were determined in male 16–18 wk old lean and obese Zucker rats. Vasoconstrictor reactivity to Uridine 5′ triphosphate in small pulmonary arteries was similar between lean and obese rats. Contrary to our hypothesis medial wall thickness was significantly thinner in 20–60 μm arterioles from obese animals as compared to lean animals. For 60–100 μm and 100–200 μm arterioles, there were no significant differences in medial wall thickness between groups. The right ventricular/total heart weight ratio was similar between groups. These results suggest that the obese Zucker rat may not be an appropriate model for obesity-associated pulmonary hypertension. This work was supported by NIH F32HL082438 and NIH HL-51971 and HL 63958

Prostanoid production and pulmonary arterial responses to reactive oxygen species (ROS) are altered in newborn piglets with chronic hypoxia‐induced pulmonary hypertension

Prostanoid production and pulmonary arterial responses to reactive oxygen species (ROS) are altered in newborn piglets with chronic hypoxia‐induced pulmonary hypertension

Analysis of Responses to Kava Kava in the Feline Pulmonary Vascular Bed

This study was designed to test the hypothesis that kava kava induces a depressor response in the pulmonary vascular bed of the cat and to identify the pathways involved in the mediation or modulation of these effects. In separate experiments, the effects of L-N5-(1-iminoethyl)ornithine hydrochloride (L-NIO), a nitric oxide synthase inhibitor, glibenclamide, an ATP-sensitive K+ channel blocker, meclofenamate, a nonselective cyclooxygenase inhibitor, nicardipine, a calcium channel blocker, bicuculline, a gamma-aminobutyric acid (GABA)A receptor antagonist, and saclofen, a GABAB antagonist, were investigated on pulmonary arterial responses to kava kava (kava), pinacidil, an ATP-sensitive K+ channel activator, bradykinin, an inducer of nitric oxide synthase, 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF-97541), a GABAB receptor agonist, and muscimol, a GABAA receptor agonist. Lobar arterial perfusion pressure and systemic pressure were continuously monitored, electronically averaged, and recorded. Under elevated tone conditions in the isolated left lower lobe of the feline vascular bed, kava induced a dose-dependent vasodepressor response that was not significantly altered after administration of L-NIO, glibenclamide, meclofenamate, or saclofen. Responses to kava were significantly reduced after administration of either nicardipine or bicuculline. When the calcium channel blocker nicardipine was administered in addition to the GABA blocker bicuculline, there was near complete attenuation of the kava-induced vasodepressor responses. The results of this investigation suggest that kava has potent vasodepressor activity in the feline lung bed and that this response is mediated or modulated by both a calcium channel- and GABA receptor-sensitive pathway.

The effects of sufentanil in the feline pulmonary vascular bed

The purpose of this prospective vehicle controlled study was to test the hypothesis that sufentanil induces a depressor response in the pulmonary vascular bed of the cat and identify the receptors involved in the mediation or modulation of these effects. In separate experiments, the effects of diphenydramine (histamine receptor blocker), glibenclamide (ATP-sensitive K+ channel blocker), l- N 5-(1-Iminoethyl) ornithine hydrochloride ( l-NIO) (nitric oxide synthase inhibitor), nimesulide (selective cyclooxygenase (COX)-2 inhibitor), and naloxone (opiate receptor antagonist) were investigated on pulmonary arterial responses to sufentanil and other agonists in the feline pulmonary vascular bed. The lobar arterial perfusion pressures were continuously monitored, electronically averaged, and recorded. In the feline pulmonary vascular bed of the isolated left lower lobe, sufentanil induced a dose-dependent vasodepressor response that was not significantly altered after administration of glibenclamide, l-NIO, and nimesulide. However, the responses to sufentanil were significantly attenuated following administration of diphenhydramine and naloxone. The results of the present study suggest that sufentanil has potent vasodepressor activity in the pulmonary vascular bed of the cat and that this response may be mediated or modulated by both histaminergic and opioid receptor sensitive pathways.

The Effects of Meperidine in the Pulmonary Vascular Bed of the Cat

The purpose of this study was to test the hypothesis that meperidine induces a dilator response in the feline pulmonary vascular bed, and to identify receptors involved in the mediation or modulation of these effects. Prospective vehicle controlled study. University research laboratory. Intact chest preparation; adult mongrel cats. In separate experiments, the effects of diphenydramine (histamine H(1)-receptor antagonist), glibenclamide (adenosine triphosphate-sensitive K+ channel blocker), L-N(5)-(1-Iminoethyl) ornithine hydrochloride (L-NIO) (nitric oxide synthase inhibitor), naloxone (opioid receptor antagonist), and nimesulide (selective cyclooxygenase-2 inhibitor) were investigated on pulmonary arterial responses to meperidine and other agonists in the feline lung bed. The systemic pressure and lobar arterial perfusion pressure were continuously monitored, electronically averaged, and permanently recorded. Under elevated tone conditions in the isolated left lower lobe vascular bed of the cat, meperidine induced a dose-dependent vasodilator response that was not significantly altered after administration of glibenclamide, L-NIO, and nimesulide. Responses to meperidine were significantly attenuated after the administration of diphenydramine and naloxone. The results suggest that meperidine has potent vasodilator activity in the feline pulmonary vascular bed, and these responses are mediated or modulated, in part, by opioid and histamine receptor-sensitive pathways.