Hypoxic Pulmonary Vasoconstriction In Rats Research Articles

Vagotomy Improves Hypoxic Pulmonary Vasoconstriction in Rats Subjected to Brain Ischemia-Reperfusion Injury.

Background: Pulmonary dysfunction is one of the critical complications of a stroke. However, it remains unclear whether the mechanism is caused by either neurogenic or inflammatory reactions. The present study aimed to determine the effect of cerebral ischemia-reperfusion injury and the role of the vagus nerve on hypoxic pulmonary vasoconstriction (HPV) in rats.Methods: This study was performed at Shiraz University of Medical Sciences, Shiraz, Iran, 2018. Male Sprague Dawley rats (n=56) were divided into four groups, namely the sham, vagotomy (Vag), 1 hour of ischemia followed by 23 hours of reperfusion without vagotomy (I/R) and with vagotomy (I/R+Vag). Neurological deficit scores and total infarct volumes of brains were measured in the I/R and I/R+Vag groups. Pulmonary artery pressure and lung weight were continuously registered during ventilation with normoxic and hypoxic gases in the isolated lungs. The blood gas parameters and the lung malondialdehyde (MDA) level of each group were also evaluated. ANOVA, with Tukey’s post hoc test and t test, was used to compare the variables in the experimental groups.Results: The infarct volume of the brains in the I/R and I/R+Vag groups were similar. HPV in the I/R group was lower than those in the sham and Vag groups, while vagotomy reversed this response in the I/R+Vag group (P=0.004). In the I/R group, PO2 and pH were lower, and PCO2 was higher than those in the sham and Vag groups. The lung MDA level in the I/R group was higher than that in the Vag group (P=0.019).Conclusion: Brain ischemia-reperfusion injury decreased HPV independent of increased MDA in the lung, whereas vagotomy improved HPV by repairing the blood-gas barrier and oxygen sensing.

Hypoxic pulmonary vasoconstriction is lacking in rats with type 1 diabetes.

Hypoxic pulmonary vasoconstriction (HPV) is the most important feature of intact lung circulation that matches local blood perfusion to ventilation. The main goal of this work was to study the effects of diabetes on the development of HPV in rats. The experimental design comprised diabetes mellitus induction by streptozotocin, video-morphometric measurements of the lumen area of intrapulmonary arteries (iPAs) using perfused lung tissue slices and patch-clamp techniques. It was shown that iPA lumen size was significantly reduced under physical and chemical hypoxia (7-10mm Hg) in normal iPA, but, on the contrary, it clearly increased in diabetic lung slices. The amplitude of the outward K+ current in diabetic iPAs smooth muscle cells (SMCs) was two-fold greater than that seen in healthy cells. Chemical hypoxia led to significant decrease in the amplitude of the K+ outward current in healthy iPA SMCs while it was without effect in diabetic cells. The data obtained clearly indicate a significant dysregulation of vascular tone in pulmonary circulation under diabetes, ie diabetes damages the adaptive mechanism for regulating blood flow from poorly ventilated to better ventilated regions of the lung under hypoxia. This effect could be clinically important for patients with diabetes who have acute or chronic lung diseases associated with the lack of blood oxygenation.

Oxygen-sensing in the Lung is Regulated by Mitochondrial Complex I Ndufs2: Role of Mitochondria-derived Hydrogen Peroxide in Hypoxic Pulmonary Vasoconstriction

Resistance pulmonary arteries (PA) constrict in response to alveolar hypoxia; conversely the systemic vasculature dilates. Hypoxic pulmonary vasoconstriction (HPV) matches ventilation to perfusion, optimizing systemic oxygen delivery. The core mechanism of HPV is intrinsic to pulmonary artery smooth muscle cells (PASMC) and involves mitochondrial electron transport chain (ETC)-mediated redox regulation of oxygen-sensitive ion channels culminating in increased cytosolic calcium ([Ca2+]i). However, the molecular identity of the mitochondrial O2-sensor and the mechanism by which it regulates vascular tone remains unknown. We hypothesize that the O2-sensor resides in ETC complex I and initiates HPV by varying H2O2 in proportion to PO2. The primary objective was to identify the mitochondrial redox O2-sensor. A secondary goal was identify the ETC-derived reactive oxygen species (ROS) that initiates HPV. Mitochondria were isolated from lungs or kidneys of adult male Sprague-Dawley rats, housed under conditions of normoxia or chronic hypoxia (FiO2 0.1 for 2-3 weeks). Mitochondria-conditioned media (MCM) was then infused into an isolated, perfused lung to examine the effects on HPV. The effects of acute hypoxia on mitochondrial-derived H2O2 and [Ca2+]i was assessed in PASMC using with a dynamic, mitochondria-targeted H2O2 probe and FURA2-AM, respectively. Immunocaptured ETC complex I from pulmonary and renal arterial SMCs was assessed by gel electrophoresis to identify differentially expressed subunits. HPV was attenuated by MCM from normoxic lung (nLM), but not MCM from chronically hypoxic lung or kidney. Catalase attenuated the effects of nLM. Acute hypoxia (~40 mmHg) decreased H2O2 within 112±7 seconds, followed, within 205±34 seconds, by increased [Ca2+]i. The expression of a Complex I subunit, NADH dehydrogenase [ubiquinone] iron-sulfur protein 2 (Ndufs2), was increased in PA versus renal artery SMC. siRNA knockdown of Ndufs2 (siNdufs2) decreased normoxic H2O2 levels and prevented hypoxia-induced increases in [Ca2+]i. Right heart catheterization and intravital microscopy demonstrated that in vivo nebulization of siNdufs2 selectively attenuated HPV in rats and mice. Mitochondrial-derived H2O2 originating from ETC Complex I in PASMC acts as a normoxic vasodilator. Acute hypoxia decreases this vasodilator, leading to HPV. Ndufs2 is a requisite component of the PASMC’s mitochondrial O2-sensor, and acts through its dynamic ability to regulate H2O2 production.

Macrophage migration inhibitory factor contributes to hypoxic pulmonary vasoconstriction in rats

BackgroundHypoxic pulmonary vasoconstriction may lead to pulmonary hypertension, but the underlying mechanisms of persistent vasoconstriction are still unclear. There is evidence that pulmonary inflammation contributes to the abnormalities of function in the pulmonary artery (PA) following chronic hypoxia exposure. Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine, and we found that expression of MIF was increased in the smooth muscle of PA from hypoxic pulmonary hypertensive rats. Therefore, the aim of the study was to investigate the role of MIF in modulating vasoreactivity of isolated PA rings. MethodsSprague–Dawley rats were challenged by intermittent chronic hypoxia exposure for 4weeks to establish hypoxic pulmonary hypertension models. Subsequently, immunohistochemistry and western blot assay were used to examine the MIF expression in pulmonary artery. Moreover, isometric force displacement was measured in isolated intrapulmonary artery. ResultsIn the isolated PA, our results showed that MIF mediated the enhanced pulmonary arterial vasoconstriction in response to chronic hypoxia, and the delayed hypoxic constriction in a biphasic pattern of constriction occurs in response to acute hypoxia. We also present the finding that MIF had no effect on force on its own, but concentration-dependently potentiated constrictions pre-evoked by phenylephrine under normoxic condition. The potentiation was independent of the endothelium. MIF-induced potentiation of phenylephrine-evoked constriction was partially inhibited by PKC inhibitor chelerythrine, p38 inhibitor SB 203580, ERK1/2 inhibitor U0126, respectively. ConclusionsOur results suggested that MIF enhanced vasoconstriction of pulmonary artery elicited by agonist through PKC, p38 and ERK1/2 signal pathways, which may contributes to hypoxic pulmonary vasoconstriction.

Role of arachidonic acid-derived metabolites in the control of pulmonary arterial pressure and hypoxic pulmonary vasoconstriction in rats

BackgroundThe roles of arachidonic acid (AA) metabolites in hypoxia-induced pulmonary vasoconstriction (HPV), a critical physiological mechanism that prevents ventilation/perfusion mismatch, are still incompletely understood. MethodsPulmonary arterial pressure was measured in ventilated/perfused rat lungs. Isometric tones of rat intralobar pulmonary arteries were also measured, using a myograph. ResultsHypoxia (Po2, 3%)-induced pulmonary arterial pressure increases (ΔPAPhypox) were stable with blood-mixed perfusate, but decayed spontaneously. ΔPAPhypox was inhibited by 29%, 16%, and 28% by the thromboxane A2 (TXA2) antagonist SQ-29548, the 5-lipoxygenase inhibitor, MK886, and the leukotriene D4 antagonist, LY-171883, respectively. The prostacyclin synthase inhibitor tranylcypromine augmented ΔPAPhypox by 5%, whereas inhibition of cytochrome P450 did not affect ΔPAPhypox. Consistently, the TXA2 analogue U46619 increased ΔPAPhypox whereas prostacyclin abolished ΔPAPhypox. However, leukotriene D4 had no direct effect on ΔPAPhypox. In the isolated pulmonary arteries, pretreatment with U46619 was essential to demonstrate hypoxia-induced contraction. ConclusionsThe above results suggest that TXA2 and cysteinyl leukotrienes, other than leukotriene D4, are endogenous factors that facilitate HPV in rats. The indispensable role of TXA2-induced pretone in the HPV of isolated pulmonary arteries indicates that the signal from thromboxane receptors might be a critical component of oxygen sensation mechanisms.

AMP-activated protein kinase and hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction is a vital homeostatic mechanism that aids ventilation–perfusion matching in the lung, for which the underlying mechanism(s) remains controversial. However, our most recent investigations strongly suggest that hypoxic pulmonary vasoconstriction is precipitated, at least in part, by the inhibition of mitochondrial oxidative phosphorylation by hypoxia, an increase in the AMP/ATP ratio and consequent activation of AMP-activated protein kinase (AMPK). Unfortunately, these studies lacked the definitive proof that can only be provided by selectively blocking AMPK-dependent signalling cascades. The aim of the present study was, therefore, to determine the effects of the AMPK inhibitor compound C upon: (1) phosphorylation in response to hypoxia of a classical AMPK substrate, acetyl CoA carboxylase, in rat pulmonary arterial smooth muscle and (2) hypoxic pulmonary vasoconstriction in rat isolated intrapulmonary arteries. Acetyl CoA carboxylase phosphorylation was increased approximately 3 fold in the presence of hypoxia ( pO 2 = 16–21 mm Hg, 1 h) and 5-aminoimidazole-4-carboxamide riboside (AICAR; 1 mM; 4 h) and in a manner that was significantly attenuated by the AMPK antagonist compound C (40 μM). Most importantly, pre-incubation of intrapulmonary arteries with compound C (40 μM) inhibited phase II, but not phase I, of hypoxic pulmonary vasoconstriction. Likewise, compound C (40 μM) inhibited constriction by AICAR (1 mM). The results of the present study are consistent with the activation of AMPK being a key event in the initiation of the contractile response of pulmonary arteries to acute hypoxia.

Superoxide dismutase mimetic tempol inhibits hypoxic pulmonary vasoconstriction in rats independently on either nitric oxide production or basal tone of pulmonary vessels

Hypoxic pulmonary vasoconstriction (HPV) is regulated by changes in the production of and interactions among reactive oxygen species (ROS). There is a controversy as to whether HPV is mediated by an increase or a decrease in ROS production. Also, the role of nitric oxide (NO) in HPV remains unclear. We investigated whether the inhibition of HPV by the antioxidant tempol was dependent on the concentration of NO, and how its effect was influenced by increased basal pulmonary vascular tone.In isolated rat lungs we measured vasoconstrictor responses to acute hypoxia before and after administration of tempol during perfusion with or without L‐NAME and after increase of basal vascular tone in the perfused lungs by increasing the potassium ion concentration in the perfusate by 15 mmol/l.Administration of tempol significantly decreased vasoconstriction response to acute hypoxic challenge both in controls (89% less) and in L‐NAME group (100% less), the vasoconstrictor response did not differ significantly between these groups. The administration of tempol significantly decreased HPV both in K+ treated (96% less) and in K+ non‐treated group (68% less), the vasoconstrictor response did not differ significantly between these groups.Inhibition of HPV by the SOD mimetic tempol does not depend on either NO production or basal tone of the pulmonary vessels.GACR 305/05/0672, GAUK 7415/2007

Superoxide dismutase mimetic tempol inhibits hypoxic pulmonary vasoconstriction in rats independently of nitric oxide production

Hypoxic pulmonary vasoconstriction (HPV), an important physiological mechanism, is regulated by changes in the production of and interactions among reactive oxygen species (ROS). There is controversy, however, over whether HPV is mediated by an increase or a decrease in ROS production. Also, the role of NO in HPV remains unclear. The aim of this study was to investigate whether the inhibition of HPV by the antioxidant tempol was dependent on the concentration of NO, and how its effect was influenced by increased basal pulmonary vascular tone. In isolated rat lungs, we measured vasoconstrictor responses to acute ventilatory hypoxia before and after administration of tempol during perfusion with or without L-NAME. We found that tempol abolished HPV independently of NO production. When we increased basal vascular tone by K(+)-induced depolarization, we also found that tempol completely inhibited HPV. Our results indicate that inhibition of HPV by the superoxide dismutase mimetic tempol does not depend on either NO production or a decrease in basal vascular tone.

Reduced Pulmonary Vascular Reactivity after Cold Exposure to Acute Hypoxia: A Role of Nitric Oxide (NO)

Exposure to high altitude causes pulmonary hypertension and alterations in pulmonary vascular reactivity. Among the environmental factors, cold exposure has been suggested to be involved in the development of pulmonary hypertension. However, little information is available about pulmonary vascular reactivity after cold exposure. We examined whether cold exposure can cause changes in pulmonary vascular reactivity to acute hypoxia and the possible participation of endogenous nitric oxide. We measured mean systemic (Psa) and pulmonary artery pressures (Ppa) in conscious rats after 1-week cold exposure (3.5 +/- 1.0 degrees C). Subsequently, we investigated hypoxic pulmonary vasoconstriction (HPV) with and without endogenous NO inhibition using N(G)-nitro-L-arginine methyl ester (3 mg/kg) or 7-nitroindazole (1 mg/kg). Cold exposure for 1 week caused a small but significant increase in Ppa, but not in Psa. Neither Ppa nor Psa showed significant changes after both NO inhibitions in rats exposed to cold. However, cold exposure caused a blunted HPV and an increase in plasma nitrite-nitrate concentration compared with rats kept in a neutral environment (24.0 +/- 1.0 degrees C). In addition, NO inhibition by N(G)-nitro-L-arginine methyl ester partially restored the blunted HPV in rats exposed to cold, but not 7-nitroindazole, a selective inhibitor of neuronal NO synthase. We concluded that cold exposure alters pulmonary vascular reactivity to acute hypoxia, and augmented endothelial NO bioactivity plays a counterregulatory role in response to acute hypoxia during cold exposure in rats.

Effects of Glibenclamide and L-NAME on Hypoxic Pulmonary Vasoconstriction in Rats

Effects of Glibenclamide and L-NAME on Hypoxic Pulmonary Vasoconstriction in Rats

Inhibition of K(Ca) channels restores blunted hypoxic pulmonary vasoconstriction in rats with cirrhosis.

Rats with liver cirrhosis exhibit the hepatopulmonary syndrome composed of blunted hypoxic pulmonary vasoconstriction and arterial hypoxemia. The purpose of this study was to investigate the roles of nitric oxide (NO) and endothelin-1 (ET-1) in the blunted hypoxic pressor response (HPR) in rats with common bile duct ligation (CBDL). Lungs from CBDL rats exhibited markedly blunted HPR, increased endothelial NO synthase (NOS) protein expression, and decreased ET-1 mRNA and peptide expression. The blunted HPR was not reversed by sequential NOS and soluble guanylyl cyclase inhibition by nitro-L-arginine and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), respectively, or by NOS inhibition combined with ET-1 addition. The blunted HPR was not due to a generalized inability to vasoconstrict because perfusion pressure was equally elevated by increased perfusate KCl in CBDL and sham lungs. After KCl vasoconstriction, HPR was potentiated and did not differ between CBDL and sham lungs. Blunted HPR was also completely restored in CBDL lungs treated with nitro-L-arginine, ODQ, and the Ca(2+)-activated K(+) channel blockers apamin and charybdotoxin. These results indicate that although CBDL-induced liver cirrhosis is associated with increased NO and decreased ET-1 in the lung, the blunted HPR is a result of additional factors and appears to involve Ca(2+)-activated K(+) channel activation.

Carbon monoxide inhibits hypoxic pulmonary vasoconstriction in rats by a cGMP-independent mechanism.

Hypoxia activates erythropoietin-producing cells, chemoreceptor cells of the carotid body and pulmonary artery smooth muscle cells (PSMC) with a comparable arterial PO2 threshold of some 70 mmHg. The inhibition by CO of the hypoxic responses in the two former cell types has led to the proposal that a haemoprotein is involved in the detection of the PO2 levels. Here, we report the effect of CO on the hypoxic pulmonary vasoconstriction (HPV). Pulmonary arterial pressure (PAP) was measured in an in situ, blood-perfused lung preparation. PAP in normoxia (20% O2, 5% CO2) was 15.2+/-1.8 mmHg, and hypoxia (2% O2, 5% CO2) produced a DeltaPAP of 6.3+/-0.4 mmHg. Addition of 8% or 15% CO to the hypoxic gas mixture reduced the DeltaPAP by 88.3+/-2.7% and 78.2+/-6.1% respectively. The same levels of CO did not affect normoxic PAP nor reduced the DeltaPAP produced by angiotensin II. The effect of CO was studied after inhibition of the NO-cyclic guanosine monophosphate (cGMP) cascade with N-methyl-l-arginine (5.10(-5) M) or methylene blue (1.4.10(-4) M). It was found that both inhibitors more than doubled the hypoxic DeltaPAP without altering the effectiveness of CO to inhibit the HPV. In in vitro experiments we verified the inhibition of guanylate cyclase by measuring the levels of cGMP in segments of the pulmonary artery. Cyclic GMP levels were 1.4+/-0.2 (normoxia), 2.5+/-0.3 (hypoxia) and 3.3+/-0.5 pmole/mg tissue (hypoxia plus 8% CO); sodium nitroprusside increased normoxic cGMP levels about fourfold. Methylene blue reduced cGMP levels to less than 10% in all cases, and abolished the differences among normoxic, hypoxic and hypoxic plus CO groups. It is concluded that CO inhibits HPV by a NO-cGMP independent mechanism and it is proposed that a haemoprotein could be involved in O2-sensing in PSMC.

Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats.

Nitric oxide (NO), a vasodilator involved in the regulation of pulmonary vascular tone, is synthesized by a family of enzymes, nitric oxide synthases (NOS). To investigate whether adenoviral-mediated overexpression of constitutive endothelial NOS (ceNOS) would attenuate hypoxic pulmonary vasoconstriction, we aerosolized 3 X 10(9) plaque forming units of a recombinant adenovirus containing the ceNOS gene (AdCMVceNOS) into rat lungs. Four days after infection, transgene expression was confirmed using immunoblot techniques. Diffuse ceNOS immunostaining was detected in alveoli and medium-sized and small pulmonary vessels of AdCMVceNOS-transduced lungs. AdCMVceNOS-transduction was associated with an 86% increase in [3H]arginine to [3H]citrulline conversion and a rise in pulmonary cGMP levels from 7 +/- 1 to 59 +/- 9 pmol/mg protein in lungs from AdCMVceNOS versus control rats, (P < 0.05). During acute hypoxia (FIO2 = 0.10) for 25 min, mean pulmonary artery pressure (PAP) increased significantly from 17 +/- 1 to 27 +/- 1 mmHg in rats aerosolized with saline (n = 4) and from 18 +/- 1 to 28 +/- 1 mmHg in rats given an adenoviral vector expressing a nuclear-targeted beta-galactosidase gene (AdCMV beta gal, n = 8). In contrast, in AdCMVceNOS-transduced rats (n = 8) the hypoxia-induced increase in PAP was significantly attenuated (18 +/- 1 to 23 +/- 2 mmHg). Systemic blood pressure was not affected by aerosol gene transfer. Thus, adenoviral-mediated ceNOS gene transfer to rat lungs increases ceNOS expression and activity, and reduces acute hypoxic pulmonary vasoconstriction. Aerosolized recombinant adenovirus overexpressing vasodilatory proteins can act as a selective pulmonary vasodilator and may hold promise as a future therapeutic strategy for pulmonary hypertension.

Effect of the Calcium Antagonist Amlodipine on the Two Phases of Hypoxic Pulmonary Vasoconstriction in Rat Large and Small Isolated Pulmonary Arteries

Calcium antagonists inhibit hypoxic pulmonary vasoconstriction (HPV), which was recently shown to be biphasic in isolated vessels, but the sensitivity of the two phases to calcium antagonism is unknown. We studied HPV in rat isolated large pulmonary arteries (PA) and resistance pulmonary arteries (PRV), using a small vessel myograph. Two phases of acute hypoxic pulmonary vasoconstriction were confirmed to occur in both sizes of vessel. The first phase was short-lived and was followed by a more persistent phase of gradual onset. The magnitude of the first phase of contraction was greater than the second (p < 0.01). The first phase was reproducible, but the second was variable. Tension generated per square millimeter of vessel during both phases of hypoxic contraction was significantly greater in PRV than in PA (p < 0.05). Amlodipine caused dose-dependent inhibition of the first phase of HPV (p = 0.01), with a greater effect in PRV (p < 0.01). The second phase was not significantly inhibited. These results confirm that HPV is biphasic in isolated large and small PA, with a greater sensitivity of the first phase to calcium antagonism. Therefore, the first phase may represent HPV as observed in vivo.

A Study of Endothelium-dependent Pulmonary Arterial Relaxation and the Role of Nitric oxide on Acute Hypoxic Pulmonary Vasoconstriction in Rats

Backgroud: Since the demonstration of the fact that vascular relaxation by acetylcholine(Ach) results from the release of relaxing factor from the endothelium, the identity and physiology of this endothelium-derived relaxing factor(EDRF) has been the target for many researches. EDRF has been identified as nitric oxide(NO). With the recent evidences that EDRF is an important mediator of vascular tone, there have been increasing interests in defining the role of the EDRF as a potential mediator of hypoxic pulmonary vasoconstriction. But the role of EDRF in modulating the pulmonary circulation is not compeletely clarified. To investigate the endothelium-dependent pulmonary vasodilation and the role of EDRF during hypoxic pulmonary vasoconstriction, we studied the effects of -monomethyl-L-arginine(L-NMMA) and L-arginine on the precontracted pulmonary arterial rings of the rat in normoxia and hypoxia. Mothods: The pulmonary arteries of male Sprague Dawley(300~350g) were dissected free of surrounding tissue, and cut into rings. Rings were mounted over fine rigid wires, in organ chambers filled with 20ml of Krebs solution bubbled with 95 percent oxygen and 5 percent carbon dioxide and maintained at . Changes in isometric tension were recorded with a force transducer(FT.03 Grass, Quincy, USA) Results: 1) Precontraction of rat pulmonry artery with intact endothelium by phenylephrine(PE, ) was relaxed completely by acetylcholine(Ach, ) and sodium nitroprusside(SN, ), but relaxing response by Ach in rat pulmonary artery with denuded endothelium was significantly decreased. 2) L-NMMA() pretreatment inhibited Ach()-induced relaxation, but L-NMMA () had no effect on relaxation induced by SN(). 3) Pretreatment of the L-arginine() significantly reversed the inhibition of the Ach ()-induced relaxation caused by L-NMMA() 4) Pulmonary arterial contraction by PE() was stronger in hypoxia than normoxia but relaxing response by Ach() was decreased, 5) With pretreatment of L-arginine(), pulmonary arterial relaxation by Ach() in hypoxia was reversed to the level of relaxation in normoxia. Conclusion: It is concluded that rat pulmonary arterial relaxation by Ach is dependent on the intact endothelium and is largely mediated by NO. Acute hypoxic pulmonary vasoconstriction is related to the suppression on NO formation in the vascular endothelium.

Effect of cigarette smoking on hypoxic pulmonary vasoconstriction and its relation to animal species and period of smoking.

The alteration in hypoxic pulmonary vasoconstriction (HPV) induced by cigarette smoking was studied in Wistar rats, piglets and in humans. The percentage change of pulmonary vascular resistance (delta PVR%) and the amplitude of the systolic wave in impedance pneumorheogram (delta H%) were used to estimate the strength of HPV. It was observed that immediately after acute cigarette smoking, HPV in rats increased (delta PVR% from 55.0 +/- 15.6% to 102.3 +/- 12.4%), which is mainly mediated by leukotrienes (LTs); whereas HPV in piglets decreased (delta PVR% from 65.2 +/- 12.5% to 55.9 +/- 9.8%), which is mainly mediated by beta-adrenergic receptors, and HPV in humans also increased (delta H% from 20.6 +/- 2.6% to 31.1 +/- 4.1%), in which prostaglandins and leukotrienes may play the role of mediators. However, after one-month cigarette smoking, the HPV in rats fell significantly (delta PVR% 11.4 +/- 1.6%). An increase in synthesis of vasodilative prostaglandins and a decrease in leukotrienes synthesis may be the contributing factors to this alteration in HPV.

Effects of isoprenaline, adrenaline and selective α1- and α2- adrenoceptor stimulation on hypoxic pulmonary vasoconstriction in rat isolated perfused lungs

In the rat pulmonary vasculature perfused with blood in situ vasoconstriction induced by hypoxia was reversed by isoprenaline (doses > 1 ng) and adrenaline (doses > 30 ng) and exacerbated by phenylephrine but not UK 14304. Doses of adrenaline < 30 ng had no effect, except in the presence of propranolol (1 μM) or phentolamine (3 μM) when they caused vasoconstriction and vasodilation respectively, showing that, at dose levels < 30 ng, adrenaline's β- adrenoceptor vasodilator properties were balanced by its α- adrenoceptor vasoconstrictor properties. The pressor effects of adrenaline, in the presence of propranolol, were antagonised by prazosin (0.1 μM) but not by equi-molar concentrations of rauwolscine. These results suggest that the α- adrenoceptor agonist property of adrenaline is of benefit to its use as an inhaled bronchodilator because unopposed β- adrenoceptor stimulation can reverse hypoxic pulmonary vasoconstriction in poorly ventilated regions of the lung, promote further ventilation/ perfusion mismatching and lower PaO 2. They further suggest that adrenaline affects pulmonary vascular tone in the rat via α 1- adrenoceptors, stimulation of α 2- adrenoceptors having no effect.

Almitrine bismesylate reduces hypoxic pulmonary vasoconstriction in isolated rat lungs.

The purpose of this study is to test how almitrine bismesylate (Alm) affects the function of pulmonary vasculature during normoxic ventilation, and whether low doses of Alm not causing detectable vasoconstriction during normoxic ventilation potentiate hypoxic pulmonary vasoconstriction (HPVC). Isolated Wistar male rat lungs were perfused with homologous blood at constant flow, and venous and ventilatory pressure. In the first experiment, after equilibration, dose-response curves to Alm (from 0 to 1000 ng/ml, n = 10) were measured under the ventilation with normoxic gas mixture (21% O2, 5% CO2, 74% N2). It was found that Alm causes a dose-dependent pulmonary vasoconstriction. In the second experiment, low doses of Alm (125 mg/ml) or diluent of Alm (malic acid) was injected to the blood reservoir. This doses of Alm did not cause significant vasoconstriction during normoxic gas ventilation compared with malic acid. After stabilization of pulmonary arterial pressure, the lungs were exposed to three cycles of normoxia (10 min) and hypoxia (10 min) through ventilation with gas containing 21% or 2% O2 and 5% CO2. It was observed that low doses of Alm significantly reduce HPVC (p less than 0.05) on the later periods of the first and the second hypoxic challenges. However, no significant difference was revealed among two groups in the third hypoxic challenge. Directly measured blood Alm concentration was significantly lower in the third challenge than in the first challenge. Responses to angiotensin II were not decreased by Alm. In conclusion, high doses of Alm constrict pulmonary vasculature dose-dependently, and low doses of the drug not causing vasoconstriction during normoxia reduce HPVC in rat.

The role of leukotrienes in acute hypoxic pulmonary vasoconstriction in rats.

In this study, we investigated the possible role of leukotrienes in the mediation of hypoxic pulmonary vasoconstriction (HPV) in rats. Diethylcarbamazine citrate (DEC), an inhibitor of leukotriene synthesis, can block HPV, while minimally affecting the angiotensin II pressor response. The inhibition of HPV by DEC was not affected by cyclooxygenase or histamine H1-receptor blocker, and the HPV response could be increased by cyclooxygenase blocker. It is suggested that the inhibitory effect of DEC on HPV may not be related to the actions of prostaglandins, histamine and angiotensin II. HPV in male Sprague-Dawley rats and female Hilltop rats was completely and significantly counteracted by the leukotriene receptor blocker FPL55712, respectively. This lends further support to the hypothesis that leukotrienes might be the most important mediators of HPV in rats.

Influence of perfusate PO2 on hypoxic pulmonary vasoconstriction in rats.

The purpose of these studies was to evaluate the influence of perfusate oxygen tension on hypoxic pulmonary vasoconstriction and to identify the site at which both alveolar and perfusate gas tensions stimulate hypoxic pulmonary vasoconstriction. Lungs from adult rats were ventilated and perfused in vitro at constant temperature, PCO2, and pH, with a perfusion circuit incorporating a membrane oxygenator that allowed independent control of the alveolar and perfusate gas tensions. Blood flow to the lung was constant (0.06 ml per g body weight per min), and pulmonary vascular resistance was therefore proportional to pulmonary artery pressure. In study 1, the pulmonary artery pressor response to zero or 22 mm Hg alveolar oxygen was measured when the perfusate oxygen tensions were approximately 8, 26, 41, 64, or 128 mm Hg. The pressor response as a percent of the maximum pressure change was progressively reduced as perfusate oxygen tension increased. For alveolar oxygen tension of zero; the pressor response = 128 -39 (Log PPO2) and r = 0.8 (P less than 0.01), the effect of perfusate gas tension on the response to alveolar gas tension of 22 mm Hg was similar. These results demonstrate that the stimulus for hypoxic pulmonary vasoconstriction is a function of both alveolar and perfusate oxygen tension. In study 2, the response to alveolar oxygen tension of 42 mm Hg was measured with mean perfusate oxygen tensions of 130, 52, and 17 mm Hg. In six animals with forward perfusion, the responses decreased with increasing perfusate oxygen tension, as in study 1. In another six animals, with retrograde perfusion, the responses to alveolar hypoxia were not altered when perfusate oxygen tension was increased. These results demonstrate that the sensor region for hypoxic pulmonary vasoconstriction is precapillary. These studies confirm and extend previous hypotheses that alveolar and perfusate oxygen tensions together, determine the PO2 at a precapillary site to stimulate hypoxic pulmonary vasoconstriction.