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Role of NO Pathway, Calcium and Potassium Channels in the Peripheral Pulmonary Vascular Tone in Dogs

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Role of NO Pathway, Calcium and Potassium Channels in the Peripheral Pulmonary Vascular Tone in Dogs Copyright #ERS Journals Ltd2001 Eur Respir J 2001; 17: 20±26 European Respiratory Journal Printedin UK ± all rights reserved ISSN 0903-1936 Role of NO pathway, calcium and potassium channels in the peripheral pulmonary vascular tone in dogs F. Chabot, F. Schrijen, C. Saunier Role of NO pathway, calcium and potassium channels in the peripheral pulmonary INSERM U14, Plateau de Brabois, vascular tone in dogs. F. Chabot, F. Schrijen, C. Saunier. #ERS Journals Ltd 2001. C.O. 10, Vandúuvre-les-Nancy and ABSTRACT: Because hypoxic pulmonary vasoconstriction occurs mainly in the small Service des Maladies Respiratoires et pulmonary arteries, the authors investigated the effects of drugs acting on the nitric ReÂanimation Respiratoire, CHU Nancy-Brabois, Vandúuvre-les-Nancy, oxide NO)pathway and the calcium and potassium channels in the peripheral France. pulmonary circulation, without interference with the overall pulmonary or systemic circulation. Correspondence: F. Chabot, Service Mixed venous blood was infused in wedged areas to study the pressure/¯ow des Maladies Respiratoires et relationship and to compute peripheral pulmonary vascular resistance PPVR). The ReÂanimation Respiratoire, CHU authors studied the effects of Nv-nitro-l-arginine methyl ester l-NAME), an NO Nancy-Brabois, rue du Morvan, synthase inhibitor, sodium nitroprusside SNP, an NO donor), the calcium channel 54500, Vandúuvre-les-Nancy, France. blockers verapamil, nifedipine and nicardipine, and the potassium channel opener Fax: 33 0383154023 levcromakalim, during normoxia and acute mild normocapnic hypoxia. Keywords: Anaesthetized dogs In the peripheral pulmonary circulation, l-NAME caused an increase in PPVR ATP-sensitivepotassiumchannelopener during normoxia z95%; p<0.001)and hypoxia z60%; p<0.01). Following the calcium channel inhibitors increase by l-NAME, SNP decreased PPVR during normoxia -24%; p<0.05)and hypoxia hypoxia -23%; p<0.05). Verapamil, nifedipine and nicardipine did not modify PPVR peripheral pulmonary circulation during normoxia but during hypoxia they decreased PPVR -28%, nonsigni®cant; -27%, pulmonary vasoreactivity p<0.01 and -33%, p<0.05, respectively). Levcromakalim did not modify PPVR during normoxia or hypoxia. Received: May 19 2000 In conclusion, the nitric oxide pathway and voltage-dependent calcium channels, and Accepted after revision September 15 2000 not adenosine triphosphate sensitive potassium channels, play an important role in the control of peripheral pulmonary circulation in dogs. Eur Respir J2001; 17: 20±26. Segmental differences in vasomotor reactivity are NO-induced relaxation in the proximal part of the well documented in the pulmonary vasculature. Hypo- pulmonary artery have been emphasized, in vitro [5]. xia causes sustained constriction in resistance pulmo- Various inhibitors of NO synthase ;NOS) have been nary arteries [1] while causing a biphasic response in shown to increase the normoxic pulmonary vascular conduit pulmonary arteries [2]. Investigations on resis- tone in some [6, 7] but not in all [8, 9] experiments. tance vessels have been performed mainly in vitro on The inhibition of NO synthesis increases hypoxic small isolated pulmonary artery rings. Some authors pulmonary vasoconstriction in intact lungs, suggesting investigated the relationship between pressure and ¯ow an increased NO synthesis in response to hypoxia and/ in the pulmonary circulation in vivo for a lobe in situ or vasoconstriction [6]. [3], but the preparation included predominantly con- The calcium and potassium channels seem also to duit vessels and the ¯ow changes induced modi®cations play a role in the mechanism of hypoxic pulmonary of other variables. Because alveolar hypoxia is an vasoconstriction ;HPV). Potassium channel blockers important regulator of pulmonary vascular tone and cause pulmonary vasoconstriction [10] largely through causes vasoconstriction mainly in small pulmonary their effects on membrane potential and calcium chan- arteries, the authors studied, in vivo, the pharmacology nels. It has been proposed that hypoxia might inhibit of the vasomotor response of the peripheral pulmonary outward potassium current in pulmonary smooth circulation, during normoxia and mild acute hypoxia. muscle cells, causing membrane depolarization and Under physiological conditions, the vasodilator nitric thus permitting calcium entry through the voltage- oxide ;NO) is continually released by endothelial cells dependent calcium channels sensitive to dihydropyr- and regulates organ and perfusion pressure and ¯ow [4]. idine [11]. Calcium channel blockers like verapamil, a Endogenous NO may contribute to the maintenance of phenylalkylamine, have been shown to inhibit HPV normal pulmonary vasomotor tone. Pulmonary vas- [12], but Young et al. [13] did not observe this inhi- cular tone is also regulated by the activity of calcium bition with verapamil whereas nifedipine, a dihydropir- and potassium channels, and the links between acti- idine, appeared to be a more effective pulmonary vation of both calcium and potassium channels and vasodilator. PERIPHERAL PULMONARY VASOREACTIVITY 21 Studies of the peripheral pulmonary circulation are as cardiac output ;CO), were measured with the dif®cult to perform in vivo. The present authors studied Swan-Ganz catheter. Blood samples were withdrawn the pressure/¯ow relationship in a small peripheral simultaneously from both femoral and pulmonary portion of the pulmonary vascular bed, excluding most arterial catheters to determine arterial and mixed of the large conduit arteries, where pressure could be venous blood gases. To determine the pressure/¯ow increased by hypoxia or pharmacologically modi®ed curve, one lumen of the double lumen catheter was without in¯uencing the rest of the circulation [14]. This connected to a pressure transducer, the other one to a technique was used to study, during normoxia or acute peristaltic pump ;Ismatec, Zurich, Switzerland). Blood normocapnic hypoxia, the action of the NO pathway was withdrawn through the pump from the distal by the administration of sodium nitroprusside ;SNP), lumen of the thermodilution catheter, which was lying an NO donor, or by inhibition of NOS by Nv-nitro-l- free in the pulmonary artery. Blood ¯ow was monitored arginine methyl ester ;l-NAME). The role of calcium with a Transonic Systems ;Ithaca, NY, USA) ¯ow- channels was studied by a blockade with verapamil, meter. The catheters were primed with blood. Drugs nifedipine and nicardipine, and the role of potassium or control solution ;isotonic glucose 50 g.L-1), were channels by the administration of a potassium channel administered with an electrical syringe ;Vial SE 400, opener, levcromakalim, in the peripheral pulmonary Grenoble, France) and added to the blood infusion, vasculature. with a rate of infusion equal to 15% of that of the blood infusion. To study the pressure/¯ow curves, blood ¯ow was Material and methods increased by steps from 0 to y5, 8 and 10 mL.min-1; each ¯ow was maintained for ¢1 min, and the pressure All experiments were conducted according to the was measured after equilibration at the end of each Helsinki convention for the care and use of animals. period. The drugs were used at increasing concentra- tions. After the pressure/¯ow runs had been completed, Study design contrast medium was slowly infused into the wedged catheter, until the draining vein was visualized. The In anaesthetized dogs breathing spontaneously, vaso- volume infused was taken as a measurement of the active drugs were infused in a distal portion of the lung volume of the wedged area. The angiogram was always vascular bed, and the pressure/¯ow relationship was performed after the end of the pharmacological study determined to compute the peripheral pulmonary since a previous study showed that contrast medium vascular resistance ;PPRV). Isotonic glucose was used increased the PPVR [15]. as control. The drugs were given while the dogs bre- At the end of the experiment, the special catheter was athed either room air, or a hypoxic mixture ;O 10%, 2 withdrawn, and blood was sampled from the pulmo- CO 3%, balance N ). 2 2 nary artery via the thermodilution catheter, in order to calibrate the ¯owmeter with a stop-watch and a Peripheral pulmonary vascular resistance model graduated tube. The system used has been described previously in detail [14]. Anaesthesia was induced with an initial dose Hypoxia of 20 mg.kg-1 thiopental i.v., and maintained by a slow- The dogs breathed alternately, at random, room air rate infusion ;14 mg.kg-1.h-1), with an electrical syringe or a hypoxic mixture ;O 10%, CO 3%, N 87%) ;Vial SE 400, Grenoble, France). The dogs were in- 2 2 2 administered from a bag through a nonrebreathing tubated with a cuffed tracheal cannula whilst breathing valve. Haemodynamic data were measured after 10 min spontaneously. Under sterile conditions, a femoral hypoxic ventilation. During this time, blood ¯ow was artery was cannulated with a catheter, and an external maintained in the wedged area, after which, the jugular vein with two catheters: a conventional Swan- pressure/¯ow curve was determined. Before switching Ganz thermodilution catheter, with the proximal lumen between normoxia and hypoxia, the double lumen opening at 20 cm from the tip, and a 7F custom-made catheter was wedged in another site. Different drugs balloon catheter with both lumens extending to the tip were tested in different areas, except for sodium ;part No 600518 model, American Edwards Labora- nitroprusside after l-NAME. tories, Santa
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