AJP - Lung AJP: Regulatory, Integrative and Comparative Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Lung Cell Mol Physiol 278: L968-L973, 2000;
1040-0605/00 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Halla, T. R.
Right arrow Articles by Gordon, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Halla, T. R.
Right arrow Articles by Gordon, J. B.
Vol. 278, Issue 5, L968-L973, May 2000

Mediators of alkalosis-induced relaxation of piglet pulmonary veins

Ted R. Halla, Jane A. Madden, and John B. Gordon

Departments of Pediatrics and Neurology, Medical College of Wisconsin and Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Pulmonary venous constriction leads to significant pulmonary hypertension and increased edema formation in several models using newborns. Although alkalosis is widely used in treating neonatal and pediatric pulmonary hypertension, its effects on pulmonary venous tone have not previously been directly measured. This study sought to determine whether alkalosis caused pulmonary venous relaxation and, if so, to identify the mediator(s) involved. Pulmonary venous rings (500-µm external diameter) were isolated from 1-wk-old piglets and precontracted with the thromboxane mimetic U-46619. Responses to hypocapnic alkalosis were then measured under control conditions after inhibition of endothelium-derived modulator activity or K+ channels. In control rings, alkalosis caused a 34.4 ± 4.8% decrease in the U-46619-induced contraction. This relaxation was significantly blunted in rings without functional endothelium and in rings treated with nitric oxide synthase or guanylate cyclase inhibitors. However, neither cyclooxygenase inhibition nor voltage-dependent, calcium-dependent, or ATP-dependent K+-channel inhibitors altered alkalosis-induced relaxation. These data suggest that alkalosis caused significant dilation of piglet pulmonary veins that was mediated by the nitric oxide-cGMP pathway.

nitric oxide; guanosine 3',5'-cyclic monophosphate; isolated vessels; U-46619


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ALKALOSIS IS WIDELY USED in treating neonatal and pediatric pulmonary hypertension (3, 26). This practice is based on clinical (8, 27) and laboratory (10, 12, 18, 19, 25, 30, 34, 35) studies showing that both hypocapnic and metabolic alkalosis acutely reduced pulmonary vasoconstriction due to hypoxia, thromboxane, and other stimuli in newborns of several species. In isolated pulmonary arteries, alkalosis caused relaxation (17), and in isolated lamb (18) and rat lungs (14), vascular occlusion studies suggested that the alkalosis-induced reduction in total pulmonary vascular resistance (PVR) was due predominantly to arterial vasodilation. However, responses to alkalosis have not previously been directly measured in pulmonary veins. Because pulmonary venous constriction due to hypoxia or thromboxane contributes significantly to pulmonary hypertension and edema formation (6, 11, 29, 41), we sought to determine whether alkalosis causes pulmonary venous dilation and, if so, to identify the mediator(s) involved.

Although alkalosis-induced pulmonary vasodilation is well described, the mechanism of the response remains unknown and the mediator(s) uncertain (1, 12, 14, 17, 19, 25, 37, 39, 40). Gordon et al. (17) previously found that alkalosis-induced relaxation of 500-µm-diameter piglet pulmonary artery rings was blocked by inhibitors of the nitric oxide (NO)-cGMP pathway. In contrast, alkalosis-induced pulmonary vasodilation in intact piglets (19) seemed to be mediated by PGI2. This discordance between preparations could reflect heterogeneity in modulator synthesis and/or activity between arteries and veins within the pulmonary vasculature (15, 16, 36). Therefore, we hypothesized that, unlike pulmonary arteries (17), alkalosis-induced relaxation of piglet pulmonary veins is not mediated by the NO-cGMP pathway. To test this hypothesis and identify the contribution of other putative mediators of the response, the effects of alkalosis were measured in precontracted pulmonary venous rings under control conditions and after inhibition of the NO-cGMP pathway, dilator PG synthesis, or K+-channel activation.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Preparation. This study was approved by the Institutional Animal Care and Use Committees of the Medical College of Wisconsin and the Zablocki Veterans Affairs Medical Center (Milwaukee, WI). As in the previous study by Gordon et al. (17) on pulmonary artery rings, 1-wk-old piglets (n = 24) were anesthetized with ketamine (40 mg/kg im), acepromazine (1.5 mg/kg im), and pentobarbital sodium (25 mg/kg ip). Heparin (5,000 U iv) was administered through a carotid artery catheter and the piglets were killed by exsanguination. The lungs were removed, immersed in cold modified Krebs solution (MKS), and refrigerated at 4°C. At the time of study, 500-µm-external-diameter veins were gently dissected out and cut into 2-mm-long rings. The veins were identified by 1) tracing them back from extrapulmonary veins through four or five generations and 2) their relatively translucent walls and lesser muscularization compared with similar-sized arteries (20, 23, 31). Stainless steel hooks were inserted through the lumen of each venous ring, and the lower hook was attached to the base of a 10-ml organ bath (Harvard Apparatus, South Natick, MA) that was filled with MKS maintained at 37.5°C and bubbled with 6% CO2-21% O2-balance N2 to achieve a pH of approx 7.40. The top hook was suspended from an isometric force transducer (model 52-9529, Harvard Apparatus) mounted on a micromanipulator (model 55020, Stoelting, Chicago, IL) with which vessel tension could be adjusted as needed. Tension was constantly recorded on flatbed recorders during the experiment (model L6514-4, Linseis, Princeton Junction, NJ).

Protocol. In preliminary KCl length-tension experiments (data not shown), we found that the optimal resting tension of 500-µm-diameter piglet pulmonary veins was 500 mg. Therefore, resting tension was set at 500 mg in all subsequent alkalosis experiments. Veins were allowed to equilibrate at this resting tension for 60-90 min before any interventions. Vascular smooth muscle integrity was then assessed by measuring the responses to three successive challenges with 40 mM KCl. The veins were washed with fresh MKS and allowed to stabilize at resting tension for 20 min between each KCl challenge. After the final wash, the veins were submaximally contracted with approx 10-8 M U-46619 (termed U-46619 challenge 1), a concentration found to induce 70% of maximal contraction in preliminary experiments (data not shown). Veins that failed to exhibit an increase in tension of at least 200 mg/mg vein wt in response to the third KCl challenge or to U-46619 challenge 1 were excluded from further study.

After a stable response to U-46619 challenge 1 (approx 20 min), endothelial integrity was assessed by measuring the responses to 10-7 M ACh. If ACh caused >35% reduction in the U-46619 challenge 1 response, endothelial function was considered intact and the veins were assigned to either control (Con) or one of the inhibitor-treated groups (Table 1). If ACh caused <15% reduction in the U-46619 challenge 1 response, the veins were considered to have nonfunctional endothelium and were assigned to the Endo- group. After the ACh response was measured, all veins were washed with fresh MKS and returned to resting tension. Inhibitors were added (Table 1), and baseline tension was measured after 30 min. Submaximal contraction was again induced with U-46619 (termed U-46619 challenge 2), and the stable increase in tension was measured (after approx 20 min). Then CO2 was reduced from 6 to 2%, resulting in a rapid (<5 min) increase in pH to approx 7.60, and the stable alkalotic vein tension was measured after 15 min. The gas mixture was then returned to 21% O2-6% CO2-balance N2, resulting in a rapid return to control pH of approx 7.40, and vessel tension was measured again. A final response to the endothelium-dependent vasodilators ACh or the calcium ionophore A-23187 was then measured in control veins and veins treated with NO-cGMP pathway inhibitors. At the end of each experiment, rings were blotted dry and weighed, and all tension measurements were normalized to vessel weight (in mg tension/mg vein wt).

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Study groups and inhibitors

Study groups. Each vein was assigned to only one of the study groups indicated in Table 1. Inhibitors were not added to Con or Endo- veins. Concentrations of the different inhibitors used in this study were based on those previously reported (7, 9, 17, 21, 22, 28, 36). Inhibition of NO synthase by 10-4 M Nomega -nitro-L-arginine (L-NNA) was confirmed in the L-NNA group by comparing endothelium-dependent relaxation to ACh or A-23187 before and after addition of the inhibitor to the bath. ACh caused a 78.8 ± 2.8% decrease in the U-46619 challenge 1 response (i.e., before addition of the inhibitor) and a 4.2 ± 1.0% after 10-4 M L-NNA. A-23817 caused a 42.5 ± 5.4% decrease in U-46619-induced constriction in preliminary studies of control veins (data not shown) and a 6.6 ± 8.5% decrease after addition of 10-4 M L-NNA in this study. Similarly, ACh- and A23187-induced relaxation was significantly blunted in a group treated with 10-5 M 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ; data not shown). In addition, relaxation to 10-6 M sodium nitroprusside was reduced from 43.7 ± 6.5% under control conditions to 6.6 ± 5.9% after addition of 10-5 M ODQ in preliminary experiments. Previous studies (17, 28, 36) found that 10-5 M meclofenamate and 10-5 M indomethacin both effectively inhibit cyclooxygenase (Cyclo). Because the effects of these inhibitors were similar in the current study, they were combined into a single Cyclo-inhibited group.

Although ATP-dependent K+ (KATP)-channel activation was effectively blocked by 10-5 M glibenclamide (Glib) in piglet pulmonary arteries (17) and in another study (9), we found that full inhibition of 10-8 to 10-7 M cromakalim-induced relaxation of piglet veins required 10-4 M Glib. Therefore, this higher concentration was used in the Glib group in this study. Iberiotoxin (IbTX) has previously been used in concentrations ranging from 10-9 to 10-7 M to inhibit Ca2+-dependent K+ (KCa)-channel activation (17, 22). We used the higher concentration to block KCa-channel activation in the IbTX group in this study. Voltage-dependent K+ (KV)-channel inhibition has been described with concentrations of 4-aminopyridine (4-AP) between 10-3 and 10-2 M in previous studies of pulmonary vessels (5, 43). However, in patch-clamp studies, 10-3 M 4-AP was sufficient to block KV-channel opening (1, 5), and higher concentrations caused smooth muscle depolarization through non-KV-dependent mechanisms (21). Therefore, we measured the responses to alkalosis after adding 10-3 M 4-AP in the 4-AP group.

Drugs and solutions. MKS consisted of (in mM) 120 NaCl, 4.7 KCl, 1.7 NaH2PO4, 0.2 MgSO4 · H2O, 2.5 CaCl2 · 2H2O, 20 NaHCO3, and 10 glucose. For the KCl challenges, the MKS NaCl and KCl concentrations were changed to 80 and 40 mM, respectively, to maintain isosmolar conditions. ACh, IbTX, sodium nitroprusside (all from Sigma, St. Louis, MO), and meclofenamate (BIOMOL Research Laboratories, Plymouth Meeting, PA) were prepared in normal saline. Stock solutions of indomethacin (Sigma) and U-46619 (BIOMOL) were prepared in ethanol and added to normal saline. Glib, ODQ (Sigma), and A-23187 (BIOMOL) were prepared in DMSO. L-NNA (Sigma) was dissolved with a small amount of HCl in saline. 4-AP (Sigma) was dissolved in water, and the pH was then titrated back to 7.40 with HCl. Neither addition of the different inhibitors nor their vehicles in the volumes (10-100 µl) used in this study altered the pH of the MKS. All drug concentrations are expressed as final molar concentrations in the organ bath.

Data analysis. Data are expressed as means ± SE. The number of veins and piglets in each group are indicated in Figs. 1-4 and Tables 1 and 2. In no case were more than two veins from a single piglet assigned to a particular study group. Absolute tension and changes in tension in response to various interventions are expressed in milligrams per milligram of vessel weight. To facilitate comparisons among different groups, the percent reduction in the U-46619 challenge 2 response by alkalosis was also calculated and shown. Data were analyzed by t-test or one-way or two-way repeated-measures ANOVA as appropriate with SigmaStat version 2.03 statistical software (SPSS, Chicago, IL). Data were considered significant at P < 0.05, and Fisher's least significant difference test was used to identify differences between or within groups when the ANOVA was significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

There were no differences in piglet weight (2.96 ± 0.07 kg) or age (6-9 days) among the different groups. Vein weight and diameter, eucapnic and hypocapnic pH and PCO2, and tension in response to 40 mM KCl and U-46619 challenge 1 were also similar among the groups (mean values for all veins are shown in Table 2). ACh caused a 78.7 ± 2.8% decrease in the U-46619 challenge 1 response of the 67 veins with intact endothelium compared with a 5.0 ± 2.7% decrease in the six Endo- veins (P < 0.05). Resting tension increased significantly with the addition of L-NNA and ODQ in the L-NNA and ODQ groups, respectively, but was unchanged in the Con and Endo- veins or after addition of other inhibitors (Fig. 1).

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Vessel characteristics



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 1.   Resting tension increased after addition of either Nomega -nitro-L-arginine (L-NNA) or 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) to bath. Con, control; Endo-, nonfunctional endothelium; Cyclo, cyclooxygenase; Glib, glibenclamide; IbTX, iberiotoxin; 4-AP, 4-aminopyridine. Nos. in parentheses, no. of veins, piglets/group. * Significantly greater than Con.

Alkalosis caused a significant decrease in absolute U-46619 challenge 2 tension in Con and Cyclo veins but not in the L-NNA, ODQ, or Endo- groups (Fig. 2A). In addition, the percent reduction in the U-46619 challenge 2 response was significantly greater in the Con and Cyclo groups than in the others (Fig. 2B). Neither absolute tension measured during alkalosis (Fig. 3A) nor the percent decrease in the U-46619 challenge 2 response differed among the Con and K+ channel-inhibited groups (Fig. 3B).


View larger version (25K):
[in this window]
[in a new window]
  		Fig. 2.   A: resting tension and tension measured after 2nd submaximal contraction induced by U-46619 (U-46619 challenge 2; #2) were higher in L-NNA, Endo-, and ODQ groups compared with Con group (*). Alkalosis decreased U-46619 challenge 2 tension in Con and Cyclo groups (**). B: percent decrease in U-46619 challenge 2 response during alkalosis was significantly blunted in L-NNA, Endo-, and ODQ groups (dagger ). Nos. in parentheses, no. of veins, piglets/group. All differences were significant at P < 0.05.



View larger version (26K):
[in this window]
[in a new window]
  		Fig. 3.   A: K+-channel inhibition had no effect on absolute tension under any study condition. B: percent decrease in U-46619 challenge 2 response during alkalosis did not differ between groups. Nos. in parentheses, no. of veins, piglets/group.

Resting tension and tension measured during U-46619 challenge 2 were significantly higher in L-NNA, ODQ, and Endo- groups compared with those in the other groups (Fig. 2), raising the possibility that their blunted alkalosis-induced responses were simply due to their greater baseline tone. To address this question, Con veins were divided into high-tension and low-tension subgroups based on whether their responses to U-46619 challenge 2 were above or below the median U-46619 challenge 2 tension achieved in all Con veins (2,348.2 mg/mg vein wt). Although all tension measurements were higher in the Con high-tension than in the Con low-tension groups (Fig. 4A), the absolute decrease in tension during alkalosis was actually greater in the Con high-tension veins. However, the percent decrease in U-46619 challenge 2 response was similar in both groups (Fig. 4B). Thus higher baseline tension did not appear to contribute to the blunted alkalosis-induced responses of the Endo-, L-NNA, and ODQ veins.


View larger version (16K):
[in this window]
[in a new window]
  		Fig. 4.   A: tension was greater under all study conditions in Con high-tension compared with Con low-tension veins (*). Alkalosis caused a greater absolute decrease in tension in Con high-tension veins. B: percent decrease in U-46619 challenge 2 response during alkalosis was similar in both groups. Nos. in parentheses, no. of veins, piglets/group.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Pulmonary veins are thin walled and have relatively little smooth muscle compared with pulmonary arteries in human (20), porcine (31), and ovine (23) newborns. However, veins from newborn lambs and piglets constricted to hypoxia and thromboxane, contributing to pulmonary hypertension and increased edema formation (6, 11, 29, 41). Our finding in this study that alkalosis relaxed Con piglet pulmonary venous rings after preconstriction with the thromboxane analog U-46619 (Figs. 2-4) suggests that alkalosis may reduce venous constriction, with a consequent decrease in pulmonary hypertension and edema formation. In contrast to isolated veins, alkalosis failed to alter venous resistance in vascular occlusion studies of hypoxic lamb lungs (18) and U-46619-treated rat lungs (14). This may reflect limitations of the vascular occlusion technique in identifying responses of 500-µm-diameter pulmonary veins. Alternatively, there may be interspecies or interpreparation differences in the apparent effects of different pressor stimuli and alkalosis on venous tone. Further studies measuring the effects of alkalosis on pulmonary hemodynamics and fluid filtration in various species will be needed to evaluate the efficacy of alkalosis in reducing pulmonary venous hypertension and the resultant pulmonary edema.

Alkalosis-induced relaxation was significantly blunted in veins without functional endothelium and in those treated with a NO synthase inhibitor. But it was not blocked in veins treated with Cyclo inhibitors (Fig. 2). These data suggest that alkalosis-induced pulmonary venous dilation is mediated by endothelium-derived NO. This conclusion is consistent with the previous study by Gordon et al. (17) on piglet pulmonary artery rings and is supported by studies showing that extracellular alkalosis increases cytosolic pH (2) and Ca2+ concentration (38), two potent stimuli for NO synthesis (13, 24). Guanylate cyclase inhibition also blocked alkalosis-induced relaxation in both piglet pulmonary veins (Fig. 2) and pulmonary arteries (17), suggesting that NO acted through a cGMP-dependent mechanism. Although NO-cGMP-mediated vasodilation appeared to involve KV- or KCa-channel activation in some studies (33, 42, 43), this did not appear to be the case in the alkalosis-induced response of piglet vessels because K+-channel inhibition had no effect on alkalosis-induced relaxation of either pulmonary veins (Fig. 4) or arteries (17).

In contrast to piglet pulmonary vessels, NO did not appear to contribute to alkalosis-induced vasodilation in rabbit (39) or rat (14) lungs. PGI2 synthesis, like NO synthesis, is enhanced by increased endothelial cell cytosolic Ca2+ (32). Furthermore, Cyclo inhibition blocked alkalosis-induced vasodilation in rat (40) and lamb (25) lungs. Thus some of the interspecies differences in the mediator of alkalosis-induced vasodilation may reflect interspecies differences in dominant endothelium-derived modulator synthesis (4). Non-endothelium-dependent mechanisms of alkalosis-induced vasodilation may also contribute (12) because patch-clamp studies of isolated dog and rat pulmonary artery smooth muscle cells have shown that alkalosis opened and acidosis closed KV channels in the absence of endothelium (1, 5).

In addition to interspecies differences, intraspecies differences in the apparent mediator of alkalosis-induced vasodilation have been described in studies of lambs (12, 25), piglets (17, 19), and rats (37, 40) with different preparations. We speculated that the discordance between isolated piglet pulmonary artery rings in which NO synthase inhibition blocked alkalosis-induced relaxation (17) and intact piglets in which the PGI2 synthase inhibitor tranylcypromine inhibited the response (19) was due to heterogeneity in synthesis and/or activity of endothelium-derived modulators within the pulmonary circuit (15, 16, 36). However, contrary to our hypothesis, alkalosis-induced relaxation of piglet pulmonary veins was also mediated by the NO-cGMP pathway (Fig. 2). Although our findings do not exclude the possibility that smaller vessels within the whole lung respond differently to alkalosis than 500-µm-diameter veins and arteries, several other interpreparation differences such as pressor stimuli, type and specificity of inhibitors, perfusate, and neuroendocrine factors may also contribute. Future studies must determine how species and preparation differences alter the effects of alkalosis on the pulmonary vasculature if the mechanism of alkalosis-induced pulmonary vasodilation is to be elucidated.


    ACKNOWLEDGEMENTS

This work was supported by the Children's Hospital Foundation of the Children's Hospital of Wisconsin and the Department of Pediatrics of the Medical College of Wisconsin (Milwaukee, WI).


    FOOTNOTES

J. A. Madden was supported by funds from Veterans Affairs Medical Research.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: J. B. Gordon, Children's Hospital of Wisconsin, Critical Care Section MS 681, PO Box 1997, Milwaukee, WI 53201 (E-mail: jgordon{at}mcw.edu).

Received 18 August 1999; accepted in final form 6 December 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Ahn, DS, and Hume JR. pH regulation of voltage-dependent K+ channels in canine pulmonary arterial smooth muscle cells. Pflügers Arch 433: 758-765, 1997[Web of Science][Medline].

2.   Austin, C, and Wray S. Extracellular pH signals affect rat vascular tone by rapid transduction into intracellular pH changes. J Physiol (Lond) 466: 1-8, 1993[Abstract/Free Full Text].

3.   Baffa, JM, and Gordon JB. Pathophysiology, diagnosis, and management of pulmonary hypertension in infants and children. J Intensive Care Med 11: 90-107, 1996.

4.   Barnard, JW, Wilson PS, Moore TM, Thompson WJ, and Taylor AE. Effect of nitric oxide and cyclooxygenase products on vascular resistance in dog and rat lungs. J Appl Physiol 74: 2940-2948, 1993[Abstract/Free Full Text].

5.   Berger, M, Vandier C, Bonnet P, Jackson W, and Rusch N. Intracellular acidosis differentially regulates KV channels in coronary and pulmonary vascular muscle. Am J Physiol Heart Circ Physiol 275: H1351-H1359, 1998[Abstract/Free Full Text].

6.   Bressack, MA, and Bland RD. Alveolar hypoxia increases lung fluid filtration in unanesthetized newborn lambs. Circ Res 46: 111-116, 1980[Free Full Text].

7.   Brunner, F, Schmidt K, Nielsen EB, and Mayer B. Novel guanylyl cyclase inhibitor potently inhibits cyclic GMP accumulation in endothelial cells and relaxation of bovine pulmonary artery. J Pharmacol Exp Ther 277: 48-53, 1996[Abstract/Free Full Text].

8.   Chang, AC, Zucker HA, Hickey PR, and Wessel DL. Pulmonary vascular resistance in infants after cardiac surgery: role of carbon dioxide and hydrogen ion. Crit Care Med 23: 568-574, 1995[Web of Science][Medline].

9.   Clapp, LH, Davey R, and Gurney AM. ATP-sensitive K+ channels mediate vasodilation produced by lemakalim in rabbit pulmonary artery. Am J Physiol Heart Circ Physiol 264: H1907-H1915, 1993[Abstract/Free Full Text].

10.   Fike, CD, and Hansen TN. The effect of alkalosis on hypoxia-induced pulmonary vasoconstriction in lungs of newborn rabbits. Pediatr Res 25: 383-388, 1989[Web of Science][Medline].

11.   Fike, CD, and Kaplowitz MR. Pulmonary venous pressure increases during alveolar hypoxia in isolated lungs of newborn pigs. J Appl Physiol 73: 552-556, 1992[Abstract/Free Full Text].

12.   Fineman, JR, Wong J, and Soifer SJ. Hyperoxia and alkalosis produce pulmonary vasodilation independent of endothelium-derived nitric oxide in newborn lambs. Pediatr Res 33: 341-346, 1993[Web of Science][Medline].

13.   Fleming, I, Hecker M, and Busse R. Intracellular alkalinization induced by bradykinin sustains activation of the constitutive nitric oxide synthase in endothelial cells. Circ Res 74: 1220-1226, 1994[Abstract/Free Full Text].

14.   Gao, Y, Tassiopoulos A, McGraw D, Hauser M, Camporesi E, and Hakim T. Segmental pulmonary vascular responses to changes in pH in rat lungs: role of nitric oxide. Acta Anaesthesiol Scand 43: 64-70, 1999[Web of Science][Medline].

15.   Gao, Y, Tolsa J-F, and Raj J. Heterogeneity in endothelium-derived nitric oxide-mediated relaxation of different sized pulmonary arteries of newborn lambs. Pediatr Res 44: 723-729, 1998[Web of Science][Medline].

16.   Geiger, M, Stone A, Mason S, Oldham K, and Guice K. Differential nitric oxide production by microvascular and macrovascular endothelial cells. Am J Physiol Lung Cell Mol Physiol 273: L275-L281, 1997[Abstract/Free Full Text].

17.   Gordon, J, Halla TR, Fike CD, and Madden JA. Mediators of alkalosis-induced relaxation in pulmonary arteries from normoxic and chronically hypoxic piglets. Am J Physiol Lung Cell Mol Physiol 276: L155-L163, 1999[Abstract/Free Full Text].

18.   Gordon, JB, Martinez FR, Keller PA, Tod ML, and Madden JA. Differing effects of acute and prolonged alkalosis on hypoxic pulmonary vasoconstriction. Am Rev Respir Dis 148: 1651-1656, 1993[Web of Science][Medline].

19.   Hammerman, C, and Aramburo MJ. Effects of hyperventilation on prostacyclin formation and on pulmonary vasodilation after group B beta -hemolytic streptococci-induced pulmonary hypertension. Pediatr Res 29: 282-287, 1991.

20.   Haworth, SG, and Hislop AA. Pulmonary vascular development: normal values of peripheral vascular structure. Am J Cardiol 52: 578-583, 1983[Web of Science][Medline].

21.   Ishida, Y, and Honda H. Inhibitory action of 4-aminopyridine on Ca2+-ATPase of the mammalian sarcoplasmic reticulum. J Biol Chem 268: 4021-4024, 1993[Abstract/Free Full Text].

22.   Jackson, W, and Blair K. Characterization and function of Ca2+-activated K+ channels in arteriolar muscle cells. Am J Physiol Heart Circ Physiol 274: H27-H34, 1998[Abstract/Free Full Text].

23.   Michel, RP, Gordon JB, and Chu K. Development of the pulmonary vasculature in newborn lambs: structure-function relationships. J Appl Physiol 70: 1255-1264, 1991[Abstract/Free Full Text].

24.   Mitchell, JA, De Nucci G, Warner TD, and Vane JR. Alkaline buffers release EDRF from bovine cultured aortic endothelial cells. Br J Pharmacol 103: 1295-1302, 1991[Web of Science][Medline].

25.   Moreira, GA, O'Donnell DC, Tod ML, Madden JA, and Gordon JB. Discordant effects of alkalosis on elevated pulmonary vascular resistance and vascular reactivity in lamb lungs. Crit Care Med 27: 1838-1842, 1999[Web of Science][Medline].

26.   Morin, FC, III, and Stenmark KR. Persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med 151: 2010-2032, 1995[Web of Science][Medline].

27.   Morray, JP, Lynn AM, and Mansfield PB. Effect of pH and PCO2 on pulmonary and systemic hemodynamics after surgery in children with congenital heart disease and pulmonary hypertension. J Pediatr 113: 474-479, 1988[Web of Science][Medline].

28.   O'Donnell, DC, Tod ML, and Gordon JB. Developmental changes in endothelium-dependent relaxation of pulmonary arteries: role of EDNO and prostanoids. J Appl Physiol 81: 2013-2019, 1996[Abstract/Free Full Text].

29.   Raj, JU, and Chen P. Micropuncture measurement of microvascular pressures in isolated lamb lungs during hypoxia. Circ Res 59: 398-404, 1986[Abstract/Free Full Text].

30.   Redding, GJ, Gibson RL, Davis CB, and Truog WE. Effects of respiratory alkalosis on thromboxane-induced pulmonary hypertension in piglets. Pediatr Res 24: 558-562, 1988[Web of Science][Medline].

31.   Rendas, A, Branthwaite M, Lennox S, and Reid L. Response of the pulmonary circulation to acute hypoxia in the growing pig. J Appl Physiol 52: 811-814, 1982[Abstract/Free Full Text].

32.   Ritter, JM, Frazer CE, and Taylor GW. pH-dependent stimulation by Ca2+ of prostacyclin synthesis in rat aortic rings: effects of drugs and inorganic ions. Br J Pharmacol 91: 439-446, 1987[Web of Science][Medline].

33.   Saqueton, C, Miller R, Porter V, Milla C, and Cornfield D. NO causes perinatal pulmonary vasodilation through K+-channel activation and intracellular Ca2+ release. Am J Physiol Lung Cell Mol Physiol 276: L925-L932, 1999[Abstract/Free Full Text].

34.   Schreiber, MD, Heymann MA, and Soifer SJ. Increased arterial pH, not decreased PaCO2, attenuates hypoxia-induced pulmonary vasoconstriction in newborn lambs. Pediatr Res 20: 113-117, 1986[Web of Science][Medline].

35.   Schreiber, MD, and Soifer SJ. Respiratory alkalosis attenuates thromboxane-induced pulmonary hypertension. Crit Care Med 16: 1225-1228, 1988[Web of Science][Medline].

36.   Steinhorn, RH, Morin FC, III, Gugino SF, Giese EC, and Russell JA. Developmental differences in endothelium-dependent responses in isolated ovine pulmonary arteries and veins. Am J Physiol Heart Circ Physiol 264: H2162-H2167, 1993[Abstract/Free Full Text].

37.   Vandier, C, Dimson O, Jackson WF, Bonnet P, and Rusch NJ. Potassium current in pulmonary and coronary arterial smooth muscle cells is differentially regulated by NH4Cl-induced changes in intracelluar pH (Abstract). FASEB J 10: A105, 1996.

38.   Wakabayashi, I, and Groschner K. Divergent effects of extracellular and intracellular alkalosis on Ca2+ entry pathways in vascular endothelial cells. Biochem J 323: 567-573, 1997.

39.   Yamaguchi, K, Takasugi T, Fujita H, Mori M, Oyamada Y, Suzuki K, Miyata A, Aoki T, and Suzuki Y. Endothelial modulation of pH-dependent pressor response in isolated perfused rabbit lungs. Am J Physiol Heart Circ Physiol 270: H252-H258, 1996[Abstract/Free Full Text].

40.   Yamaguchi, T, O'Brien RF, Hanson WL, Wagner WW, Jr, and McMurtry IF. Prostacyclin contributes to inhibition of hypoxic pulmonary vasoconstriction by alkalosis. Prostaglandins 38: 53-63, 1989[Web of Science][Medline].

41.   Yoshimura, K, Tod ML, Pier KG, and Rubin LJ. Role of venoconstriction in thromboxane-induced pulmonary hypertension and edema in lambs. J Appl Physiol 66: 929-935, 1989[Abstract/Free Full Text].

42.   Yuan, XJ, Tod ML, Rubin LJ, and Blaustein MP. NO hyperpolarizes pulmonary artery smooth muscle cells and decreases the intracellular Ca2+ concentration by activating voltage-gated K+ channels. Proc Natl Acad Sci USA 93: 10489-10494, 1996[Abstract/Free Full Text].

43.   Zhao, Y, Wang J, Rubin L, and Yuan X. Inhibition of KV and KCa channels antagonizes NO-induced relaxation in pulmonary artery. Am J Physiol Heart Circ Physiol 272: H904-H912, 1997[Abstract/Free Full Text].

Am J Physiol Lung Cell Mol Physiol 278(5):L968-L973
1040-0605/00 $5.00 Copyright © 2000 the American Physiological Society


This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. B. Gordon, M. A. VanderHeyden, T. R. Halla, E. P. Cortez, G. Hernandez, S. T. Haworth, C. A. Dawson, and J. A. Madden
What leads to different mediators of alkalosis-induced vasodilation in isolated and in situ pulmonary vessels?
Am J Physiol Lung Cell Mol Physiol, May 1, 2003; 284(5): L799 - L807.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
S. Mizuno, Y. Demura, S. Ameshima, S. Okamura, I. Miyamori, and T. Ishizaki
Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells
Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L113 - L119.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
E. D. Michelakis, E. K. Weir, X. Wu, A. Nsair, R. Waite, K. Hashimoto, L. Puttagunta, H. G. Knaus, and S. L. Archer
Potassium channels regulate tone in rat pulmonary veins
Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1138 - L1147.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
M. A. Vander Heyden, T. R. Halla, J. A. Madden, and J. B. Gordon
Multiple Ca2+-dependent modulators mediate alkalosis-induced vasodilation in newborn piglet lungs
Am J Physiol Lung Cell Mol Physiol, March 1, 2001; 280(3): L519 - L526.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Halla, T. R.
Right arrow Articles by Gordon, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Halla, T. R.
Right arrow Articles by Gordon, J. B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online