ADP-ribosyl Cyclase and Cyclic ADP-ribose Hydrolase Act as a Redox Sensor

Abstract

Hypoxic pulmonary vasoconstriction is unique to pulmonary arteries and serves to match lung perfusion to ventilation. However, in disease states this process can promote hypoxic pulmonary hypertension. Hypoxic pulmonary vasoconstriction is associated with increased NADH levels in pulmonary artery smooth muscle and with intracellular Ca2+ release from ryanodine-sensitive stores. Because cyclic ADP-ribose (cADPR) regulates ryanodine receptors and is synthesized from β-NAD+, we investigated the regulation by β-NADH of cADPR synthesis and metabolism and the role of cADPR in hypoxic pulmonary vasoconstriction. Significantly higher rates of cADPR synthesis occurred in smooth muscle homogenates of pulmonary arteries, compared with homogenates of systemic arteries. When the β-NAD+:β-NADH ratio was reduced, the net amount of cADPR accumulated increased. This was due, at least in part, to the inhibition of cADPR hydrolase by β-NADH. Furthermore, hypoxia induced a 10-fold increase in cADPR levels in pulmonary artery smooth muscle, and a membrane-permeant cADPR antagonist, 8-bromo-cADPR, abolished hypoxic pulmonary vasoconstriction in pulmonary artery rings. We propose that the cellular redox state may be coupled via an increase in β-NADH levels to enhanced cADPR synthesis, activation of ryanodine receptors, and sarcoplasmic reticulum Ca2+ release. This redox-sensing pathway may offer new therapeutic targets for hypoxic pulmonary hypertension. Hypoxic pulmonary vasoconstriction is unique to pulmonary arteries and serves to match lung perfusion to ventilation. However, in disease states this process can promote hypoxic pulmonary hypertension. Hypoxic pulmonary vasoconstriction is associated with increased NADH levels in pulmonary artery smooth muscle and with intracellular Ca2+ release from ryanodine-sensitive stores. Because cyclic ADP-ribose (cADPR) regulates ryanodine receptors and is synthesized from β-NAD+, we investigated the regulation by β-NADH of cADPR synthesis and metabolism and the role of cADPR in hypoxic pulmonary vasoconstriction. Significantly higher rates of cADPR synthesis occurred in smooth muscle homogenates of pulmonary arteries, compared with homogenates of systemic arteries. When the β-NAD+:β-NADH ratio was reduced, the net amount of cADPR accumulated increased. This was due, at least in part, to the inhibition of cADPR hydrolase by β-NADH. Furthermore, hypoxia induced a 10-fold increase in cADPR levels in pulmonary artery smooth muscle, and a membrane-permeant cADPR antagonist, 8-bromo-cADPR, abolished hypoxic pulmonary vasoconstriction in pulmonary artery rings. We propose that the cellular redox state may be coupled via an increase in β-NADH levels to enhanced cADPR synthesis, activation of ryanodine receptors, and sarcoplasmic reticulum Ca2+ release. This redox-sensing pathway may offer new therapeutic targets for hypoxic pulmonary hypertension. hypoxic pulmonary vasoconstriction sarcoplasmic reticulum cyclic ADP-ribose ryanodine receptor Since it was first described over 50 years ago, hypoxic pulmonary vasoconstriction (HPV)1 has been recognized as the critical and distinguishing characteristic of the blood vessels of the lung (1Von Euler U.S. Liljestrand G. Acta Physiol. Scand. 1946; 12: 301-320Crossref Scopus (758) Google Scholar). Thus, in marked contrast to systemic arteries, which dilate in response to hypoxia, pulmonary arteries constrict. Physiologically, HPV contributes to the matching of lung perfusion and ventilation. However, when alveolar hypoxia is global, as it is in disease states such as cystic fibrosis, emphysema, and mountain sickness, it results in pulmonary hypertension, which can ultimately lead to right heart failure. Unfortunately, the precise mechanisms that underpin HPV remain to be identified, and current therapies for hypoxic pulmonary hypertension are poor. Certain key characteristics of HPV have been described. In isolated pulmonary arteries, HPV is biphasic. An initial transient constriction (phase 1) is followed by a slowly developing, sustained phase of constriction (phase 2). It is widely thought that the first phase of constriction is initiated by a reduction in membrane K+conductance in pulmonary artery smooth muscle cells (2Post J. Hume J. Archer S. Weir E. Am. J. Physiol. 1992; 262: C882-C890Crossref PubMed Google Scholar, 3Archer S.L. Huang J. Henry T. Peterson D. Weir E.K. Circ. Res. 1993; 73: 1100-1112Crossref PubMed Scopus (332) Google Scholar, 4Osipenko O.N. Evans A.M. Gurney A.M. Br. J. Pharmacol. 1997; 120: 1461-1470Crossref PubMed Scopus (122) Google Scholar), membrane depolarization, and Ca2+ influx through voltage-gated Ca2+ channels (5Harder D. Madden J. Dawson C. J. Appl. Physiol. 1985; 59: 1389-1393Crossref PubMed Scopus (76) Google Scholar, 6Madden J. Vadula M. Kurup V. Am. J. Physiol. 1992; 263: L384-L393Crossref PubMed Google Scholar, 7Cornfield D. Stevens T. McMurty I. Abman S. Rodman D. Am. J. Physiol. 1993; 265: L1-L4Crossref PubMed Google Scholar, 8Salvaterra C. Goldman W. Am. J. Physiol. 1993; 264: L323-L328Crossref PubMed Google Scholar). Phase 2 of the constriction is tonic and may depend on the release of a vasoconstrictor from the endothelium, which sensitizes the contractile apparatus to Ca2+ (9Kovitz K.L. Aleskowitch J.T. Sylvester J.T. Flavahan N.A. Am. J. Physiol. 1993; 260: L516-L521Google Scholar, 10Robertson T.P. Aaronson P.I. Ward J.P.T. Am. J. Physiol. 1995; 268: H301-H307PubMed Google Scholar). Our recent findings (11Dipp M. Nye P.C.G. Evans A.M. J. Physiol. 2000; 526: S26PGoogle Scholar) do not support the above hypothesis. They suggest that hypoxia may, by activating a mechanism intrinsic to pulmonary artery smooth muscle cells, induce intracellular Ca2+ release from ryanodine-sensitive stores in the absence of transmembrane Ca2+ influx. This proposal is also supported by the findings of others (12Jabr R.I. Toland H. Gelband C.H. Wang X.X. Hume J.R. Br. J. Pharmacol. 1997; 122: 21-30Crossref PubMed Scopus (121) Google Scholar, 13Gelband C.H. Gelband H. Circulation. 1997; 96: 3647-3654Crossref PubMed Scopus (88) Google Scholar). Also, we have established that the hypoxia-induced SR Ca2+ release initiates and maintains acute HPV (11Dipp M. Nye P.C.G. Evans A.M. J. Physiol. 2000; 526: S26PGoogle Scholar). Details of the signal transduction pathway remain to be clarified. One possibility is that the β-NAD+ metabolite cyclic ADP-ribose (cADPR; Refs.14Lee H.C. Walseth T.F. Bratt G.T. Hayes R.N. Clapper D.L. J. Biol. Chem. 1989; 264: 1608-1615Abstract Full Text PDF PubMed Google Scholar, 15Walseth T. Aarhus R. Zeleznikar R. Lee H.C. Biochim. Biophys. Acta. 1991; 1094: 113-120Crossref PubMed Scopus (112) Google Scholar, 16Galione A. Science. 1993; 259: 325-326Crossref PubMed Scopus (220) Google Scholar), a messenger that regulates SR Ca2+ release via ryanodine receptors (RyRs) in a variety of cell types (17Galione A. Lee H.C. Busa W.B. Science. 1991; 253: 1143-1146Crossref PubMed Scopus (553) Google Scholar, 18Galione A. Summerhill R.S. Sorrentino V. Ryanodine Receptors. CRC Press, Boca Raton, FL1996: 52-70Google Scholar, 19Lee H.C. Physiol. Rev. 1997; 77: 1133-1164Crossref PubMed Scopus (332) Google Scholar), plays a role in this process. We have investigated the role of the β-NAD+:β-NADH ratio in regulating cADPR synthesis in pulmonary artery smooth muscle because of the fact that (a) the cellular redox couple β-NAD+ is the recognized substrate for cADPR synthesis; (b) the redox state of O2-sensing cells is uniquely sensitive to changes in the level of O2 (20Duchen M.R. J. Physiol. 1999; 516: 1-17Crossref PubMed Scopus (533) Google hypoxia has been to the ratio in O2-sensing cells to cells (20Duchen M.R. J. Physiol. 1999; 516: 1-17Crossref PubMed Scopus (533) Google Scholar, M.R. J. Physiol. PubMed Scopus Google Scholar), cells C. C. H. E. 1993; Google Scholar), and pulmonary artery smooth muscle cells S.L. Huang J. Henry T. Peterson D. Weir E.K. Circ. Res. 1993; 73: 1100-1112Crossref PubMed Scopus (332) Google Scholar, T. S. A. T. S. Am. J. Physiol. PubMed Google and the hypoxia-induced in the ratio in cells with a to the hypoxia-induced increase in intracellular Ca2+ M.R. J. Physiol. PubMed Scopus Google Scholar). We that the for cADPR synthesis and metabolism are in pulmonary artery smooth muscle, as to systemic artery smooth We that hypoxia, by β-NADH cADPR which in an increase in cADPR levels in pulmonary artery smooth Furthermore, we that a membrane-permeant cADPR antagonist, 8-bromo-cADPR, the sustained phase of role of and cADPR hydrolase as a redox is and by and and in and arteries, arteries, and and was by the with a and artery and in of and was by an a for at to and was at of cADPR from and metabolism of was in of smooth muscle at for cADPR a Ca2+ release muscle cells isolated as described Gurney A.M. Physiol. 1991; PubMed Scopus Google Scholar). to cells in at for at and in (a) (b) of and with for at was by and in an intracellular and as described A. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. 1997; Scopus Google Scholar). also and and and was as a in Ca2+ induced by at of in a cADPR was by of ryanodine receptors D.L. Walseth T.F. Lee H.C. J. Biol. Chem. 262: Full Text PDF PubMed Google Scholar) and by with A. J. PubMed Scopus Google Scholar). substrate was of the cyclic was with and of and Walseth T.F. Lee H.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar). in with by and cell membrane and Evans Press, Scholar). the in isolated pulmonary artery smooth muscle cells at current and the cell of the as described A.M. O.N. Gurney A.M. J. Physiol. Scopus Google Scholar). and an and and was and was 2 and 2 from the the of the pulmonary in on to the of an was to be to pulmonary and have been described W. J. Physiol. 265: Scholar). in as for with and at and in a of was with to a of arteries first to of to and was to be and with hypoxic via a was an O2 and to the to to the When the of the arteries was by the with of the was by the of to induced by and of the pulmonary artery in that and with hypoxic as described above from the and in of was a of a described H.C. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar). the was to and for the in an for to for of was by for was by the of 2 was by at for that with the with and for as described T. Aarhus R. Zeleznikar R. Lee H.C. Biochim. Biophys. Acta. 1991; 1094: 113-120Crossref PubMed Scopus (112) Google Scholar). of cADPR in was by on the with a a was at for to cADPR to on of was abolished by of by of to was was for of synthesis of and of to described A. C. J. H. in CRC Press, Boca Raton, Scholar, Walseth T.F. Lee H.C. 1997; PubMed Scopus Google Scholar). from from which was from and which was from was by of and as the for In was in the of cADPR synthesis from β-NAD+ in smooth muscle homogenates from of the pulmonary as by the synthesis was when of cADPR synthesized of a of by This was at when of cADPR been of in that an substrate for a cyclic when was to smooth muscle homogenates of of the pulmonary When was in was with of a increase in the was with 2). increase in was on cyclic and because it was by the also A. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google and A. J. 1997; Scopus Google Scholar). Because and intracellular with have been Walseth T.F. Lee H.C. Science. 1993; 262: PubMed Scopus Google Scholar), it was to not cADPR be synthesized because this be to an intracellular this we the in the cellular from of smooth muscle homogenates from of the pulmonary that the synthesis of cADPR was in of the membrane However, the of synthesis was in the SR and at of compared with of in the of in the and cell and of in the 2 a for cADPR of metabolism was in the SR and at of compared with of in the In the hydrolase in the and cell and in the was 2 the of a to the level of membrane associated in level of was for the compared with for the and for the and cell the a level of and cADPR hydrolase the and cADPR hydrolase the membrane 2 cADPR synthesis and pulmonary artery smooth muscle cells isolated from the level of synthesis was in smooth muscle Thus, a with of cADPR in cells and in and cells 2 in the level of cADPR synthesis in pulmonary artery smooth muscle cells, was at the This may be a of (a) the of the Ca2+ release to cADPR and (b) the for of the synthesized cADPR to in the that the was to have on the Ca2+ release 2 a of an isolated and pulmonary artery smooth muscle cell in the level of cADPR synthesis by homogenates of pulmonary and systemic smooth muscle a with of cADPR was in smooth muscle homogenates from of the pulmonary be in homogenates of the the level of cADPR synthesis was to pulmonary artery of in homogenates of the in the of the pulmonary artery and in the that the of of cADPR in the of artery homogenates followed a in smooth muscle homogenates of the in and in homogenates of the In contrast to cADPR synthesis, a amount of cADPR was in homogenates of the and the arteries findings suggest that and cADPR may an role in the regulation of pulmonary artery smooth muscle cell the of synthesis of cADPR from a of β-NAD+ to the of synthesis of cADPR from β-NADH β-NADH can be to be a substrate for in pulmonary artery smooth However, of β-NADH in with β-NAD+ to a increase in cADPR synthesis when compared with the synthesis in the of β-NAD+ the of β-NADH on the synthesis of cADPR from a of β-NAD+ in smooth muscle homogenates from of the pulmonary β-NADH increased the of synthesis of cADPR from β-NAD+ in a of synthesis of cADPR increased from of in the absence of β-NADH to a of of in the of β-NADH. fact that β-NADH increased cADPR synthesis from a of β-NAD+ the possibility that β-NADH may this via the inhibition of cADPR that β-NADH the of cADPR in pulmonary artery smooth muscle In smooth muscle homogenates of of the pulmonary of cADPR in the absence of β-NADH. This to in the of 2 β-NADH and was in the of β-NADH. findings suggest that net amount of cADPR accumulated from β-NAD+ may be increased by β-NADH in a and This may be due, at least in part, to the inhibition by β-NADH of cADPR that the amount of cADPR synthesis with β-NADH may be due, in part, to the β-NAD+ We a receptor to the cADPR of pulmonary artery smooth muscle and hypoxic that the level of cADPR in of the pulmonary artery increased in the of hypoxia from to the increase in cADPR induced by hypoxia was in of the pulmonary in which we a 10-fold increase in cADPR from to We the of pulmonary artery smooth muscle Ca2+ stores to This was by cADPR from a in the cell and in current in intracellular Ca2+ by changes in the membrane via the activation of channels in smooth muscle cells isolated from and of the pulmonary In the absence of cADPR the membrane was at in with the findings of others Lee J. Physiol. 1999; Scopus Google Scholar). In marked the of intracellular of cADPR from the the membrane the at the of the cADPR induced a of the membrane a at which in the membrane When the in membrane the smooth muscle cells to and it to the smooth muscle cells in a cell for of the membrane from the cell to in membrane and cell not the ryanodine-sensitive SR stores been by of ryanodine and the membrane at for the of the activation of channels was by the fact that the was not in the of not not suggest that cADPR can induce from ryanodine-sensitive SR stores in pulmonary artery smooth muscle We investigated the of a membrane-permeant of A. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), on HPV in isolated pulmonary artery rings. that hypoxia induced a characteristic constriction in an pulmonary artery the response in the absence of the pulmonary artery initial transient constriction in the slowly developing, tonic phase of constriction is the constriction to a level above that is for the of to (11Dipp M. Nye P.C.G. Evans A.M. J. Physiol. 2000; 526: S26PGoogle Scholar) have that the initial transient constriction and the on Ca2+ release from ryanodine-sensitive SR stores. and of the on the hypoxic constriction of and arteries with of the for the constriction in the and absence of 8-bromo-cADPR, with and the of the transient constriction in the of In marked the phase of the hypoxia-induced constriction was abolished in the and absence of the suggest that SR Ca2+ release is to hypoxia-induced constriction of pulmonary artery smooth However, the of phase 2 of HPV also the release of an vasoconstrictor T.P. Aaronson P.I. Ward J.P.T. Am. J. Physiol. 1995; 268: H301-H307PubMed Google Scholar). Because abolished phase 2 of HPV when the was we that this was due, in part, to inhibition of vasoconstrictor release from the the of the of the vasoconstrictor in the smooth We that the vasoconstrictor constriction by the smooth muscle to Ca2+ and that it not to Ca2+ in right T.P. Aaronson P.I. Ward J.P.T. Am. J. Physiol. 1995; 268: H301-H307PubMed Google Scholar). Thus, we arteries that have been by Ca2+ from the to on release of the vasoconstrictor hypoxia, when SR Ca2+ release has been by Because pulmonary artery constriction by the smooth muscle cell membrane and activating voltage-gated Ca2+ we to pulmonary arteries with in the of We to a constriction in to the constriction that was by hypoxia and by also a response to hypoxia as the response of the to hypoxia the been with the of on the constriction to hypoxia, the been with and when as a of the constriction to hypoxia induced a constriction in to in the and absence of of phase in the absence of and in the absence of in the absence of and in the of and in the of and of phase 2 of HPV of to hypoxia in the absence of and in the absence of in the absence of and in the of and in the of and This that SR Ca2+ release to hypoxia, it not hypoxia-induced release of the the constriction to Ca2+ pulmonary vasoconstriction is not by in pulmonary arteries with constriction to pulmonary artery was to hypoxia for the artery from the to hypoxia, the was to first a response to was with and to hypoxia a response to was with 8-bromo-cADPR, with and to hypoxia results from the artery at of which is on acute HPV of in isolated pulmonary artery not This the that the cADPR is We have investigated the role of cADPR and cADPR as a redox in pulmonary artery smooth Our findings suggest that increased cADPR synthesis may in part, the hypoxia-induced increase in SR in pulmonary artery smooth muscle and to We a level of cADPR in smooth muscle homogenates from pulmonary arteries, synthesis be in smooth muscle homogenates from arteries. was with to the metabolism of a amount of metabolism was in homogenates of and artery smooth we have that synthesis and metabolism of cADPR findings to an role for cADPR hydrolase and cADPR in the regulation of pulmonary artery for this proposal from the fact that the level of cADPR synthesis in pulmonary artery homogenates was to artery higher in homogenates from the it was in the homogenates of the Because the of the hypoxic constriction is also to artery Pharmacol. Full Text PDF PubMed Scopus (88) Google Scholar, T.P. Ward J.P.T. Am. J. Physiol. Google Scholar), the of hypoxia to pulmonary arteries with the levels of smooth muscle and cADPR hydrolase An is that hypoxia may increase the of synthesis of cADPR in pulmonary artery smooth In a of we that β-NADH induced a increase in the of cADPR synthesis from a and of substrate Because β-NADH was to be a substrate for cADPR synthesis, this was We also β-NADH to in a cADPR metabolism in pulmonary artery smooth muscle Thus, β-NADH may promote an increase in cADPR from β-NAD+, at least in part, by the metabolism of cADPR by a cADPR of β-NADH on cADPR synthesis may be of to the regulation of O2-sensing cells because the redox state of such cells is uniquely sensitive to changes in O2 S.L. Huang J. Henry T. Peterson D. Weir E.K. Circ. Res. 1993; 73: 1100-1112Crossref PubMed Scopus (332) Google Scholar, M.R. J. Physiol. 1999; 516: 1-17Crossref PubMed Scopus (533) Google M.R. J. Physiol. PubMed Scopus Google Scholar, C. C. H. E. 1993; Google Scholar), and hypoxia has been to increase β-NADH levels in O2-sensing cells to S.L. Huang J. Henry T. Peterson D. Weir E.K. Circ. Res. 1993; 73: 1100-1112Crossref PubMed Scopus (332) Google Scholar, M.R. J. Physiol. 1999; 516: 1-17Crossref PubMed Scopus (533) Google Scholar, M.R. J. Physiol. PubMed Scopus Google Scholar, C. C. H. E. 1993; Google Scholar, T. S. A. T. S. Am. J. Physiol. PubMed Google Scholar). of pulmonary artery smooth muscle suggest that β-NAD+ levels may be in the and hypoxia and that hypoxia a in β-NAD+ levels a increase in β-NADH suggest that β-NADH in the smooth muscle may increase at least hypoxia from T. S. A. T. S. Am. J. Physiol. PubMed Google Scholar) to T. S. A. T. S. Am. J. Physiol. PubMed Google Scholar). However, it be that of β-NAD+ and β-NADH levels are of the levels that may be in a of and that the for of the They do not which may in of β-NAD+ and β-NADH levels In fact and the for cADPR synthesis and metabolism may be in cellular from the membrane to the M. J. 2000; PubMed Scopus Google Scholar). In hypoxia may the redox state of the by Sylvester J.T. Am. J. Physiol. 2000; Scholar) the redox state (20Duchen M.R. J. Physiol. 1999; 516: 1-17Crossref PubMed Scopus (533) Google Scholar). It that β-NAD+:β-NADH of and T. S. A. T. S. Am. J. Physiol. PubMed Google Scholar), and the is to the of β-NAD+:β-NADH over which that we may an increase in cADPR synthesis from the above findings and the fact that the hypoxia-induced increase in in cells over the as the hypoxia-induced increase in intracellular Ca2+ M.R. J. Physiol. PubMed Scopus Google Scholar), it that hypoxia may promote SR Ca2+ release by the ratio and by cADPR This proposal support from the that cADPR levels increased when pulmonary arteries to hypoxia Furthermore, a increase in cADPR was in in of the pulmonary Thus, the the of the hypoxia-induced increase in cADPR was to artery as is the of the arteries to hypoxia Pharmacol. Full Text PDF PubMed Scopus (88) Google Scholar, T.P. Ward J.P.T. Am. J. Physiol. Google Scholar). In we first that cADPR induced Ca2+ release from ryanodine-sensitive SR stores in isolated pulmonary artery smooth muscle cells, as hypoxia (11Dipp M. Nye P.C.G. Evans A.M. J. Physiol. 2000; 526: S26PGoogle Scholar, R.I. Toland H. Gelband C.H. Wang X.X. Hume J.R. Br. J. Pharmacol. 1997; 122: 21-30Crossref PubMed Scopus (121) Google Scholar, 13Gelband C.H. Gelband H. Circulation. 1997; 96: 3647-3654Crossref PubMed Scopus (88) Google Scholar). We investigated the role of cADPR in a membrane-permeant cADPR antagonist, Our findings suggest that hypoxia and from ryanodine-sensitive SR stores. first transient phase of constriction to hypoxia in the of Thus, a O2-sensing mechanism the ryanodine-sensitive SR associated with this phase of HPV (11Dipp M. Nye P.C.G. Evans A.M. J. Physiol. 2000; 526: S26PGoogle Scholar). have that phase of HPV may from an initial in levels and inhibition of the SR Ca2+ to an increase in the net of Ca2+ from the SR T.P. D. Aaronson P.I. Ward J.P.T. J. Physiol. 2000; PubMed Scopus Google This may in promote influx because of the activation of the current T.P. D. Aaronson P.I. Ward J.P.T. J. Physiol. 2000; PubMed Scopus Google Scholar). findings T.P. D. Aaronson P.I. Ward J.P.T. J. Physiol. 2000; PubMed Scopus Google Scholar) and (11Dipp M. Nye P.C.G. Evans A.M. J. Physiol. 2000; 526: S26PGoogle Scholar), do not support the (2Post J. Hume J. Archer S. Weir E. Am. J. Physiol. 1992; 262: C882-C890Crossref PubMed Google Scholar, 3Archer S.L. Huang J. Henry T. Peterson D. Weir E.K. Circ. Res. 1993; 73: 1100-1112Crossref PubMed Scopus (332) Google Scholar, 4Osipenko O.N. Evans A.M. Gurney A.M. Br. J. Pharmacol. 1997; 120: 1461-1470Crossref PubMed Scopus (122) Google Scholar, D. Madden J. Dawson C. J. Appl. Physiol. 1985; 59: 1389-1393Crossref PubMed Scopus (76) Google Scholar, 6Madden J. Vadula M. Kurup V. Am. J. Physiol. 1992; 263: L384-L393Crossref PubMed Google Scholar, 7Cornfield D. Stevens T. McMurty I. Abman S. Rodman D. Am. J. Physiol. 1993; 265: L1-L4Crossref PubMed Google Scholar, 8Salvaterra C. Goldman W. Am. J. Physiol. 1993; 264: L323-L328Crossref PubMed Google Scholar) that phase of HPV in isolated vessels is by through voltage-gated Ca2+ In marked the sustained phase of acute HPV in pulmonary artery which is also by ryanodine-sensitive SR Ca2+ release (11Dipp M. Nye P.C.G. Evans A.M. J. Physiol. 2000; 526: S26PGoogle Scholar), was by This that a sustained increase in SR and constriction may depend on an increase in cADPR synthesis HPV the was that the tonic phase of HPV in isolated pulmonary artery was abolished by and be the arteries with and findings suggest that an increase in cADPR levels and SR Ca2+ release in the smooth muscle is for the of acute that not (a) constriction to Ca2+ (b) the release of the vasoconstrictor in response to hypoxia, the increase in by the Thus, the release of the vasoconstrictor the tonic phase of HPV (9Kovitz K.L. Aleskowitch J.T. Sylvester J.T. Flavahan N.A. Am. J. Physiol. 1993; 260: L516-L521Google Scholar, 10Robertson T.P. Aaronson P.I. Ward J.P.T. Am. J. Physiol. 1995; 268: H301-H307PubMed Google Scholar, T.P. Ward J.P.T. Am. J. Physiol. Google Scholar) may be to promote pulmonary artery constriction in the absence of SR Ca2+ the fact that the vasoconstrictor may a associated and increase smooth muscle M. Ward J.P.T. Aaronson P.I. Evans A.M. Br. J. Pharmacol. 2000; PubMed Scopus Google and the it may be of that the level of cADPR synthesis is at least 2 of higher in pulmonary artery smooth muscle it is in systemic artery smooth Thus, in pulmonary artery smooth muscle hypoxia may induce an increase in cADPR levels at least 2 of that in systemic artery smooth This may a for the pulmonary of systemic arteries dilate in response to This is a because ryanodine receptor and may be in systemic and pulmonary smooth muscle A. E. G. J. Physiol. 1991; PubMed Scopus Google Scholar), and can be in a M. Biophys. Res. 1997; PubMed Scopus Google Scholar, A. J. 1999; PubMed Scopus Google Scholar, A. A. H. Sorrentino V. J. PubMed Scopus Google Scholar). In findings suggest that (a) the for the metabolism of cADPR are higher in pulmonary artery smooth muscle are in systemic artery smooth (b) the of was in the pulmonary arteries, which the to an increase in β-NADH increased the net amount of cADPR synthesized from β-NAD+, and this was due, at least in part, to the inhibition by β-NADH of cADPR hypoxia increased cADPR levels in pulmonary cADPR induced Ca2+ release from ryanodine-sensitive SR stores in pulmonary artery smooth muscle and 8-bromo-cADPR, a cADPR antagonist, abolished the sustained phase of acute HPV in arteries. We propose that cADPR and cADPR as a redox that changes in the cellular redox to SR Ca2+ release and that cADPR is the of acute This pathway may offer an new therapeutic for the of hypoxic pulmonary hypertension. It is also that this pathway may a role in (a) and (b) Ca2+ in cells, in which cADPR may and in which in and in Ca2+ H. S. 1997; PubMed Scopus Google Scholar, T. J. 1997; PubMed Scopus Google Scholar, R. 1999; PubMed Scopus Google Scholar). We are to for