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Effect of hypoxia on vasodilator responses to S-nitroso-N-acetylpenicillamine and levcromakalim in guinea pig basilar artery

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Abstract

Ischaemic stroke is characterised by reduction of blood flow, tissue hypoxia, energy depletion and neuronal death. Drugs causing vasodilatation of cerebral arteries may potentially enhance blood supply to the ischaemic area and improve clinical outcome. However, vasodilators could also reduce cerebral blood flow in the ischaemic region by acting on blood vessels in non-ischaemic tissue, a phenomenon known as blood flow steal. To explore whether these drugs could act selectively on cerebral blood vessels in a hypoxic environment, we examined the effect of hypoxia on vasodilator responses to the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and the ATP-dependent potassium channel (KATP) opener levcromakalim in guinea-pig basilar arteries contracted by endothelin-1. Hypoxia considerably enhanced the vasodilator responses to SNAP, while those to levcromakalim were unaffected. In the presence of the NO synthase inhibitor NG-nitro-L-arginine, hypoxia no longer enhanced the vasodilator response to SNAP and suppressed responses to levcromakalim. The results show that the NO donor SNAP, but not the KATP opener levcromakalim, is a more effective vasodilator of cerebral arteries contracted by endothelin-1 during hypoxia than under control conditions. Hypoxia-induced inhibition of basal NO synthesis could explain this enhancement of the vasodilator response to SNAP. Thus, NO donors may have a selective effect on blood vessels in ischaemic brain areas and therefore warrant further evaluation as therapeutic agents in cerebral ischaemia.

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References

  • Ahmed N, Nasman P, Wahlgren NG (2000) Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke 31:1250–1255

    CAS  PubMed  Google Scholar 

  • Ames A III, Wright RL, Kowada M, Thurston JM, Majno G (1968) Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol 52:437–453

    PubMed  Google Scholar 

  • Ashcroft FM, Gribble FM (1998) Correlating structure and function in ATP-sensitive K+ channels. Trends Neurosci 21:288–294

    CAS  PubMed  Google Scholar 

  • Astrup J, Siesjo BK, Symon L (1981) Thresholds in cerebral ischemia—the ischemic penumbra. Stroke 12:723–725

    CAS  PubMed  Google Scholar 

  • Auch-Schwelk W, Vanhoutte PM (1991) Calcium antagonists inhibit contractions to norepinephrine in the rat aorta, in the absence, but not in the presence of the endothelium. Gen Pharmacol 22:595–602

    Article  CAS  PubMed  Google Scholar 

  • Bari F, Louis TM, Meng W, Busija DW (1996) Global ischemia impairs ATP-sensitive K+ channel function in cerebral arterioles in piglets. Stroke 27:1874–1880; discussion 1880–1881

    CAS  PubMed  Google Scholar 

  • Bath FJ, Butterworth RJ, Bath PM (2000) Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev 2

  • Butterworth RJ, Cluckie A, Jackson SH, Buxton-Thomas M, Bath PM (1998) Pathophysiological assessment of nitric oxide (given as sodium nitroprusside) in acute ischaemic stroke. Cerebrovasc Dis 8:158–165

    CAS  PubMed  Google Scholar 

  • Chiueh CC (1999) Neuroprotective properties of nitric oxide. Ann NY Acad Sci 890:301–311

    CAS  PubMed  Google Scholar 

  • Faraci FM, Heistad DD (1998) Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 78:53–97.

    CAS  PubMed  Google Scholar 

  • Fredricks KT, Liu Y, Rusch NJ, Lombard JH (1994) Role of endothelium and arterial K+ channels in mediating hypoxic dilation of middle cerebral arteries. Am J Physiol 267:H580–H586

    CAS  PubMed  Google Scholar 

  • Fujita H, Takizawa S, Nanri K, Matsushima K, Ogawa S, Shinohara Y (1997) Potassium channel opener reduces extracellular glutamate concentration in rat focal cerebral ischemia. Brain Res Bull 43:365–368

    Article  CAS  PubMed  Google Scholar 

  • Heurteaux C, Bertaina V, Widmann C, Lazdunski M (1993) K+ channel openers prevent global ischemia-induced expression of c-fos, c-jun, heat shock protein, and amyloid beta-protein precursor genes and neuronal death in rat hippocampus. Proc Natl Acad Sci USA 90:9431–9435

    Google Scholar 

  • Högestätt ED, Andersson KE, Edvinsson L (1983) Mechanical properties of rat cerebral arteries as studied by a sensitive device for recording of mechanical activity in isolated small blood vessels. Acta Physiol Scand 117:49–61

    PubMed  Google Scholar 

  • Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265:1883–1885

    CAS  PubMed  Google Scholar 

  • Husken BC, Pfaffendorf M, van Zwieten PA (1997) ATP-sensitive potassium channels in isolated rat aorta during physiologic, hypoxic, and low-glucose conditions. J Cardiovasc Pharmacol 29:130–135

    Article  CAS  PubMed  Google Scholar 

  • Joshi S, Young WL, Pile-Spellman J, Fogarty-Mack P, Sciacca RR, Hacein-Bey L, Duong H, Vulliemoz Y, Ostapkovich N, Jackson T (1997) Intra-arterial nitrovasodilators do not increase cerebral blood flow in angiographically normal territories of arteriovenous malformation patients. Stroke 28:1115–1122

    CAS  PubMed  Google Scholar 

  • Levy DE, Van Uitert RL, Pike CL (1979) Delayed postischemic hypoperfusion: a potentially damaging consequence of stroke. Neurology 29:1245–1252

    CAS  PubMed  Google Scholar 

  • Lipton SA, Choi YB, Sucher NJ, Chen HS (1998) Neuroprotective versus neurodestructive effects of NO-related species. Biofactors 8:33–40

    CAS  PubMed  Google Scholar 

  • Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012

    CAS  PubMed  Google Scholar 

  • Petersson J, Andersson KE, Brandt L, Högestätt ED (1997a) Modulation by the endothelium of the inhibitory effects of pinacidil and nimodipine on endothelin-induced contraction in cerebral arteries. Pharmacol Toxicol 80:30–37

    CAS  PubMed  Google Scholar 

  • Petersson J, Zygmunt PM, Högestätt ED (1997b) Characterization of the potassium channels involved in EDHF-mediated relaxation in cerebral arteries. Br J Pharmacol 120:1344–1350

    CAS  PubMed  Google Scholar 

  • Petersson J, Zygmunt PM, Jonsson P, Högestätt ED (1998) Characterization of endothelium-dependent relaxation in guinea pig basilar artery—effect of hypoxia and role of cytochrome P450 mono-oxygenase. J Vasc Res 35:285–294

    CAS  PubMed  Google Scholar 

  • Petersson J, Ryman T, Högestätt ED (2000) Vasodilator effects of KRN2391, levcromakalim and 3-morpholino-sydnonimin in human pial and omental arteries. Naunyn Schmiedebergs Arch Pharmacol 362:68–73

    Article  CAS  PubMed  Google Scholar 

  • Reshef A, Sperling O, Zoref-Shani E (1998) Opening of ATP-sensitive potassium channels by cromakalim confers tolerance against chemical ischemia in rat neuronal cultures. Neurosci Lett 250:111–114

    Article  CAS  PubMed  Google Scholar 

  • Ryman T, Petersson J, Andersson KE, Brandt L, Högestätt ED (1993) Effects of pinacidil on cerebral and mesenteric arteries—influence of the endothelium. Naunyn Schmiedebergs Arch Pharmacol 348:298–304

    CAS  PubMed  Google Scholar 

  • Schulz W, Jost S, Kober G, Kaltenbach M (1985) Relation of antianginal efficacy of nifedipine to degree of coronary arterial narrowing and to presence of coronary collateral vessels. Am J Cardiol 55:26–32

    CAS  PubMed  Google Scholar 

  • Standen NB, Quayle JM, Davies NW, Brayden JE, Huang Y, Nelson MT (1989) Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 245:177–180

    CAS  PubMed  Google Scholar 

  • Stauton M, Drexler C, Dulitz MG, Ekbom DC, Schmeling WT, Farber NE (1999) Effects of hypoxia-reoxygenation on microvascular endothelial function in the rat hippocampal slice. Anesthesiology 91:1462–1469

    CAS  PubMed  Google Scholar 

  • Sugai K, Yaganisawa T, Motohashi O, Suzuki M, Yoshimoto T (1999) Levcromakalim decreases cytoplasmic Ca2+ and vascular tone in basilar artery of SAH model dogs. J Cardiovasc Pharmacol 33:868–875

    Article  CAS  PubMed  Google Scholar 

  • Taggart MJ, Wray S (1998) Hypoxia and smooth muscle function: key regulatory events during metabolic stress. J Physiol 509:315–325

    CAS  PubMed  Google Scholar 

  • Takaba H, Nagao T, Yao H, Kitazono T, Ibayashi S, Fujishima M (1997) An ATP-sensitive potassium channel activator reduces infarct volume in focal cerebral ischemia in rats. Am J Physiol 273:R583–R586

    CAS  PubMed  Google Scholar 

  • Taylor SG, Weston AH (1988) Endothelium-derived hyperpolarizing factor: a new endogenous inhibitor from the vascular endothelium. Trends Pharmacol Sci 9:272–274

    Article  CAS  PubMed  Google Scholar 

  • Thomas JE, Rosenwasser RH (1999) Reversal of severe cerebral vasospasm in three patients after aneurysmal subarachnoid hemorrhage: initial observations regarding the use of intraventricular sodium nitroprusside in humans. Neurosurgery 44:48–57; discussion 57–58

    CAS  PubMed  Google Scholar 

  • Zhang F, White JG, Iadecola C (1994) Nitric oxide donors increase blood flow and reduce brain damage in focal ischemia: evidence that nitric oxide is beneficial in the early stages of cerebral ischemia. J Cereb Blood Flow Metab 14:217–226

    Google Scholar 

  • Zygmunt PM, Waldeck K, Högestätt ED (1994) The endothelium mediates a nitric oxide-independent hyperpolarization and relaxation in the rat hepatic artery. Acta Physiol Scand 152:375–384

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Swedish Research Council (grant no. 11582.), the Heart and Lung Foundation and the Medical Faculty of Lund (ALF). J.P. was supported by the Medical Faculty of Lund (ALF). The study was approved by the local ethics committee for experimental animal studies.

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Correspondence to Jesper Petersson.

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Movahed, P., Högestätt, E.D. & Petersson, J. Effect of hypoxia on vasodilator responses to S-nitroso-N-acetylpenicillamine and levcromakalim in guinea pig basilar artery. Naunyn-Schmiedeberg's Arch Pharmacol 367, 532–537 (2003). https://doi.org/10.1007/s00210-003-0711-x

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