Skip to main content

Local Metabolic Factors and Vasoactivity

  • Chapter
  • First Online:
Biology of Vascular Smooth Muscle: Vasoconstriction and Dilatation
  • 816 Accesses

Abstract

The regulation of vasoreactivity by local metabolites is a key mechanism to ensure adequate blood flow so that adequate O2 are supplied for the needed tissues and metabolic wastes are timely removed. Many metabolic factors may participate in the regulation of vascular activity such as local Po2, Pco2, pH, K+, adenosine, and lactate. These metabolic factors affect vasoactivity either by directly acting on vascular smooth muscle cells (VSMCs) or by acting on the endothelial cells, resulting in altered cytosolic Ca2+ level and Ca2+ sensitivity of myofilaments in VSMCs and thus altered vasoactivity. For a metabolic factor to be involved, it must be released in a sufficient amount from the tissues and diffuse to the nearby vasculature. Since the formation and release profile of metabolic factors vary under different conditions, their relative importance in affecting vasoactivity varies under different conditions. Under most conditions there appears no single factor that is indispensable for the metabolic regulation of vasoactivity. More likely this process is regulated by multiple factors in a redundant manner. Such a concept is exemplified in exercise-induced vasodilatation in skeletal muscle.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aalkjaer C, Hughes A (1991) Chloride and bicarbonate transport in rat resistance arteries. J Physiol 436:57–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aalkjaer C, Boedtkjer E, Choi I, Lee S (2014) Cation-coupled bicarbonate transporters. Compr Physiol 4:1605–1637

    Article  PubMed  PubMed Central  Google Scholar 

  • Ballard HJ (2014) ATP and adenosine in the regulation of skeletal muscle blood flow during exercise. Sheng Li Xue Bao 66:67–78

    CAS  PubMed  Google Scholar 

  • Baretella O, Xu A, Vanhoutte PM (2014) Acidosis prevents and alkalosis augments endothelium-dependent contractions in mouse arteries. Pflugers Arch 466:295–305

    Article  CAS  PubMed  Google Scholar 

  • Berne RM (1963) Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Phys 204:317–322

    CAS  Google Scholar 

  • Berwick ZC, Payne GA, Lynch B, Dick GM, Sturek M, Tune JD (2010) Contribution of adenosine A2A and A2B receptors to ischemic coronary dilation: role of KV and KATP channels. Microcirculation 17:600–607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boedtkjer E, Aalkjaer C (2012) Intracellular pH in the resistance vasculature: regulation and functional implications. J Vasc Res 49:479–496

    Article  CAS  PubMed  Google Scholar 

  • Boedtkjer E, Praetorius J, Aalkjaer C (2006) NBCn1 (slc4a7) mediates the na+-dependent bicarbonate transport important for regulation of intracellular pH in mouse vascular smooth muscle cells. Circ Res 98:515–523

    Article  CAS  PubMed  Google Scholar 

  • Boedtkjer E, Praetorius J, Fuchtbauer EM, Aalkjaer C (2008) Antibody-independent localization of the electroneutral Na+-HCO3 − cotransporter NBCn1 (slc4a7) in mice. Am J Phys Cell Physiol 294:C591–C603

    Article  CAS  Google Scholar 

  • Boedtkjer E, Praetorius J, Matchkov VV, Stankevicius E, Mogensen S, Füchtbauer AC, Simonsen U, Füchtbauer EM, Aalkjaer C (2011) Disruption of Na+,HCO3 − cotransporter NBCn1 (slc4a7) inhibits NO-mediated vasorelaxation, smooth muscle Ca2+ sensitivity, and hypertension development in mice. Circulation 124:1819–1829

    Article  CAS  PubMed  Google Scholar 

  • Boedtkjer E, Damkier HH, Aalkjaer C (2012) NHE1 knockout reduces blood pressure and arterial media/lumen ratio with no effect on resting pHi in the vascular wall. J Physiol 590:1895–1906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brooks GA (2016) Energy flux, lactate shuttling, mitochondrial dynamics, and hypoxia. Adv Exp Med Biol 903:439–455

    Article  PubMed  Google Scholar 

  • Brosius FC III, Pisoni RL, Cao X, Deshmukh G, Yannoukakos D, Stuart-Tilley AK, Haller C, Alper SL (1997) AE anion exchanger mRNA and protein expression in vascular smooth muscle cells, aorta, and renal microvessels. Am J Phys 273:F1039–F1047

    CAS  Google Scholar 

  • Buckler KJ (2015) TASK channels in arterial chemoreceptors and their role in oxygen and acid sensing. Pflugers Arch 467:101310–101325

    Article  Google Scholar 

  • Calderón-Sánchez E, Fernández-Tenorio M, Ordóñez A, López-Barneo J, Ureña J (2009) Hypoxia inhibits vasoconstriction induced by metabotropic Ca2+ channel-induced Ca2+ release in mammalian coronary arteries. Cardiovasc Res 82:115–124

    Article  PubMed  Google Scholar 

  • Chen YL, Wolin MS, Messina EJ (1996) Evidence for cGMP mediation of skeletal muscle arteriolar dilation to lactate. J Appl Physiol 81:349–354

    CAS  PubMed  Google Scholar 

  • Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets--what are the challenges? Nat Rev Drug Discov 12:265–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng B, Essackjee HC, Ballard HJ (2000) Evidence for control of adenosine metabolism in rat oxidative skeletal muscle by changes in pH. J Physiol 522:467–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coburn RF, Moreland S, Moreland RS, Baron CB (1992) Rate-limiting energy-dependent steps controlling oxidative metabolism-contraction coupling in rabbit aorta. J Physiol 448:473–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Damkier HH, Nielsen S, Praetorius J (2006) An anti-NH2-terminal antibody localizes NBCn1 to heart endothelia and skeletal and vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 290:H172–H180

    Article  CAS  PubMed  Google Scholar 

  • Detar R, Bohr DF (1968) Oxygen and vascular smooth muscle contraction. Am J Phys 214:241–244

    CAS  Google Scholar 

  • Deussen A, Ohanyan V, Jannasch A, Yin L, Chilian W (2012) Mechanisms of metabolic coronary flow regulation. J Mol Cell Cardiol 52:794–801

    Article  CAS  PubMed  Google Scholar 

  • Dou D, Zheng X, Ying L, Ye L, Gao Y (2013) Sulfhydryl-dependent dimerization and cGMP-mediated vasodilatation. J Cardiovasc Pharmacol 62:1–5

    Article  CAS  PubMed  Google Scholar 

  • Duncker DJ, Bache RJ (2008) Regulation of coronary blood flow during exercise. Physiol Rev 88:1009–1086

    Article  CAS  PubMed  Google Scholar 

  • Edlund A, Sollevi A, Wennmalm A (1989) The role of adenosine and prostacyclin in coronary flow regulation in healthy man. Acta Physiol Scand 135:39–46

    Article  CAS  PubMed  Google Scholar 

  • Fleming I, Hecker M, Busse R (1994) Intracellular alkalinization induced by bradykinin sustains activation of the constitutive nitric oxide synthase in endothelial cells. Circ Res 74:1220–1226

    Article  CAS  PubMed  Google Scholar 

  • Frøbert O, Haink G, Simonsen U, Gravholt CH, Levin M, Deussen A (2006) Adenosine concentration in the porcine coronary artery wall and A2A receptor involvement in hypoxia-induced vasodilatation. J Physiol 570:375–384

    Article  PubMed  Google Scholar 

  • Furchgott RF (1966) Metabolic factors that influence contractility of vascular smooth muscle. Bull N Y Acad Med 42:996–1006

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gebremedhin D, Yamaura K, Harder DR (2008) Role of 20-HETE in the hypoxia-induced activation of Ca2+-activated K+ channel currents in rat cerebral arterial muscle cells. Am J Physiol Heart Circ Physiol 294:H107–H120

    Article  CAS  PubMed  Google Scholar 

  • Gerlach E, Deuticke B, Dreisbach RH (1963) Der Nucleotid-Abbau im Herzmuskel bei Sauerstoffmangel und seine mögliche Bedeutung für die Coronardurchblutung. Naturwissenschaften 50:228–229

    Article  CAS  Google Scholar 

  • Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. Respir Physiol 128:277–297

    Article  CAS  PubMed  Google Scholar 

  • Halestrap AP (2012) The monocarboxylate transporter family-structure and functional characterization. IUBMB Life 64:1–9

    Article  CAS  PubMed  Google Scholar 

  • Heaps CL, Bowles DK (2002) Gender-specific K+-channel contribution to adenosine-induced relaxation in coronary arterioles. J Appl Physiol 92:550–558

    Article  CAS  PubMed  Google Scholar 

  • Hedegaard ER, Nielsen BD, Kun A, Hughes AD, Krøigaard C, Mogensen S, Matchkov VV, Fröbert O, Simonsen U (2014) KV7 channels are involved in hypoxia-induced vasodilatation of porcine coronary arteries. Br J Pharmacol 171:69–82

    Article  CAS  PubMed  Google Scholar 

  • Hellsten Y (1999) The effect of muscle contraction on the regulation of adenosine formation in rat skeletal muscle cells. J Physiol 518:761–768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones DP (1986) Intracellular diffusion gradients of O2 and ATP. Am J Phys Cell Physiol 250:C663–C675

    CAS  Google Scholar 

  • Joyner MJ, Casey DP (2015) Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol Rev 95:549–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katz A, Sahlin K (1988) Regulation of lactic acid production during exercise. J Appl Physiol 65:509–518

    CAS  PubMed  Google Scholar 

  • Lamb IR, Murrant CL (2015) Potassium inhibits nitric oxide and adenosine arteriolar vasodilatation via KIR and Na+/K+ ATPase: implications for redundancy in active hyperaemia. J Physiol 593:5111–5126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leach RM, Sheehan DW, Chacko VP, Sylvester JT (2000) Energy state, pH, and vasomotor tone during hypoxia in precontracted pulmonary and femoral arteries. Am J Phys Lung Cell Mol Phys 278:L294–L304

    CAS  Google Scholar 

  • Lynge J, Hellsten Y (2000) Distribution of adenosine A1, A2A and A2B receptors in human skeletal muscle. Acta Physiol Scand 169:283–290

    Article  CAS  PubMed  Google Scholar 

  • Marshall JM, Ray CJ (2012) Contribution of non-endothelium-dependent substances to exercise hyperaemia: are they O2 dependent? J Physiol 590:6307–6320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Merkus D, Haitsma DB, Fung TY, Assen YJ, Verdouw PD, Duncker DJ (2003) Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways. Am J Physiol Heart Circ Physiol 285:H424–H433

    Article  CAS  PubMed  Google Scholar 

  • Montoya JJ, Fernández N, Monge L, Diéguez G, Villalón AL (2011) Nitric oxide-mediated relaxation to lactate of coronary circulation in the isolated perfused rat heart. J Cardiovasc Pharmacol 58:392–398

    Article  CAS  PubMed  Google Scholar 

  • Mortensen SP, Gonzalez-Alonso J, Nielsen JJ, Saltin B, Hellsten Y (2009) Muscle interstitial ATP and norepinenphrine concentrations in the human leg during exercise and ATP infusion. J Appl Physiol 107:1757–1762

    Article  CAS  PubMed  Google Scholar 

  • Neo BH, Kandhi S, Ahmad M, Wolin MS (2010) Redox regulation of guanylate cyclase and protein kinase G in vascular responses to hypoxia. Respir Physiol Neurobiol 174:259–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ngo AT, Riemann M, Holstein-Rathlou NH, Torp-Pedersen C, Jensen LJ (2013) Significance of KATP channels, L-type Ca2+ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles in vivo. BMC Physiol 13:8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nyberg M, Mortensen SP, Thaning P, Saltin B, Hellsten Y (2010) Interstitial and plasma adenosine stimulate nitric oxide and prostacyclin formation in human skeletal muscle. Hypertension 56:1102–1108

    Article  CAS  PubMed  Google Scholar 

  • Occhipinti R, Boron WF (2015) Mathematical modeling of acid-base physiology. Prog Biophys Mol Biol 117(1):43–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pittman RN, Duling BR (1973) Oxygen sensitivity of vascular smooth muscle. Microvasc Res 6:202–211

    Article  CAS  PubMed  Google Scholar 

  • Pries AR, Secomb TW (2014) Making microvascular networks work: angiogenesis, remodeling, and pruning. Physiology (Bethesda) 29:446–455

    Google Scholar 

  • Saitoh S, Zhang C, Tune JD, Potter B, Kiyooka T, Rogers PA, Knudson JD, Dick GM, Swafford A, Chilian WM (2006) Hydrogen peroxide: a feed-forward dilator that couples myocardial metabolism to coronary blood flow. Arterioscler Thromb Vasc Biol 26:2614–2621

    Article  CAS  PubMed  Google Scholar 

  • Sanjani MS, Teng B, Krahn T, Tilley S, Ledent C, Mustafa SJ (2011) Contributions of A2A and A2B adenosine receptors in coronary flow responses in relation to the KATP channel using A2B and A2A/2B double-knockout mice. Am J Physiol Heart Circ Physiol 301:H2322–H2333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarelius I, Pohl U (2010) Control of muscle blood flow during exercise: local factors and integrative mechanisms. Acta Physiol (Oxford) 199:349–365

    Article  CAS  Google Scholar 

  • Schrage WG, Joyner MJ, Dinenno FA (2004) Local inhibition of nitric oxide and prostaglandins independently reduce forearm exercise hyperaemia in humans. J Physiol 557:599–611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schrage WG, Dietz NM, Joyner MJ (2006) Effects of combined inhibition of ATP-sensitive potassium channels, nitric oxide, and prostaglandins on hyperemia during moderate exercise. J Appl Physiol 100:1506–1512

    Article  CAS  PubMed  Google Scholar 

  • Schumacker PT (2011) Lung cell hypoxia: role of mitochondrial reactive oxygen species signaling in triggering responses. Proc Am Thorac Soc 8:477–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharifi SM, Zhou X, Asano S, Tilley SL, Ledent C, Teng B, Dick GM, Mustafa SJ (2013) Interactions between A2A adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia. Am J Physiol Heart Circ Physiol 304:H1294–H1301

    Article  Google Scholar 

  • Smani T, Hernandez A, Urena J, Castellano AG, Franco-Obregon A, Ordonez A, López-Barneo J (2002) Reduction of Ca2+ channel activity by hypoxia in human and porcine coronary myocytes. Cardiovasc Res 53:97–104

    Article  CAS  PubMed  Google Scholar 

  • Sparks HV (2011) Effect of local metabolic factors on vascular smooth muscle. Compr Physiol Supplement 7: Handbook of Physiology, The Cardiovascular System, Vascular Smooth Muscle, pp 475–513

    Google Scholar 

  • Stowe DF (1981) Heart bioassay of effluent of isolated, perfused guinea pig hearts to examine the role of metabolites regulating coronary flow during hypoxia. Basic Res Cardiol 76:359–364

    Article  CAS  PubMed  Google Scholar 

  • Sylvester JT, Shimoda LA, Aaronson PI, Ward JP (2012) Hypoxic pulmonary vasoconstriction. Physiol Rev 92:367–520

    Article  CAS  PubMed  Google Scholar 

  • Tune JD, Richmond KN, Gorman MW, Feigl EO (2000) Role of nitric oxide and adenosine in control of coronary blood flow in exercising dogs. Circulation 101:2942–2948

    Article  CAS  PubMed  Google Scholar 

  • Wang T, Sodhi J, Mentzer RM Jr, Van Wylen DG (1994) Changes in interstitial adenosine during hypoxia: relationship to oxygen supply: demand imbalance, and effects of adenosine deaminase. Cardiovasc Res 28:1320–1325

    Article  CAS  PubMed  Google Scholar 

  • Wardle RL, Gu M, Ishida Y, Paul RJ (2007) Rho kinase is an effector underlying Ca2+-desensitizing hypoxic relaxation in porcine coronary artery. Am J Physiol Heart Circ Physiol 293:H23–H29

    Article  CAS  PubMed  Google Scholar 

  • Weir EK, Archer SL (2010) The role of redox changes in oxygen sensing. Respir Physiol Neurobiol 174:182–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou X, Teng B, Tilley S, Mustafa SJ (2013) A1 adenosine receptor negatively modulates coronary reactive hyperemia via counteracting A2A-mediated H2O2 production and KATP opening in isolated mouse hearts. Am J Physiol Heart Circ Physiol 305:H1668–H1679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Gao, Y. (2017). Local Metabolic Factors and Vasoactivity. In: Biology of Vascular Smooth Muscle: Vasoconstriction and Dilatation. Springer, Singapore. https://doi.org/10.1007/978-981-10-4810-4_9

Download citation

Publish with us

Policies and ethics