Muscarinic Receptors on Endothelial Cells

  • John D. Catravas
  • Alain B. Legrand
  • Una S. Ryan
  • Robert S. Aronstam


Until this decade, muscarinic acetylcholine receptors (mAChR) were generally treated as a homogeneous population of membrane bound glycoproteins. In 1980, differences between mAChR located in certain brain areas and ganglia and those located in the heart and ileum were reported and two subtypes of mAChR were proposed based on receptor affinity for the antagonist pirenzepine. Receptors with high affinity for pirenzipine (cerebral cortex, hippocampus, striatum and ganglia) were termed M1 and those exhibiting lower affinity (found in the heart, intestinal smooth muscle, cerebellum and brainstem) were termed M2 (Hammer et al., 1980; Hammer and Giachetti, 1982; Berrie et al., 1986). Pharmacological studies with recently developed organ- and subtype- specific antagonists suggest that the M2 subtype can be further distinguished into M, and M2β subtypes located in the heart and ileum, respectively (Giachetti et al., 1986; Lambrecht et al., 1984; 1987; Bonner et al., 1987). More recent analysis of the genes encoding mAChR has clearly revealed at least 4 distinct receptor subtypes (Ml, M2, M3, M4; Figure 1) which are the products of different genes (Kubo et al., 1986; 1986a; Bonner et al., 1989; Peralta et al., 1989,1987a). M2 defined by genetic analysis corresponds to the M2 receptor defined pharmacologically, while Ml, M3 and M4 mAChR demonstrate significant similarity in their affinity to agonists and antagonists and probably contribute to the pharmacologically-defined M1 receptor population. (Peralta et al., 1987). A fifth muscarinic receptor gene has recently been described (M5; Bonner et al, 1988), although its expression has not been demonstrated in any tissue.


Muscarinic Receptor Muscarinic Acetylcholine Receptor Endothelium Derive Relax Factor Muscarinic Receptor Antagonist mAChR Subtype 


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  1. Altiere, R.J., Kiritsy-Roy, J.A., and Catravas, J.D. Acetylcholine-induced contractions in isolated rabbit pulmonary arteries: role of thromboxane A2. J. Pharmacol Exp. Ther. 236:535–541, 1986.PubMedGoogle Scholar
  2. Altiere, R.J. Thompson, D.C. and Catravas, J.D. Dichotomous actions of endothelium-derived factors modulating vasomotor tone in rabbit pulmonary arteries. Putin. Pharmacol. (In Press)Google Scholar
  3. Berrie, C.P., Birdsall, N.J.M., Hulme, E.C., Keen, M., Stockton, J.M. and Wheatley, M. Muscarinic receptor subclasses: the binding properties of the soluble receptor binding sites. Trends Pharmacol Sci. 7:8–13, 1986.Google Scholar
  4. Bonner, T.I., Young, A.C., Brann, M.R. and Buckley, N.J. Cloning and Expression of the Human and Rat m5 Muscarinic Acetylcholine Receptor Genes. Neuron. 1:403–410, 1988.PubMedCrossRefGoogle Scholar
  5. Brown, E.B., Kendall, D.A. and Nahorski, S.R. Inositol phospholipid hydrolysis in rat cerebral cortical slices: I. Receptor characterization. J. Neurochem. 42:1379, 1984.PubMedCrossRefGoogle Scholar
  6. Catravas, J.D. and Aronstam, R.S. Muscarinic systems of the pulmonary endothelium. In Pulmonary Endothelium in Health and Disease, ed. by U.S. Ryan, Dekker, New York, pp.307–326, 1987.Google Scholar
  7. El-Kashef, J., and Catravas, J.D. Prostanoid mediation of the vasoconstrictor actions of acetylcholine in the rabbit pulmonary circulation in vivo. Am. J. Physiol. 251:H808–H814, 1986.Google Scholar
  8. Furchgott, R.F., and Bursztyn, P. Comparison of dissociation constants and of relative efficacies of selected agonists acting on parasympathetic receptors. Ann NY. Acad Sci. 144:882–899, 1967.CrossRefGoogle Scholar
  9. Furchgott, R.F., and Zawadzki, J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle of acetylcholine. Nature 288:373–376, 1980.PubMedCrossRefGoogle Scholar
  10. Giachetti, A., Micheletti, R. and Montagna, E. Cardioselective profile of AF-DX 116, a muscarinic M2 receptor antagonist. Life Sci. 38:1663–1672, 1986.PubMedCrossRefGoogle Scholar
  11. Gil, D.W. and Wolfe, B.B. Pirenzepine distinguishes between muscarinic receptor-mediated phosphoinositide breakdown and inhibition of adenyl cyclase. J. Pharmacol. Exp. Then 232: 608–616, 1985.Google Scholar
  12. Gillis, C.N., and Pitt, B.R. The fate of circulating amines within the pulmonary circulation. Annu. Rev. Physiol 44:269–280, 1982.PubMedCrossRefGoogle Scholar
  13. Gilman, A.G.G Proteins and dual control of adenylate cyclase. Cell 36:577–579, 1984.PubMedCrossRefGoogle Scholar
  14. Gonzales, R.A. and Crews, F.T. Characterization of the cholinergic stimulation of phosphoinositide hydrolysis in rat brain slices. J. Neurosci. 4:3120–3127, 1984.PubMedGoogle Scholar
  15. Hammer, R., Berrie, C.P., Birdsall, N.J.M., Burgen, A.S.V. and Hulme, E.C. Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature 283:90–92, 1980.PubMedCrossRefGoogle Scholar
  16. Hammer, R. and Giachetti, A. Muscarinic receptor subtypes: Ml and M2. Biochemical and functional characterization. Life Sci. 31:2991–2998, 1982.PubMedCrossRefGoogle Scholar
  17. Jakobs, K.H., Aktories, K. and Schultz, G. GTP-dependent inhibition of cardiac adenylate cyclase by muscarinic cholinergic agonists. Naun. Schmied. Arch. Pharmacol 310:113–119, 1979.CrossRefGoogle Scholar
  18. Kubo, T. Fujuda, K., Mikami, A., Maeda, A., Takahashi, H., Mishina, M., Haga, T., Haga, K., Ichiyama, A., Kangawa, K., Kojima, M., Matsuo, H., Hirose, T. and Numa, S. Cloning, sequencing and expression of complementary DNA encoding the muscarinic acetylcholine receptor. Nature 323:411–416, 1986.PubMedCrossRefGoogle Scholar
  19. Kubo, T., Maeda, A., Sugimoteo, K., Akiba, I., Mikami, A., Takahashi, H., Haga, T., Haga, K., Ichiyama, A., Kangawa, K., Matsuo, H., Hirose, T. and Numa, S. Primary structure of porcine cardiac distribution acetylcholine receptor deduced from the cDNA sequence. FEBS Lett. 209:367–372, 1986a.PubMedCrossRefGoogle Scholar
  20. Lambrecht, G., Moser, U., Mutschler, E., Wess, J., Linoh, H., Strecker, M. and Tacke, R. Hexahydro-sila-difenidol: A selective antagonist on iliac muscarinic receptors. Nairn. Schmied. Arch. Pharmacol. 325:suppl.R, 62, 1984.CrossRefGoogle Scholar
  21. Lambrecht, G., Mutschler, E., Moser, U., Riotte, J., Wagner, M. and Wess, J. Heterogeneity in muscarinic receptors: Evidence from pharmacological and electrophysiological studies with selective antagonists. In International Symposium on Muscarinic Cholinergic Mechanisms, ed. by S. Cohen and M. Sokolovsky, Freud Publishing House Ltd., Tel-Aviv, p. 245, 1987.Google Scholar
  22. Legrand, A.B., Narayanan, T.K., Ryan, U.S., Aronstam, R.S. and Catravas, J.D. Modulation of adenylate cyclase activity in cultured bovine pulmonary arterial endothelial cells. Biochem Pharmacol. 38:423–430, 1989.PubMedCrossRefGoogle Scholar
  23. Narayanan, R.K., and Aronstam, R.S. Allosteric effect of gallamine on muscarinic cholinergic receptor binding: influence of guanine nucleotides and conformational state. Neurochem. Res. 10:1397–1406, 1986.CrossRefGoogle Scholar
  24. Noronha-Blob, L., Canning, B., Costello, D. and Kinnier, W.J. Selective agents for muscarinic receptors linked to phosphoinositide breakdown. Eur. J. Pharmacol 154:161–167, 1988.PubMedCrossRefGoogle Scholar
  25. Peralta, E.G., Ashkenazi, A., Winslow, J.W., Smith, D.H., Ramachandran, J. and Capon, D.J. Distinct primary structures, ligand binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO J. 6:3923–3929, 1987.PubMedGoogle Scholar
  26. Peralta, E.G., Winslow, J.W., Peterson, G.L., Smith, D.H., Ashkenazi, A., Ramachandran, J., Schimerlik, M.I. and Capon, D.J. Primary structure and biochemical properties of an M2 muscarinic receptor. Science 236:600–605, 1987a.PubMedCrossRefGoogle Scholar
  27. Peralta, E.G., Winslow, J.W., Ashkenazi, A. and Capon, D.J. Structural basis of muscarinic acetylcholine receptor subtype diversity. Trends Pharmacol. Sci. Suppl:6–11, 1988.Google Scholar
  28. Ryan, U.S. and Maxwell, G. Isolation culture and subculture of bovine pulmonary artery endothelial cells: Mechanical methods. J. Tissue Cult. Meth. 10:3–5, 1986.CrossRefGoogle Scholar
  29. Salomon, Y., Londos, C. and Rodbell, M. A highly sensitive adenyl cyclase assay. Anal. Biochem. 58:541–548, 1974.PubMedCrossRefGoogle Scholar
  30. Watson, M., Roeske, W.R. and Yamamura, H.I. [3H]-pirenzepine and (-)-[3H]-quinuclidinyl benzilate binding to rat cerebral cortical and cardiac muscarinic cholinergic sites. II Characterization and regulation of antagonist binding to putative muscarinic subtypes. J. Pharmacol. Exp. Ther. 237:419–427, 1986.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • John D. Catravas
    • 1
    • 2
  • Alain B. Legrand
    • 1
    • 2
  • Una S. Ryan
    • 1
    • 2
  • Robert S. Aronstam
    • 1
    • 2
  1. 1.Department of Pharmacology and ToxicologyMedical College of GeorgiaAugustaUSA
  2. 2.Department of MedicineUniversity of MiamiMiamiUSA

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