Abstract
Intravenous (i.v.) injection of the endocannabinoid anandamide induces triphasic cardiovascular responses, including a pressor effect mediated via unknown central and peripheral mechanism(s). The aim of the present study was to determine the central mechanism(s) responsible for the pressor response to anandamide. For this purpose, the influence of antagonists at thromboxane A2 TP (sulotroban, daltroban, SQ 29548), NMDA (MK-801) and β2-adrenergic receptors (ICI 118551) on the pressor effect induced by i.v. and intracerebroventricularly (i.c.v.) administered anandamide was examined in urethane-anaesthetized rats. Anandamide (1.5–3 µmol/kg, i.v.) or its stable analogue methanandamide (0.75 µmol/kg, i.v.) increased blood pressure by 25%. Anandamide (0.03 μmol per animal i.c.v.) caused a pure pressor effect (by 20%) but only in the presence of antagonists of CB1 and TRPV1 receptors. The effects of cannabinoids (i.v. or i.c.v.) were diminished by i.v. daltroban, sulotroban (10 μmol/kg each), and/or SQ 29548 (1 μmol/kg). The effect of anandamide i.v. was reduced by SQ 29548 (0.02 μmol per animal i.c.v.) and by the thromboxane A2 synthesis inhibitor furegrelate i.c.v. (1.8 µmol per animal). ICI 118551, MK-801 (1 µmol/kg i.v. each), and bilateral adrenalectomy diminished the effect of anandamide i.c.v. Sulotroban (i.v.) failed to affect the response to anandamide (i.v.) in pithed rats, and anandamide and methanandamide did not bind to TP receptors in rat platelets. The present study suggests that central β2-adrenergic, NMDA and thromboxane A2 receptors are involved in the anandamide-induced adrenal secretion of catecholamines and their pressor effect in urethane-anaesthetized rats.
Similar content being viewed by others
References
Baranowska U, Göthert M, Rudź R, Malinowska B (2008) Methanandamide allosterically inhibits in vivo the function of peripheral nicotinic acetylcholine receptors containing the α7-subunit. J Pharmacol Exp Ther 326:912–917
Bátkai S, Pacher P, Osei-Hyiaman D, Radaeva S, Liu J, Harvey-White J, Offertáler L, Mackie K, Rudd MA, Bukoski RD, Kunos G (2004) Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 110:1996–2002
Bertolino F, Valentin JP, Patoiseau JF, Rieu JP, Colpaert FC, John GW (1997) Evidence for partial agonist properties of daltroban (BM 13, 505) at TP receptors in the anaesthetized open-chest rat. Naunyn-Schmiedeberg's Arch Pharmacol 356:462–466
Braszko JJ, Własienko J, Koziołkiewicz W, Janecka A, Wiśniewski K (1991) The 3-7 fragment of angiotensin II is probably responsible for its psychoactive properties. Brain Res 542:49–54
del Carmen Garcia M, Adler-Graschinsky E, Celuch SM (2003) Hypotensive effect of anandamide through the activation of CB1 and VR1 spinal receptors in urethane-anaesthetized rats. Naunyn-Schmiedeberg's Arch Pharmacol 368:270–276
Di Marzo V (2009) The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation. Pharmacol Res 60:77–84
Gao H, Peng B, Welch WJ, Wilcox CS (1997) Central thromboxane receptors: mRNA expression and mediation of pressor responses. Am J Physiol 272:R1493–R1500
Gardiner SM, March JE, Kemp PA, Bennet T (2009) Factors influencing the regional haemodynamic responses to methanandamide and anandamide in conscious rats. Br J Pharmacol 158:1143–1152
Hampson AJ, Bornheim LM, Scanziani M, Yost CS, Gray AT, Hansen BM, Leonoudakis DJ, Bickler PE (1998) Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J Neurochem 70:671–676
Hedberg A, Hall SE, Ogletree ML, Harris DN, Liu EC (1988) Characterization of [5, 6–3H]SQ 29, 548 as a high affinity radioligand, binding to thromboxane A2/prostaglandin H2-receptors in human platelets. J Pharmacol Exp Ther 245:786–792
Herman JP, Eyigor O, Ziegler DR, Jennes L (2000) Expression of ionotropic glutamate receptor subunit mRNAs in the hypothalamic paraventricular nucleus of the rat. J Comp Neurol 422:352–362
Kwolek G, Zakrzeska A, Schlicker E, Göthert M, Godlewski G, Malinowska B (2005) Central and peripheral components of the pressor effect of anandamide in urethane-anaesthetized rats. Br J Pharmacol 145:567–575
Lake KD, Martin BR, Kunos G, Varga K (1997) Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats. Hypertension 29:1204–1210
Li DP, Pan HL (2007) Glutamatergic inputs in the hypothalamic paraventricular nucleus maintain sympathetic vasomotor tone in hypertension. Hypertension 49:916–925
Malinowska B, Schlicker E (1993) Identification of endothelial H1, vascular H2 and cardiac presynaptic H3 receptors in the pithed rat. Naunyn-Schmiedeberg's Arch Pharmacol 347:55–60
Malinowska B, Godlewski G, Bucher B, Schlicker E (1997) Cannabinoid CB1 receptor-mediated inhibition of the neurogenic vasopressor response in the pithed rat. Naunyn-Schmiedeberg's Arch Pharmacol 356:197–202
Malinowska B, Kwolek G, Göthert M (2001a) Anandamide and methanandamide induce both vanilloid VR1- and cannabinoid CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats. Naunyn-Schmiedeberg's Arch Pharmacol 364:562–569
Malinowska B, Piszcz J, Koneczny B, Hryniewicz A, Schlicker E (2001b) Modulation of the cardiac autonomic transmission of pithed rats by presynaptic opioid OP4 and cannabinoid CB1 receptors. Naunyn-Schmiedeberg's Arch Pharmacol 364:233–241
Mukhtarov M, Ragozzino D, Bregestovski P (2005) Dual Ca2+ modulation of glycinergic synaptic currents in rodent hypoglossal motoneurones. J Physiol 569:817–831
Murakami Y, Okada S, Nishihara M, Yokotani K (2002) Roles of brain prostaglandin E2 and thromboxane A2 in the activation of the central sympatho-adrenomedullary outflow in rats. Eur J Pharmacol 452:289–294
Niederhoffer N, Schmidt K, Szabo B (2003) The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression. Naunyn-Schmiedeberg's Arch Pharmacol 367:434–443
Okada S, Murakami Y, Nishihara M, Yokotani K, Osumi Y (2000) Perfusion of the hypothalamic paraventricular nucleus with N-methyl-d-aspartate produces thromboxane A2 and centrally activates adrenomedullary outflow in rats. Neuroscience 96:585–590
Okada S, Yamaguchi-Shima N, Shimizu T, Arai J, Yorimitsu M, Yokotani K (2008) Centrally administered N-methyl-d-aspartate evokes the adrenal secretion of noradrenaline and adrenaline by brain thromboxane A2-mediated mechanisms in rats. Eur J Pharmacol 586:145–150
Pacher P, Bátkai S, Kunos G (2004) Haemodynamic profile and responsiveness to anandamide of TRPV1 receptor knock-out mice. J Physiol 558:647–657
Pacher P, Mukhopadhyay P, Mohanraj R, Godlewski G, Bátkai S, Kunos G (2008) Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations. Hypertension 52:601–607
Pfitzer T, Niederhoffer N, Szabo B (2005) Search for an endogenous cannabinoid-mediated effect in the sympathetic nervous system. Naunyn-Schmiedeberg's Arch Pharmacol 371:9–17
Rainbow TC, Parson B, Wolf BB (1984) Quantitative autoradiography of β1- and β2-adrenergic receptors in rat brain. Proc Natl Acad Sci USA 81:1585–1589
Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572
Sellers MM, Stallone JN (2008) Sympathy for the devil: the role of thromboxane in the regulation of vascular tone and blood pressure. Am J Physiol Heart Circ Physiol 294:H1978–H1986
Stegmeier K, Pill J, Müller-Beckmann B, Schmidt FH, Witte EC, Wolff HP, Patscheke H (1984) The pharmacological profile of the thromboxane A2 antagonist BM 13.177. A new anti-platelet and anti-thrombotic drug. Thromb Res 35:379–395
Varga K, Lake K, Martin BR, Kunos G (1995) Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide. Eur J Pharmacol 278:279–283
Varga K, Lake KD, Huangfu D, Guyenet PG, Kunos G (1996) Mechanism of the hypotensive action of anandamide in anesthetized rats. Hypertension 28:682–686
Yalcin M, Cavun S, Yilmaz MS, Savci V (2005) The involvement of central cholinergic system in the pressor effect of intracerebroventricularly injected U-46619, a thromboxane A2 analog, in conscious normotensive rats. Naunyn-Schmiedeberg's Arch Pharmacol 372:31–40
Villanueva A, Yilimaz SM, Millington WR, Cutrera RA, Stouffer DG, Parsons LH, Cheer JF, Feleder C (2009) Central cannabinoid1 receptor antagonist administration prevents endotoxic hypotension affecting norepinephrine release in the preoptic anterior hypothalamic area. Shock 32:614–620
Wagner JA, Járai Z, Bátkai S, Kunos G (2001) Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB1 receptors. Eur J Pharmacol 423:203–210
Yu M, Ives D, Ramesha CS (1997) Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. J Biol Chem 272:21181–21186
Zakrzeska A, Schlicker E, Baranowska M, Kozłowska H, Kwolek K, Malinowska B (2010) Involvement of an O-1918-sensitive receptor in the anandamide–induced delayed hypotension in anaesthetized rats. Br J Pharmacol (online)
Acknowledgements
This work was supported by the Medical University of Białystok (Poland; grant No. 3-13579F; 3-13581F). B. Malinowska and E. Schlicker were granted by the Foundation for Polish Science (FNP; Warsaw, Poland) and the German Research Foundation (DFG; Bonn, Germany) with the Copernicus Award. M. Göthert was granted by the Foundation for Polish Science with the Alexander von Humboldt Polish Honorary Research Fellowship. The authors are indebted to the Alexander von Humboldt-Stiftung (Bonn, Germany) for generously providing some of the equipment.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Malinowska, B., Zakrzeska, A., Kurz, C.M. et al. Involvement of central β2-adrenergic, NMDA and thromboxane A2 receptors in the pressor effect of anandamide in rats. Naunyn-Schmied Arch Pharmacol 381, 349–360 (2010). https://doi.org/10.1007/s00210-010-0497-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-010-0497-6