title: Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity.
abstract: As they age, Sprague-Dawley (SD) rats develop elevated systolic blood pressure associated with impaired baroreflex sensitivity (BRS) for control of heart rate. We previously demonstrated in young hypertensive (mRen2)27 rats that impaired BRS is restored by CB1 cannabinoid receptor blockade in the solitary tract nucleus (NTS), consistent with elevated content of the endocannabinoid 2-arachidonoylglycerol (2-AG) in dorsal medulla relative to normotensive SD rats. There is no effect of CB1 receptor blockade in young SD rats. We now report in older SD rats that dorsal medullary 2-AG levels are 2-fold higher at 70 versus 15 weeks of age (4.22 ± 0.61 vs. 1.93 ± 0.22 ng/mg tissue; P < 0.05). Furthermore, relative expression of CB1 receptor messenger RNA is significantly lower in aged rats, whereas CB2 receptor messenger RNA is significantly higher. In contrast to young adult SD rats, microinjection of the CB1 receptor antagonist SR141716A (36 pmole) into the NTS of older SD rats normalized BRS in animals exhibiting impaired baseline BRS (0.56 ± 0.06 baseline vs. 1.06 ± 0.05 ms/mm Hg after 60 minutes; P < 0.05). Therefore, this study provides evidence for alterations in the endocannabinoid system within the NTS of older SD rats that contribute to age-related impairment of BRS.
authors: *Department of Physiology and Pharmacology, Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, NC; †Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC; and ‡Analytical Chemistry and Pharmaceutics, RTI International, Research Triangle Park, NC.
authors: Chris L
authors: CL
authors: Schaich
authors: Hossam A
authors: HA
authors: Shaltout
authors: Megan
authors: M
authors: Grabenauer
authors: Brian F
authors: BF
authors: Thomas
authors: Patricia E
authors: PE
authors: Gallagher
authors: Allyn C
authors: AC
authors: Howlett
authors: Debra I
authors: DI
authors: Diz
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage; D063388:Endocannabinoids / Q000378:metabolism*; D005786:Gene Expression Regulation; D005989:Glycerides / Q000378:metabolism; D006339:Heart Rate; D008297:Male; D013058:Mass Spectrometry; D008845:Microinjections; D010880:Piperidines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077285:Rimonabant; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant
references: Nature. 2001 Apr 12;410(6830):822-5
references: 11298451
references: Neuroscience. 2001;104(4):1111-7
references: 11457594
references: J Neurosci Res. 2002 Nov 1;70(3):493-500
references: 12391610
references: Neuroscience. 1992;48(3):655-68
references: 1376455
references: Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H992-1000
references: 14615281
references: J Physiol. 2004 Sep 15;559(Pt 3):923-38
references: 15272041
references: Circulation. 2004 Oct 5;110(14):1996-2002
references: 15451779
references: J Pharmacol Exp Ther. 2005 Sep;314(3):1328-37
references: 15937146
references: Hypertension. 2005 Aug;46(2):333-40
references: 16009784
references: J Neurochem. 2005 Oct;95(2):437-45
references: 16086683
references: Diabetes. 2005 Oct;54(10):2838-43
references: 16186383
references: Am J Physiol. 1992 Jul;263(1 Pt 2):R89-94
references: 1636797
references: Exp Gerontol. 1992;27(3):309-20
references: 1639151
references: Am J Physiol Heart Circ Physiol. 2007 Mar;292(3):H1412-9
references: 17085537
references: Curr Drug Targets. 2006 Nov;7(11):1539-52
references: 17100593
references: J Biol Chem. 2007 Mar 16;282(11):7753-7
references: 17227758
references: Am J Physiol Regul Integr Comp Physiol. 2007 Jul;293(1):R3-R12
references: 17442786
references: J Neurophysiol. 2007 Sep;98(3):1223-30
references: 17634345
references: Neurobiol Aging. 1991 Sep-Oct;12(5):601-4
references: 1770991
references: Mol Pharmacol. 2007 Dec;72(6):1557-66
references: 17895407
references: J Cardiovasc Pharmacol. 2008 Jun;51(6):542-8
references: 18475201
references: Am J Physiol. 1991 Apr;260(4 Pt 2):H1113-20
references: 1901459
references: Neurosci Lett. 2009 Oct 2;463(2):125-9
references: 19596404
references: Hypertension. 2009 Nov;54(5):1001-8
references: 19770402
references: Am J Physiol Gastrointest Liver Physiol. 2010 Jul;299(1):G63-9
references: 20430875
references: Exp Gerontol. 1991;26(1):65-75
references: 2055285
references: EMBO J. 2011 May 03;30(12):2350-63
references: 21540834
references: Sci Signal. 2012 Mar 20;5(216):ra23
references: 22434934
references: J Biol Chem. 2012 Sep 7;287(37):31540-50
references: 22787147
references: Hypertension. 2012 Nov;60(5):1257-65
references: 23045456
references: Hypertens Res. 2013 Jan;36(1):5-13
references: 23076408
references: Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3326-41
references: 23108550
references: J Neurochem. 2013 Mar;124(6):808-20
references: 23286559
references: Nat Neurosci. 2013 Mar;16(3):300-8
references: 23354329
references: Mol Imaging Biol. 2013 Aug;15(4):384-90
references: 23508466
references: Int J Cardiol. 2013 Oct 9;168(4):4010-4
references: 23870644
references: Eur J Appl Physiol. 2014 Mar;114(3):511-9
references: 24078210
references: Int J Endocrinol. 2013;2013:865965
references: 24288531
references: Front Neurosci. 2013 Dec 13;7:238
references: 24379754
references: Br J Pharmacol. 2014 Feb;171(3):746-60
references: 24490862
references: Alzheimers Dement. 2014 Feb;10(1 Suppl):S3-11
references: 24529522
references: Am J Physiol Heart Circ Physiol. 2014 Dec 1;307(11):H1539-46
references: 25260611
references: Front Physiol. 2016 Jun 09;7:207
references: 27375489
references: Acta Physiol Scand. 1985 Sep;125(1):1-11
references: 4050486
references: Hypertension. 1995 Aug;26(2):341-7
references: 7543454
references: Life Sci. 1995;56(23-24):1941-7
references: 7776817
references: Life Sci. 1993;52(18):1461-80
references: 8387132
references: Mech Ageing Dev. 1993 Feb;67(1-2):47-63
references: 8469033
references: J Auton Nerv Syst. 1996 Nov 6;61(2):128-38
references: 8946331
references: J Physiol. 1998 Apr 1;508 ( Pt 1):237-52
references: 9490844