Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation
Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectiv...
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| Veröffentlicht in: | PloS one 2013-01, Vol.8 (1), p.e53390-e53390 |
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| creator | Iring, András Ruisanchez, Éva Leszl-Ishiguro, Miriam Horváth, Béla Benkő, Rita Lacza, Zsombor Járai, Zoltán Sándor, Péter Di Marzo, Vincenzo Pacher, Pál Benyó, Zoltán |
| description | Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectively) on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H).
In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.
Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the first time the involvement of the endocannabinoid system and CB1-receptors in the regulation of the cerebral circulation during H/H and also raise the possibility of their contribution to the autoregulation of CoBF. |
| doi_str_mv | 10.1371/journal.pone.0053390 |
| format | Article |
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In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.
Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the first time the involvement of the endocannabinoid system and CB1-receptors in the regulation of the cerebral circulation during H/H and also raise the possibility of their contribution to the autoregulation of CoBF.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0053390</identifier><identifier>PMID: 23308211</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anesthesia ; Animals ; Arachidonic Acids - pharmacology ; Arterial Pressure - drug effects ; Biology ; Blood ; Blood flow ; Blood pressure ; Cannabinoid CB1 receptors ; Cannabinoids ; Cerebral blood flow ; Cerebrovascular Circulation - drug effects ; Cortex ; Doppler effect ; Endocannabinoid system ; Endocannabinoids ; Endocannabinoids - metabolism ; Experiments ; Health aspects ; Heart Rate - drug effects ; Hemodynamics - drug effects ; Hypercapnia ; Hypercapnia - metabolism ; Hypercapnia - physiopathology ; Hypertension ; Hypertension - metabolism ; Hypertension - physiopathology ; Hypotension ; Hypoxia ; Hypoxia - metabolism ; Hypoxia - physiopathology ; Laser-Doppler Flowmetry ; Male ; Medical imaging ; Medicine ; Metabolism ; Nervous system ; Physiology ; Piperidines - pharmacology ; Pyrazoles - pharmacology ; Rats ; Rats, Wistar ; Receptor, Cannabinoid, CB1 - antagonists & inhibitors ; Receptor, Cannabinoid, CB1 - metabolism ; Receptors ; Rodents</subject><ispartof>PloS one, 2013-01, Vol.8 (1), p.e53390-e53390</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-1fa438908c1c7e8f47557c7976060f3f9d001a6c7958e39ab6a52de63920ec6d3</citedby><cites>FETCH-LOGICAL-c692t-1fa438908c1c7e8f47557c7976060f3f9d001a6c7958e39ab6a52de63920ec6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537620/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537620/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23308211$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Arai, Ken</contributor><creatorcontrib>Iring, András</creatorcontrib><creatorcontrib>Ruisanchez, Éva</creatorcontrib><creatorcontrib>Leszl-Ishiguro, Miriam</creatorcontrib><creatorcontrib>Horváth, Béla</creatorcontrib><creatorcontrib>Benkő, Rita</creatorcontrib><creatorcontrib>Lacza, Zsombor</creatorcontrib><creatorcontrib>Járai, Zoltán</creatorcontrib><creatorcontrib>Sándor, Péter</creatorcontrib><creatorcontrib>Di Marzo, Vincenzo</creatorcontrib><creatorcontrib>Pacher, Pál</creatorcontrib><creatorcontrib>Benyó, Zoltán</creatorcontrib><title>Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectively) on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H).
In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.
Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the first time the involvement of the endocannabinoid system and CB1-receptors in the regulation of the cerebral circulation during H/H and also raise the possibility of their contribution to the autoregulation of CoBF.</description><subject>Anesthesia</subject><subject>Animals</subject><subject>Arachidonic Acids - pharmacology</subject><subject>Arterial Pressure - drug effects</subject><subject>Biology</subject><subject>Blood</subject><subject>Blood flow</subject><subject>Blood pressure</subject><subject>Cannabinoid CB1 receptors</subject><subject>Cannabinoids</subject><subject>Cerebral blood flow</subject><subject>Cerebrovascular Circulation - drug effects</subject><subject>Cortex</subject><subject>Doppler effect</subject><subject>Endocannabinoid system</subject><subject>Endocannabinoids</subject><subject>Endocannabinoids - metabolism</subject><subject>Experiments</subject><subject>Health aspects</subject><subject>Heart Rate - drug effects</subject><subject>Hemodynamics - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iring, András</au><au>Ruisanchez, Éva</au><au>Leszl-Ishiguro, Miriam</au><au>Horváth, Béla</au><au>Benkő, Rita</au><au>Lacza, Zsombor</au><au>Járai, Zoltán</au><au>Sándor, Péter</au><au>Di Marzo, Vincenzo</au><au>Pacher, Pál</au><au>Benyó, Zoltán</au><au>Arai, Ken</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-01-04</date><risdate>2013</risdate><volume>8</volume><issue>1</issue><spage>e53390</spage><epage>e53390</epage><pages>e53390-e53390</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectively) on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H).
In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.
Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the first time the involvement of the endocannabinoid system and CB1-receptors in the regulation of the cerebral circulation during H/H and also raise the possibility of their contribution to the autoregulation of CoBF.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23308211</pmid><doi>10.1371/journal.pone.0053390</doi><tpages>e53390</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-01, Vol.8 (1), p.e53390-e53390 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1289066291 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Anesthesia Animals Arachidonic Acids - pharmacology Arterial Pressure - drug effects Biology Blood Blood flow Blood pressure Cannabinoid CB1 receptors Cannabinoids Cerebral blood flow Cerebrovascular Circulation - drug effects Cortex Doppler effect Endocannabinoid system Endocannabinoids Endocannabinoids - metabolism Experiments Health aspects Heart Rate - drug effects Hemodynamics - drug effects Hypercapnia Hypercapnia - metabolism Hypercapnia - physiopathology Hypertension Hypertension - metabolism Hypertension - physiopathology Hypotension Hypoxia Hypoxia - metabolism Hypoxia - physiopathology Laser-Doppler Flowmetry Male Medical imaging Medicine Metabolism Nervous system Physiology Piperidines - pharmacology Pyrazoles - pharmacology Rats Rats, Wistar Receptor, Cannabinoid, CB1 - antagonists & inhibitors Receptor, Cannabinoid, CB1 - metabolism Receptors Rodents |
| title | Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation |
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