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Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach.

Walsh SK, Hepburn CY, Keown O, Åstrand A, Lindblom A, Ryberg E, Hjorth S, Leslie SJ, Greasley PJ, Wainwright CL - Pharmacol Res Perspect (2015)

Bottom Line: While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands.The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response.AM251 caused a depressor response that was absent in GPR55(-/-) mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55(-/-) mice.

View Article: PubMed Central - PubMed

Affiliation: Institute for Health & Wellbeing Research, Robert Gordon University Riverside East, Aberdeen, AB10 7GJ, United Kingdom.

ABSTRACT
The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPγS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1 (-/-) and GPR55(-/-)) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPγS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55(-/-) mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55(-/-) mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control.

No MeSH data available.


Related in: MedlinePlus

Hemodynamic responses to CBD (50 μg kg−1) and its vehicle in normotensive anesthetized rats (A and B) and WT and GPR55−/− mice (C–E). Baseline MABP’s and HR’s for each group were SD Rat (135 ± 4 mmHg and 390 ± 4 bpm; n = 8); WT (86 ± 3 mmHg and 323 ± 4 bpm; n = 8); and GPR55−/−(87 ± 4 mmHg and 329 ± 5 bpm; n = 8), respectively. Values shown are mean ± SEM. *P < 0.05 compared to vehicle response.
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fig07: Hemodynamic responses to CBD (50 μg kg−1) and its vehicle in normotensive anesthetized rats (A and B) and WT and GPR55−/− mice (C–E). Baseline MABP’s and HR’s for each group were SD Rat (135 ± 4 mmHg and 390 ± 4 bpm; n = 8); WT (86 ± 3 mmHg and 323 ± 4 bpm; n = 8); and GPR55−/−(87 ± 4 mmHg and 329 ± 5 bpm; n = 8), respectively. Values shown are mean ± SEM. *P < 0.05 compared to vehicle response.

Mentions: In conscious WT mice, O-1602 had no effect on MABP (Fig.5A), but did induce a transient bradycardia at the highest dose tested (Fig.5B; Table3). However, in CB1−/− mice a dose-dependent depressor response was observed and the HR responses to O-1602 were markedly enhanced (Figs.6C and D; Table3). Pretreatment with CBD also unmasked a dose-dependent depressor response to O-1602 in WT mice (Fig.6E; Table3) and exacerbated the drug-induced bradycardia (Fig.6F; Table3), but did not further enhance the responses to O-1602 in CB1−/− mice (Figs.7G and H; Table2). Finally, administration of O-1602 in the presence of AM281 in GPR55−/− mice did not elicit a depressor response (Table S1).


Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach.

Walsh SK, Hepburn CY, Keown O, Åstrand A, Lindblom A, Ryberg E, Hjorth S, Leslie SJ, Greasley PJ, Wainwright CL - Pharmacol Res Perspect (2015)

Hemodynamic responses to CBD (50 μg kg−1) and its vehicle in normotensive anesthetized rats (A and B) and WT and GPR55−/− mice (C–E). Baseline MABP’s and HR’s for each group were SD Rat (135 ± 4 mmHg and 390 ± 4 bpm; n = 8); WT (86 ± 3 mmHg and 323 ± 4 bpm; n = 8); and GPR55−/−(87 ± 4 mmHg and 329 ± 5 bpm; n = 8), respectively. Values shown are mean ± SEM. *P < 0.05 compared to vehicle response.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492759&req=5

fig07: Hemodynamic responses to CBD (50 μg kg−1) and its vehicle in normotensive anesthetized rats (A and B) and WT and GPR55−/− mice (C–E). Baseline MABP’s and HR’s for each group were SD Rat (135 ± 4 mmHg and 390 ± 4 bpm; n = 8); WT (86 ± 3 mmHg and 323 ± 4 bpm; n = 8); and GPR55−/−(87 ± 4 mmHg and 329 ± 5 bpm; n = 8), respectively. Values shown are mean ± SEM. *P < 0.05 compared to vehicle response.
Mentions: In conscious WT mice, O-1602 had no effect on MABP (Fig.5A), but did induce a transient bradycardia at the highest dose tested (Fig.5B; Table3). However, in CB1−/− mice a dose-dependent depressor response was observed and the HR responses to O-1602 were markedly enhanced (Figs.6C and D; Table3). Pretreatment with CBD also unmasked a dose-dependent depressor response to O-1602 in WT mice (Fig.6E; Table3) and exacerbated the drug-induced bradycardia (Fig.6F; Table3), but did not further enhance the responses to O-1602 in CB1−/− mice (Figs.7G and H; Table2). Finally, administration of O-1602 in the presence of AM281 in GPR55−/− mice did not elicit a depressor response (Table S1).

Bottom Line: While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands.The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response.AM251 caused a depressor response that was absent in GPR55(-/-) mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55(-/-) mice.

View Article: PubMed Central - PubMed

Affiliation: Institute for Health & Wellbeing Research, Robert Gordon University Riverside East, Aberdeen, AB10 7GJ, United Kingdom.

ABSTRACT
The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPγS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1 (-/-) and GPR55(-/-)) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPγS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55(-/-) mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55(-/-) mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control.

No MeSH data available.


Related in: MedlinePlus