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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 ACEA and its vehicle in normotensive anesthetized rats, showing the time course of the depressor responses (expressed as a percentage fall in mean arterial blood pressure from baseline) in the absence (A) and presence (B) of CBD (50 μg kg−1) and percent changes in heart rate (C and D). Baseline MABP’s and HR’s for each group were control (129 ± 4 mmHg and 379 ± 8 bpm; n = 8) and CBD (135 ± 4 mmHg and 390 ± 4 bpm; n = 8), respectively. Panel (E) summarizes the mean areas above the curve for the blood pressure response (AAC in arbitrary units). All values shown are mean ± SEM; *P < 0.01 versus vehicle (within group); #P < 0.05 versus ACEA (control group).
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fig02: Hemodynamic responses to ACEA and its vehicle in normotensive anesthetized rats, showing the time course of the depressor responses (expressed as a percentage fall in mean arterial blood pressure from baseline) in the absence (A) and presence (B) of CBD (50 μg kg−1) and percent changes in heart rate (C and D). Baseline MABP’s and HR’s for each group were control (129 ± 4 mmHg and 379 ± 8 bpm; n = 8) and CBD (135 ± 4 mmHg and 390 ± 4 bpm; n = 8), respectively. Panel (E) summarizes the mean areas above the curve for the blood pressure response (AAC in arbitrary units). All values shown are mean ± SEM; *P < 0.01 versus vehicle (within group); #P < 0.05 versus ACEA (control group).

Mentions: A single bolus dose of ACEA (3 mg kg−1) produced a reproducible and pronounced depressor response in anesthetized rats (P < 0.001; Figs.2A and E), but had no effect on HR (Fig.2C). The magnitude and duration of the response to ACEA was attenuated by AM251 (1 and 3 mg kg−1) in a dose-dependent manner (P < 0.01; Figs.2A and E). In the presence of CBD alone (50 μg kg−1) the duration of the response to ACEA was blunted and consequently the AAC value was reduced by approximately 50% (P < 0.05; Figs.2B and E). Combined administration of CBD followed by AM251 5 min later, did not produce an additive blockade of the ACEA response; indeed the blockade seen with the higher dose of AM251 was no longer evident (Fig.2E). In contrast, ACEA did not produce a depressor response in anesthetized mice that could be distinguished from the response to the vehicle in either WT (Fig.3A) or GPR55−/− (Fig.3B) mice, nor was there any measurable effect on HR (Figs.3C and D).


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 ACEA and its vehicle in normotensive anesthetized rats, showing the time course of the depressor responses (expressed as a percentage fall in mean arterial blood pressure from baseline) in the absence (A) and presence (B) of CBD (50 μg kg−1) and percent changes in heart rate (C and D). Baseline MABP’s and HR’s for each group were control (129 ± 4 mmHg and 379 ± 8 bpm; n = 8) and CBD (135 ± 4 mmHg and 390 ± 4 bpm; n = 8), respectively. Panel (E) summarizes the mean areas above the curve for the blood pressure response (AAC in arbitrary units). All values shown are mean ± SEM; *P < 0.01 versus vehicle (within group); #P < 0.05 versus ACEA (control group).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: Hemodynamic responses to ACEA and its vehicle in normotensive anesthetized rats, showing the time course of the depressor responses (expressed as a percentage fall in mean arterial blood pressure from baseline) in the absence (A) and presence (B) of CBD (50 μg kg−1) and percent changes in heart rate (C and D). Baseline MABP’s and HR’s for each group were control (129 ± 4 mmHg and 379 ± 8 bpm; n = 8) and CBD (135 ± 4 mmHg and 390 ± 4 bpm; n = 8), respectively. Panel (E) summarizes the mean areas above the curve for the blood pressure response (AAC in arbitrary units). All values shown are mean ± SEM; *P < 0.01 versus vehicle (within group); #P < 0.05 versus ACEA (control group).
Mentions: A single bolus dose of ACEA (3 mg kg−1) produced a reproducible and pronounced depressor response in anesthetized rats (P < 0.001; Figs.2A and E), but had no effect on HR (Fig.2C). The magnitude and duration of the response to ACEA was attenuated by AM251 (1 and 3 mg kg−1) in a dose-dependent manner (P < 0.01; Figs.2A and E). In the presence of CBD alone (50 μg kg−1) the duration of the response to ACEA was blunted and consequently the AAC value was reduced by approximately 50% (P < 0.05; Figs.2B and E). Combined administration of CBD followed by AM251 5 min later, did not produce an additive blockade of the ACEA response; indeed the blockade seen with the higher dose of AM251 was no longer evident (Fig.2E). In contrast, ACEA did not produce a depressor response in anesthetized mice that could be distinguished from the response to the vehicle in either WT (Fig.3A) or GPR55−/− (Fig.3B) mice, nor was there any measurable effect on HR (Figs.3C and D).

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