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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.


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Blood pressure and heart rate responses to O-1602 (5–20 mg kg−1) in hypertensive SHR rats in the presence of vehicle (A); CBD (5 mg kg−1; B); AM281 (10 mg kg−1; C); or a combination of CBD and AM281 (D). Baseline MABP’s and HR’s for each group were SHR (146 ± 5 mmHg and 305 ± 10 bpm; n = 6); SHR & CBD (141 ± 5 mmHg and 296 ± 8 bpm; n = 6); SHR &AM281 (153 ± 6 mmHg and 296 ± 9 bpm; n = 7); and SHR & CBD& AM281 (151 ± 5 mmHg and 297 ± 12 bpm; n = 7), respectively. Values shown are mean ± SEM.
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fig05: Blood pressure and heart rate responses to O-1602 (5–20 mg kg−1) in hypertensive SHR rats in the presence of vehicle (A); CBD (5 mg kg−1; B); AM281 (10 mg kg−1; C); or a combination of CBD and AM281 (D). Baseline MABP’s and HR’s for each group were SHR (146 ± 5 mmHg and 305 ± 10 bpm; n = 6); SHR & CBD (141 ± 5 mmHg and 296 ± 8 bpm; n = 6); SHR &AM281 (153 ± 6 mmHg and 296 ± 9 bpm; n = 7); and SHR & CBD& AM281 (151 ± 5 mmHg and 297 ± 12 bpm; n = 7), respectively. Values shown are mean ± SEM.

Mentions: O-1602 (5–100 ng kg−1) did not produce any changes in MABP or HR in anesthetized rats (Figs. 4A, C, and E) or WT mice (Figs.4B, D, and F) over and above those seen with the vehicle. In conscious hypertensive rats, O-1602 administered in three ascending doses (5, 10, and 20 mg kg−1) spaced 20 min apart did not induce any changes in MABP (Fig.5A) or HR (Table2), even though O-1602 was given at much higher doses than those given to anesthetized rats. However, CBD pretreatment revealed a vasodepressor response to the lowest dose of O-1602 (Fig.5B, Table2) while co-administration of 10 mg kg−1 AM281 (a more selective CB1 antagonist; Ryberg et al. 2007) revealed a marked vasodepressor response, which was present for all doses and was sustained in the presence of 5 mg kg−1 CBD (Figs.5C and D). None of the interventions induced any changes in HR (Table2).


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)

Blood pressure and heart rate responses to O-1602 (5–20 mg kg−1) in hypertensive SHR rats in the presence of vehicle (A); CBD (5 mg kg−1; B); AM281 (10 mg kg−1; C); or a combination of CBD and AM281 (D). Baseline MABP’s and HR’s for each group were SHR (146 ± 5 mmHg and 305 ± 10 bpm; n = 6); SHR & CBD (141 ± 5 mmHg and 296 ± 8 bpm; n = 6); SHR &AM281 (153 ± 6 mmHg and 296 ± 9 bpm; n = 7); and SHR & CBD& AM281 (151 ± 5 mmHg and 297 ± 12 bpm; n = 7), respectively. Values shown are mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Blood pressure and heart rate responses to O-1602 (5–20 mg kg−1) in hypertensive SHR rats in the presence of vehicle (A); CBD (5 mg kg−1; B); AM281 (10 mg kg−1; C); or a combination of CBD and AM281 (D). Baseline MABP’s and HR’s for each group were SHR (146 ± 5 mmHg and 305 ± 10 bpm; n = 6); SHR & CBD (141 ± 5 mmHg and 296 ± 8 bpm; n = 6); SHR &AM281 (153 ± 6 mmHg and 296 ± 9 bpm; n = 7); and SHR & CBD& AM281 (151 ± 5 mmHg and 297 ± 12 bpm; n = 7), respectively. Values shown are mean ± SEM.
Mentions: O-1602 (5–100 ng kg−1) did not produce any changes in MABP or HR in anesthetized rats (Figs. 4A, C, and E) or WT mice (Figs.4B, D, and F) over and above those seen with the vehicle. In conscious hypertensive rats, O-1602 administered in three ascending doses (5, 10, and 20 mg kg−1) spaced 20 min apart did not induce any changes in MABP (Fig.5A) or HR (Table2), even though O-1602 was given at much higher doses than those given to anesthetized rats. However, CBD pretreatment revealed a vasodepressor response to the lowest dose of O-1602 (Fig.5B, Table2) while co-administration of 10 mg kg−1 AM281 (a more selective CB1 antagonist; Ryberg et al. 2007) revealed a marked vasodepressor response, which was present for all doses and was sustained in the presence of 5 mg kg−1 CBD (Figs.5C and D). None of the interventions induced any changes in HR (Table2).

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