Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Jun;160(3):574-84.
doi: 10.1111/j.1476-5381.2009.00579.x. Epub 2010 Jan 25.

A Cannabinoid Receptor, Sensitive to O-1918, Is Involved in the Delayed Hypotension Induced by Anandamide in Anaesthetized Rats

Affiliations
Free PMC article

A Cannabinoid Receptor, Sensitive to O-1918, Is Involved in the Delayed Hypotension Induced by Anandamide in Anaesthetized Rats

Agnieszka Zakrzeska et al. Br J Pharmacol. .
Free PMC article

Abstract

Background and purpose: Intravenous injection of the endocannabinoid anandamide induces complex cardiovascular changes via cannabinoid CB(1), CB(2) and vanilloid TRPV1 receptors. Recently, evidence has been accumulating that in vitro, but not in vivo, anandamide relaxes blood vessels, via an as yet unidentified, non-CB(1) vascular cannabinoid receptor, sensitive to O-1918 (1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene). We here examined whether the anandamide-induced hypotension in urethane-anaesthetized rats was also mediated via a non-CB(1) vascular cannabinoid receptor.

Experimental approach: Effects of two antagonists (O-1918 and cannabidiol) of the non-CB(1) vascular cannabinoid receptor on anandamide-induced changes in mean, systolic and diastolic blood pressure (MBP, SBP, DBP), mesenteric (MBF) and renal (RBF) blood flow and heart rate (HR) in urethane-anaesthetized rats was examined.

Key results: In anaesthetized rats, anandamide (1.5-3 micromol.kg(-1)) and its stable analogue methanandamide (0.5 micromol.kg(-1)) caused a delayed and prolonged decrease in MBP, SBP, DBP, MBF and RBF by about 10-30% of the respective basal values without changing HR. In pithed rats, anandamide (3 micromol.kg(-1)) decreased blood pressure by about 15-20% of the basal value without affecting HR, MBF and RBF. All vascular changes were reduced by about 30-70% by cannabidiol and O-1918 (3 micromol.kg(-1), each).

Conclusions and implications: Non-CB(1) cannabinoid vascular receptors, sensitive to O-1918, contribute to the hypotensive effect of anandamide in anaesthetized rats. Activation of these receptors may be therapeutically important as the endocannabinoid system could be activated as a compensatory mechanism in various forms of hypertension.

Figures

Figure 2
Figure 2
Influence of cannabidiol (CBD, 3 µmol·kg−1) and 1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene (O-1918) (3 µmol·kg−1) on the decreases in mean (A; MBP), systolic (B; SBP) and diastolic (C; DBP) blood pressure (phase III) induced by anandamide (AEA; 1.5–3 µmol·kg−1) and methanandamide (MethAEA; 0.5 µmol·kg−1) in urethane-anaesthetized rats. AEA and MethAEA were given twice (S1 and S2, 20 min apart). S1 and S2 were calculated as percentages of the respective basal values. CBD or O-1918 or their solvents were administered 10 min before S2. All drugs were administered i.v. Means ± SEM of 5–10 rats. *P < 0.05, **P < 0.01 compared with the respective control (CON).
Figure 1
Figure 1
Typical traces showing the changes in diastolic blood pressure, mesenteric and renal blood flow and heart rate induced by i.v. injection of anandamide (3 µmol·kg−1) in a rat anaesthetized with urethane (A) and in a rat anaesthetized with urethane and pithed (B). Arrows indicate drug application. Pithed rats received an i.v. injection of ruthenium red (3 µmol·kg−1) 5 min before anandamide. Note that the small decrease in heart rate in (B) is related to the injection per se, as it occurred identically when the drug vehicle was administered.
Figure 3
Figure 3
Influence of cannabidiol (CBD, 3 µmol·kg−1) and 1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene (O-1918) (3 µmol·kg−1) on the decrease in (A) mesenteric blood flow (MBF) and (B) renal blood flow (RBF) (phase III) induced by anandamide (AEA; 1.5–3 µmol·kg−1) and methanandamide (MethAEA; 0.5 µmol·kg−1) in urethane-anaesthetized rats. AEA and MethAEA were given twice (S1 and S2, 20 min apart). S1 and S2 were calculated as percentages of the respective basal values. CBD or O-1918 or their solvents were administered 10 min before S2. All drugs were administered i.v. Means ± SEM of 5–10 rats. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the respective control (CON).
Figure 4
Figure 4
Influence of cannabidiol (CBD, 3 µmol·kg−1) and 1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene (O-1918) (3 µmol·kg−1) on the decreases in mean (A; MBP), systolic (B; SBP) and diastolic (C; DBP) blood pressure induced by anandamide (AEA; 3 µmol·kg−1) in pithed and vagotomized rats anaesthetized with urethane. AEA was given twice (S1 and S2, 20 min apart); ruthenium red (3 µmol·kg−1) was given 5 min before S1. S1 and S2 were calculated as percentages of the respective basal values. CBD or O-1918 or their solvents were administered 10 min before S2. All drugs were administered i.v. Mean ± SEM of 4–6 rats. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the respective control (CON).
Figure 5
Figure 5
Influence of (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP 55,940) (1 µmol·kg−1) on the electrically stimulated increase in heart rate (HR) in pithed rats anaesthetized with pentobarbitone and its interaction with N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251) (3 µmol·kg−1), cannabidiol (CBD, 3 µmol·kg−1) and 1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene (O-1918) (3 µmol·kg−1). An increase in HR was induced twice (S1 and S2, 10 min apart) by electrical stimulation (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerves. AM 251, CBD or O-1918 were administered 5 min before S1. CP 55,940 was injected 5 min before S2. To quantify the effects of CP 55,940, the ratio of S2/S1 was determined. S2/S1 values are expressed as percentages of the corresponding ratios in controls. All drugs were administered i.v. Mean ± SEM of 4–10 rats. **P < 0.01, ***P < 0.001 compared with the respective control (not shown). ΔΔP < 0.001 compared with the group without antagonist.

Similar articles

See all similar articles

Cited by 11 articles

See all "Cited by" articles

Publication types

Feedback