Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors - PubMed (original) (raw)

Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors

L Moezi et al. Br J Pharmacol. 2006 Dec.

Abstract

Background and purpose: Hyperdynamic circulation and mesenteric hyperaemia are found in cirrhosis. To delineate the role of endocannabinoids in these changes, we examined the cardiovascular effects of anandamide, AM251 (CB(1) antagonist), AM630 (CB(2) antagonist) and capsazepine (VR1 antagonist), in a rat model of cirrhosis.

Experimental approach: Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, diameters of mesenteric arteriole and venule (intravital microscopy), arterial pressure, cardiac output, systemic vascular resistance and superior mesenteric artery (SMA) flow were measured after anandamide, AM251 (with or without anandamide), AM630 and capsazepine administration. CB(1), CB(2) and VR1 receptor expression in SMA was assessed by western blot and RT-PCR.

Key results: Anandamide increased mesenteric vessel diameter and flow, and cardiac output in cirrhotic rats, but did not affect controls. Anandamide induced a triphasic arterial pressure response in controls, but this pattern differed markedly in cirrhotic rats. Pre-administration of AM251 blocked the effects of anandamide. AM251 (without anandamide) increased arterial pressure and systemic vascular resistance, constricted mesenteric arterioles, decreased SMA flow and changed cardiac output in a time-dependent fashion in cirrhotic rats. Capsazepine decreased cardiac output and mesenteric arteriolar diameter and flow, and increased systemic vascular resistance in cirrhotic rats, but lacked effect in controls. Expression of CB(1) and VR1 receptor proteins were increased in cirrhotic rats. AM630 did not affect any cardiovascular parameter in either group.

Conclusions and implications: These data suggest that endocannabinoids contribute to hyperdynamic circulation and mesenteric hyperaemia in cirrhosis, via CB(1)- and VR1-mediated mechanisms.

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Figures

Figure 1

Figure 1

Effect of anandamide (3 mg kg−1) (ANM) infusion with or without preadministration of AM251 (3 mg kg−1) on cardiac index (a), MAP (b), SMA flow (c), systemic vascular resistance (d), mesenteric arteriole diameter (e) and mesenteric venule diameter (f) in cirrhotic or sham-control rats. Values are the mean±s.e.m. of 6–8 rats per group. *P<0.05 for comparison of BDL-placebo group with the corresponding sham-placebo groups. #P<0.05 for comparison of the BDL-placebo group with the corresponding BDL+AM251 groups.

Figure 2

Figure 2

Effect of AM251 (3 mg kg−1) administration on cardiac index (a), MAP (b), SMA flow (c), systemic vascular resistance (d) and mesenteric vessel diameter (e) in cirrhotic or sham-control rats. Values are the mean±s.e.m. of 6–8 rats per group. Arrows indicate time of administration of AM251. *P<0.05 for comparison of BDL group with the corresponding sham group.

Figure 3

Figure 3

Effect of capsazepine (3 mg kg−1) administration on cardiac index (a), MAP (b), SMA flow (c), systemic vascular resistance (d) and mesenteric vessel diameter (e) in cirrhotic or sham-control rats. Values are the mean±s.e.m. of 6–8 rats per group. Arrows indicate time of administration of capsazepine. *P<0.05 for comparison of BDL group with the corresponding sham group.

Figure 4

Figure 4

Effects of combination sequential AM251 (3 mg kg−1) and capsazepine (3 mg kg−1) on cardiac index (a), MAP (b), SMA flow (c), systemic vascular resistance (d) and mesenteric vessel diameters (e) in cirrhotic rats. Values are the mean±s.e.m. of 4–6 rats per group. Arrows indicate time of administration of either AM251 or capsazepine. *P<0.05 significantly different from baseline value in each group.

Figure 5

Figure 5

Western blot protein expression of CB1 (a), CB2 (b) and VR1 (c) receptor protein in SMA of sham (lanes 1–3) and BDL (lanes 4–6) rats. Lane 7 is the positive control (CB1, cerebellum; CB2, spleen and VR1, cerebrum). BDL rats show significantly increased CB1 and VR1 protein expression compared to sham-controls. CB2 expression is not significantly different between the two groups.

Figure 6

Figure 6

RT–PCR of CB1 (a), CB2 (b) and VR1 (c) receptor mRNA in SMA of sham (lanes 1–3) and BDL (lanes 4–6) rats. Lane 7 is the positive control (CB1, cerebellum; CB2, spleen; and VR1, cerebrum). BDL rats show significantly increased CB1 mRNA expression, but unchanged CB2 and VR1 mRNA expression compared to sham-controls.

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