CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function

Tiyerili, Vedat; Zimmer, Sebastian; Jung, Suzin; Wassmann, Kerstin; Naehle, Claas P.; Lütjohann, Dieter; Zimmer, Andreas; Nickenig, Georg; Waßmann, Sven

doi:10.1007/s00395-010-0090-7

Cited by 83 publications

(63 citation statements)

References 58 publications

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“…The transactivation of cannabinoid CB1 receptors by Ang II is supported by the finding that showed an inhibitory effect of AM 251, inverse agonist of CB 1 receptors, on the hypertensive effect of Ang II injected directly into the hypothalamic paraventricular nucleus of anaesthetized rats (Gyombolai et al, 2012). Vice versa, AT 1 receptor expression may be directly regulated by CB 1 receptors, namely in cultured vascular smooth muscle cells inhibition of CB 1 receptor by rimonabant and AM 251 led to down-regulation of AT 1 receptor expression (Tiyerili et al, 2010).…”

Section: Discussionmentioning

confidence: 83%

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Gyires

Rónai

Zádori

et al. 2014

Molecular and Cellular Endocrinology

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The aim of the present study was to analyze whether angiotensin II via the endocannabinoid system can induce gastric mucosal protection, since transactivation of cannabinoid CB1 receptors by angiotensin AT1 receptor in CHO cells was described. Experimental ulcer was induced by acidified ethanol given orally in male Wistar rats, CB1(+/+) wild type and CB1(-/-) knock out mice. The compounds were administered intracerebroventricularly. It was found, that 1./ Angiotensin II inhibited the ethanol-induced gastric lesions (11.9-191 pmol); the effect of angiotensin II (191 pmol) was inhibited by the CB1 receptor inverse agonist AM 251 (1.8 nmol) and the inhibitor of diacylglycerol lipase (DAGL), tetrahydrolipstatin (0.2 nmol). 2./ Angiotensin II exerted gastroprotection in wild type, but not in CB1(-/-) mice. 3./ The gastroprotective effect of angiotensin II (191 pmol) was reduced by atropine (1 mg/kg i.v.) and bilateral cervical vagotomy. In conclusion, stimulation of central angiotensin AT1 receptors via activation of cannabinoid CB1 receptors induces gastroprotection in a DAGL-dependent and vagus-mediated mechanism.

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Section: Discussionmentioning

confidence: 83%

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Gyires

Rónai

Zádori

et al. 2014

Molecular and Cellular Endocrinology

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“…receptor protein expression was significantly higher in BDL than in sham rats, providing direct evidence of CB 2 receptor up-regulation in portosystemic collateral vessels. CB receptors have been identified in various vessels, including rat aorta, 36 rat mesenteric vascular bed, 37 and human pulmonary artery. 38 However, the presence of CB receptors in the collateral vasculature and the up-regulated CB 2 receptor expression in cirrhosis have not been proven.…”

Section: Resultsmentioning

confidence: 99%

Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats

et al. 2012

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Angiogenesis in liver cirrhosis leads to splanchnic hyperemia, increased portal inflow, and portosystemic collaterals formation, which may induce lethal complications, such as gastroesophageal variceal hemorrhage and hepatic encephalopathy. Cannabinoids (CBs) inhibit angiogenesis, but the relevant influences in cirrhosis are unknown. In this study, Spraque-Dawley rats received common bile duct ligation (BDL) to induce cirrhosis. BDL rats received vehicle, arachidonyl-2-chloroethylamide (cannabinoid receptor type 1 [CB 1 ] agonist), JWH-015 (cannabinoid receptor type 2 [CB 2 ] agonist), and AM630 (CB 2 antagonist) from days 35 to 42 days after BDL. On the 43rd day, hemodynamics, presence of CB receptors, severity of portosystemic shunting, mesenteric vascular density, vascular endothelial growth factor (VEGF), VEGFR-1, VEGFR-2, phospho-VEGFR-2, cyclooxygenase (COX)-1, COX-2, and endothelial nitric oxide synthase (eNOS) expressions as well as plasma VEGF levels were evaluated. Results showed that CB 1 and CB 2 receptors were present in left adrenal veins of sham rats, splenorenal shunts (the most prominent intraabdominal shunts) of BDL rats, and mesentery of sham and BDL rats. CB 2 receptor was up-regulated in splenorenal shunts of BDL rats. Both acute and chronic JWH-015 treatment reduced portal pressure and superior mesenteric arterial blood flow. Compared with vehicle, JWH-015 significantly alleviated portosystemic shunting and mesenteric vascular density in BDL rats, but not in sham rats. The concomitant use of JWH-015 and AM630 abolished JWH-015 effects. JWH-133, another CB 2 agonist, mimicked the JWH-015 effects. JWH-015 decreased mesenteric COX-1, COX-2 messenger RNA expressions, and COX-1, COX-2, eNOS protein expressions. Furthermore, JWH-015 decreased intrahepatic angiogenesis and fibrosis. Conclusions: CB 2 agonist alleviates portal hypertension (PH), severity of portosystemic collaterals and mesenteric angiogenesis, intrahepatic angiogenesis, and fibrosis in cirrhotic rats. The mechanism is, at least partly, through COX and NOS down-regulation. CBs may be targeted in the control of PH and portosystemic collaterals. (HEPATOLOGY 2012;56:248-258) A ngiogenesis, the generation of new blood vessels from the preexisting vessels, is involved in the development of increased portal inflow and pressure as well as of portosystemic collaterals in portal hypertension (PH).1 The portosystemic collateral vascular bed is primarily triggered with an attempt to divert the stagnant portal blood flow to systemic circulation. Complications include hepatic encephalopathy caused by the noxious material draining into systemic circulation, and bleeding from the most prominent

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“…An increase in AT1R expression secondary to CB1 agonism in turn leads to increased generation of ROS by VSMC. 39 The antioxidative effect of CB1 inhibition on VSMC was also shown to contribute to better endothelial function.…”

Section: Cannabinoids and Vascular Smooth Muscle Cellsmentioning

confidence: 99%

Cannabinoids and Atherosclerotic Coronary Heart Disease

Singla

Sachdeva

Mehta

2012

Clinical Cardiology

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Marijuana is the most abused recreational drug in the United States. Cannabinoids, the active ingredients of marijuana, affect multiple organ systems in the human body. The pharmacologic effects of marijuana, based on stimulation of cannabinoid receptors CB1 and CB2, which are widely distributed in the cardiovascular system, have been well described. Activation of these receptors modulates the function of various cellular elements of the vessel wall, and may contribute to the pathogenesis of atherosclerosis. Clinically, there are reports linking marijuana smoking to the precipitation of angina and acute coronary syndromes. Recently, large published clinical trials with CB1 antagonist rimonabant did not show any significant benefit of this agent in preventing progression of atherosclerosis. In light of these findings and emerging data on multiple pathways linking cannabinoids to atherosclerosis, we discuss the literature on the role of cannabinoids in the pathophysiology of atherosclerosis. We also propose a marijuana paradox, which implies that inhalation of marijuana may be linked to precipitation of acute coronary syndromes, but modulation of the endocannabinoid system by a noninhalation route may have a salutary effect on the development of atherosclerosis.The authors have no funding, financial relationships, or conflicts of interest to disclose.

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CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function

Cited by 83 publications

References 58 publications

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats

Cannabinoids and Atherosclerotic Coronary Heart Disease

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