A cannabinoid type 2 (CB2) receptor agonist augments NOS-dependent responses of cerebral arterioles during type 1 diabetes

Abstract

While activation of cannabinoid (CB2) receptors has been shown to be neuroprotective, no studies have examined whether this neuroprotection is directed at cerebral arterioles and no studies have examined whether activation of CB2 receptors can rescue cerebrovascular dysfunction during a chronic disease state such as type 1 diabetes (T1D). Our goal was to test the hypothesis that administration of a CB2 agonist (JWH-133) would improve impaired endothelial (eNOS)- and neuronal (nNOS)-dependent dilation of cerebral arterioles during T1D. In vivo diameter of cerebral arterioles in nondiabetic and T1D rats was measured in response to an eNOS-dependent agonist (adenosine 5'-diphosphate; ADP), an nNOS-dependent agonist (N-methyl-d-aspartate; NMDA), and an NOS-independent agonist (nitroglycerin) before and 1 h following JWH-133 (1 mg/kg IP). Dilation of cerebral arterioles to ADP and NMDA was greater in nondiabetic than in T1D rats. Treatment with JWH-133 increased responses of cerebral arterioles to ADP and NMDA in both nondiabetic and T1D rats. Responses of cerebral arterioles to nitroglycerin were similar between nondiabetic and T1D rats, and JWH-133 did not influence responses to nitroglycerin in either group. The restoration in responses to the agonists by JWH-133 could be inhibited by treatment with a specific inhibitor of CB2 receptors (AM-630; 3 mg/kg IP). Thus, activation of CB2 receptors can potentiate reactivity of cerebral arterioles during physiologic and pathophysiologic states. We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular diseases via a mechanism that can increase cerebral blood flow.

Keywords: ADP; Brain; JWH-133; NMDA; Nitric oxide; Reactivity.

Figure 1.

Responses of cerebral arterioles to ADP, NMDA and nitroglycerin in nondiabetic (n=12) and T1D (n=11) rats before and during treatment with JWH-133 (1 mg/kg IP). Values are means±SE. * p < 0.05 versus response in nondiabetic rats. ** p < 0.05 versus response during treatment with JWH-133.

Figure 2.

Responses of cerebral arterioles to ADP, NMDA and nitroglycerin in nondiabetic (n=6) and T1D (n=6) rats before and during treatment with AM-630 (3 mg/kg IP) and JWH-133 (1 mg/kg IP). Values are means±SE. * p < 0.05 versus response in nondiabetic rats. ** p < 0.05 versus response in nondiabetic rats treated with AM-630 and JWH-133.

Figure 3.

Percent difference in response of cerebral arterioles to ADP and NMDA during treatment with JWH-133 or during treatment with JWH-133/AM-630 in nondiabetic (n=12) and T1D (n=11) rats. * p < 0.05 versus response in nondiabetic rats. ** p < 0.05 versus response in nondiabetic and T1D rats during treatment with JWH-133.

Figure 4.

Responses of cerebral arterioles to ADP, NMDA and nitroglycerin in nondiabetic (n=8) and T1D (n=6) rats before and after treatment with vehicle. Values are means±SE. * p < 0.05 versus response in nondiabetic rats. ** p < 0.05 versus response in nondiabetic rats treated with vehicle.