Cannabinoid CB1 Receptor Antagonist Rimonabant Decreases Levels of Markers of Organ Dysfunction and Alters Vascular Reactivity in Aortic Vessels in Late Sepsis in Rats

Cannabinoid Receptor 1 and 2 Signaling Pathways Involved in Sepsis

“…The reasons for these changes in AVP sensitivity during sepsis (refractory, unchanged, or hypersensitive depending on the vascular bed involved) are currently unknown, but some studies suggest that the explanation may be related to vascular receptor expression (64). We have shown a reduction in vasoconstriction, therefore a phenylephrine-induced hyporeactivity in the aorta 6 h after CLP, and this response returned to normal levels 24 h after CLP and observed hyper-responsiveness to AVP 24 h after aortic artery CLP (43). Rimonabant did not influence phenylephrine hyporesponsiveness, but normalized AVP hyperreactivity in the aortic rings of rats submitted to CLP.…”

“…Rimonabant did not influence phenylephrine hyporesponsiveness, but normalized AVP hyperreactivity in the aortic rings of rats submitted to CLP. This result suggests that blocking CB 1 receptors by rimonabant treatment specifically affects this response to AVP and not phenylephrine (43). Based on available data, some vascular beds appear to develop hypersensitivity at later times (i.e., late sepsis), but this may also vary according to the severity of sepsis.…”

“…CB 1 receptor activation can reduce excitatory presynaptic currents in vasopressinergic cells in the supraoptic nucleus (42). This system may be important during sepsis (43). We have proposed previously that endothelin-1 (ET-1), by activating endothelin receptor type A (ET A ) receptors present in the CNS, would induce the release of eCBs, which act retrograde at the presynaptic terminations and would cause a decrease in glutamatergic neurotransmission.…”

“…In aged rats undergoing CLP, increased plasma levels of LDH were reported, and these high levels of lactate and LDH in the bloodstream were related to multiple organ failure (59,60). CB 1 inhibition in septic rats decreased the plasma levels of LDH and lactate, however did not alter blood NOx levels (43). Moreover, we have shown that CLP induced tail vasoconstriction, which is consistent with the development of a febrile response in the first hours after CLP and the treatment with rimonabant reversed this vasoconstriction in the tail.…”

Possible Role of Adipose Tissue and the Endocannabinoid System in Coronavirus Disease 2019 Pathogenesis: Can Rimonabant Return?

“…However, several preclinical studies have been developed in the past 15 years, with one of the latest describing the molecular mechanisms underlying the inhibition by rimonabant of inflammation accompanying diet‐induced obesity in mice (7). In addition, in a rat model of bacterial sepsis, rimonabant was shown to reduce mortality and to correct vascular hyperreactivity (8), which might be relevant in the context of the worse clinical outcomes associated with COVID‐19 (2).…”