PhD Scientific Days 2022

Translational Medicine II. (Poster discussion will take place in the Aula during the Coffee Break)

Delta9-tetrahydrocannabinol conserves cardiovascular functions in a rat model of endotoxemia: involvement of endothelial molecular mechanisms and oxidative-nitrative stress.

Text of the abstract

Endotoxemia is accompanied by severe cardiovascular dysfunction, in which inflammatory processes and oxidative-nitrative stress play important roles. Recently, several research groups described that inflammatory parameters in endotoxic animal models were altered to a favorable direction as a response to the activation of cannabinoid receptors 1 and 2. Our aim was to examine the effect of cannabinoid treatment on the cardiovascular system in endotoxemia.
Male Wistar rats were treated with LPS (5 mg/kg i.v.) to induce endotoxemia. A group of animals received additional delta9-tetrahydrocannabinol THC (10 mg/kg i.p.). 24 hours later we examined their cardiac function by echocardiography and via intra ventricular pressure monitoring. Endothelium-dependent, acetylcholine induced relaxation of the thoracic aorta rings was measured by wire-myography. To evaluate the molecular mechanism, endothelial NOS, COX-2, cGMP, the oxidative stress marker 4-hydroxynonenal (HNE), the nitrative stress marker 3-nitrotyrosine (NT), and poly(ADP-ribose) polymer (PAR) was labelled by immunoshistochemistry.
A decrease in the end-systolic and the end-diastolic ventricular volumes with sustained ejection fraction and fractional shortening was found in the LPS group, which was not observed in LPS+THC animals. Endothelium-dependent relaxation worsened in the LPS group, however no significant endothelial dysfunction was present in the LPS+THC group compared to controls. cGMP staining density was reduced in both LPS treated groups independent from THC treatment, although eNOS labeling was only reduced in the LPS+THC treated animals. COX-2 staining density was only reduced in the LPS+THC treated group. Tissue oxidative (HNE) and nitrative (NT) stress increased after LPS treatment, which was reversed by THC co-treatment. The significant increase in PAR-ylation after LPS was prevented by THC.
Based on our results, we hypothesize that the reduced diastolic filling in the LPS group is a consequence of vascular dysfunction, which was prevented by THC. The mechanism of action of THC is not based on its local effect on aortic NO homeostasis. The reduced oxidative-nitrative stress and the reduced detectability of COX-2 suggest the activation of an anti-inflammatory pathway.