Biphasic effect of limonene on contraction of isolated rat aorta

Limonene, a monoterpene found in essential oils, has various activities, such as antifungal, antioxidant, neuroprotective, gastroprotective and vasorelaxant. However, the observation of limonene's biphasic effect in preclinical studies provides crucial information about its dose-dependent actions. Understanding this behavior is essential for optimizing therapeutic doses and anticipating possible side effects prior to clinical trials. The objective of this study is to provide a more detailed characterization and investigation of the mechanisms of action of limonene on the contractile tonus of isolated aorta.The experiments were carried out on aortic rings isolated from rats, subjected to isometric recording of contractions in their circular smooth muscle and exposed to different concentrations of limonene. It was found that limonene blocked the contraction induced by KCl (60 mM), but had a biphasic effect on the contraction induced by phenylephrine (0.1 μM). At lower concentrations, limonene was able to amplify the contraction induced by phenylephrine, while at higher concentrations, it inhibited it. The nitric oxide synthase blockers L-NAME and ruthenium red, a TRP ion channel blocker, did not significantly interfere with the biphasic character of limonene. However, indomethacin, a blocker of arachidonic acid derivatives, completely blocked the amplification of contraction induced by phenylephrine. In addition, limonene promoted relaxation in contractions induced by BAY-K 8644, a calcium channel agonist and by Ba²⁺. Limonene has complex effects on aortic tone, amplifying or inhibiting contractions, suggesting that the therapeutic window should be carefully studied to optimize clinical results.