Eugenol induces potent vasorelaxation in uterine arteries from pregnant goats - A promising natural therapeutic agent for hypertensive disorders of pregnancy

Hypertensive disorders of pregnancy, including preeclampsia, affect about 8-13% of pregnancies and are the leading causes of pregnancy related maternal mortality worldwide. Poorly controlled high blood pressure during pregnancy increases the risk of pregnancy complications and development of future cardiovascular diseases. However, the choice for antihypertensive therapy during pregnancy has been limited due to side effects of many commonly used antihypertensive drugs and lack of other proven safe treatment options. Eugenol is a natural phenolic compound and the main component of clove oil. It is known for its antioxidant, anti-inflammatory and vasorelaxant actions. These beneficial effects of eugenol make it as an excellent therapeutic candidate for treatment of hypertensive disorders of pregnancy. Thus, as a first step, we compared the vasorelaxant effect of eugenol on the middle uterine arterial (MUA) rings from pregnant and nonpregnant goats. Additionally, we examined the potential involvement of the transient receptor potential channel 1 (TRPV1) in mediating the actions of eugenol and compared the effects with a known TRPV1 channel agonist, capsaicin. Isometric tension was measured in MUA rings from endometrial-myometrial junctions of pregnant and nonpregnant goats precontracted with phenylephrine, using a highly sensitive isometric force transducer and an automatic organ bath. The concentration-dependent contractile response curves of eugenol were compared to capsaicin, with and without pre-incubation of the MUA rings with a selective and non-selective TRPV1 antagonists, capsazepine (CAPZ) and Ruthenium Red (RR), respectively. Capsaicin induced concentration-dependent vasorelaxation in nonpregnant PE precontracted MUA rings and the concentration-response curve shifted to the right with significantly reduced pIC50 and Rmax values in the presence of CAPZ and RR. The effects were similar in MUA rings from pregnant animals, except that there was a moderate increase in pIC50 values in the presence of RR. Similarly, eugenol induced concentration-dependent vasorelaxation in both nonpregnant and pregnant PE precontracted MUA rings and the effects were markedly antagonized by CAPZ and RR. However, compared to capsaicin, the Rmax of eugenol was increased 31.25% in nonpregnant and 97.99% in pregnant MUA rings. These results suggest that eugenol has highly potent vasorelaxant effect in MUAs and its effect is partly mediated through activation of the TRPV1 channel. Most importantly, its vasorelaxant effect is about three-fold augmented in pregnancy, suggesting its potential value as a nutraceutical agent and therapeutic candidate for treatment of hypertensive disorders of pregnancy.