(-)-Carvone Inhibits Oxytocin-induced Writhing Via Uterine Relaxation in Rodents.

(-)-Carvone, a ketone monoterpene, is the main component of essential oils from several medicinal plants and has been reported to have anti-arthriric, anticonvulsive, antidiabetic, anti-inflammatory, anticancer, and immunomodulatory effects. Therefore, this study aimed to investigate the spasmolytic activity of (-)-carvone in rodent models. The isolated virgin rat uterus was mounted in an organ bath apparatus, and the relaxing effect of ( -)-carvone and its mechanism of action were evaluated in tonic contractions induced by carbachol, KCl, PGF2α, or oxytocin. The animal model of primary dysmenorrhea was replicated with the injection of estradiol benzoate in female mice for three consecutive days, followed by intraperitoneal administration of oxytocin. Non-clinical acute toxicity evaluation was also performed. (-)-Carvone potency and effectiveness were larger in carbachol (pEC50 = 5.41 ± 0.14 and Emax = 92.63 ± 1.90% at 10-3 M) or oxytocin (pEC50 = 4.29 ± 0.17 and Emax = 86.69 ± 1.56% at 10-3 M) contractions. The effect of ( -)-carvone was altered in the presence of 4-aminopyridine, glibenclamide, L-NAME, or methylene blue. Mice pre-treated with (-)-carvone at a dose of 100 mg/kg showed a significant reduction in the number of writhing after oxytocin administration. No toxicity was observed after oral administration of 1 g/kg ( -)-carvone. Taken together, we showed that (-)-carvone reduced writhing by a spasmolytic effect, probably through the participation of KV and KATP channels and the nitric oxide pathway.

Maternal exposure to glyphosate-based herbicide causes vascular dysfunction in offspring female rats.

This study analyzed how glyphosate exposure in the gestational period affects vascular function in their female offspring and whether oxidative stress is involved in this effect. To this, pregnant Wistar rats were exposed through drinking water to 0.2% of a glyphosate commercial formulation, and we analyzed the response to acetylcholine and phenylephrine in the aorta from offspring of Glyphosate-based herbicide (O-GBH) and controls (O-CON) rats at six months of age. Relaxation to acetylcholine was reduced in O-GBH than in O-CON. Acute Indomethacin and Apocynin increased relaxation to acetylcholine in O-GBH. The aorta from O-GBH was hyperactive to phenylephrine; the preincubation with N-nitro-L-arginine methyl ester (L-NAME) increased contraction to phenylephrine more in O-CON than O-GBH. TEMPOL similarly reduced phenylephrine response, and L-NAME prevented this effect. The TBARS and GSH levels were increased in O-GBH than in O-CON. Results reinforce the concept that oxidative stress during the perinatal period contributes to the development of vascular changes in adulthood. Results also reveal that oxidative stress parameters altered, and the current levels considered safe for exposure to Glyphosate deserve further investigation, especially in the female gender.

Maternal exposure to glyphosate-based herbicide causes changes in the vascular function of offspring adult rats.

This study analyzed how glyphosate exposure in the gestational period affects vascular function in their offspring, focusing on the influence of age and whether oxidative stress is involved in this effect. To this, pregnant Wistar rats were exposed through drinking water to 0.2% of a glyphosate commercial formulation, and we analyzed the response to acetylcholine and phenylephrine in the aorta from offspring of glyphosate herbicide-based (O-GHB) and controls (O-CON) rats at 3, 6, and 12 months of age. O-GHB groups showed no changes in arterial blood pressure or aorta histological analysis. Relaxation to acetylcholine was reduced in O-GHB than O-CON. Acute TEMPOL increased relaxation to acetylcholine in O-GHB at 6 and 12 months of age. The aorta from O-GHB was hyperactive to phenylephrine only at 6 months of age. Preincubation with N-nitro-L-arginine methyl ester (L-NAME) increased contraction to phenylephrine more in O-CON than O-GHB. TEMPOL similarly reduced phenylephrine response. This effect was prevented by L-NAME. Results reinforce the concept that oxidative stress during the perinatal period contributes to the development of vascular changes in adulthood. Results also reveal that although no changes in cardiac or histological parameters have been demonstrated, the current levels considered safe for exposure to glyphosate deserve further investigation, especially during pregnancy.

Losartan reverses COX-2-dependent vascular dysfunction in offspring of hyperglycaemic rats.

AIMS: This study examined whether chronic treatment with losartan, an angiotensin II type 1 receptor (AT1R) antagonist, might reverse COX-2-mediated vascular dysfunction in mesenteric resistance arteries (MRA) from offspring of hyperglycaemic rats. MATERIALS AND METHODS: Male 12-month-old offspring of hyperglycaemic (O-DR) and normoglycaemic (O-CR) rats were treated with losartan (15mg·kg·day-1) during 2months. Third order MRA of untreated and losartan-treated O-DR and O-CR were mounted in wire myograph for isometric tension measurements. COX-2 expression was analyzed by Western blot; TxA2, PGE2 and PGF2α release was measured using commercial kits. KEY FINDINGS: O-DR showed increased blood pressure, impaired acetylcholine-induced vasodilation and increased noradrenaline-induced vasoconstriction than O-CR. All these parameters were normalized by losartan in O-DR. Pre-incubation of MRA with indomethacin (COX-1/2 inhibitor), NS-398 (COX-2 inhibitor) or tempol (superoxide dismutase mimetic) increased relaxation to acetylcholine and reduced contraction to noradrenaline only in O-DR. COX-2 expression, TxA2, PGE2 and PGF2α release were increased in O-DR. In losartan-treated O-DR, NS-398, indomethacin or tempol failed to produce any effect on acetylcholine or noradrenaline responses. Losartan treatment reduced COX-2 expression, TxA2, PGE2 and PGF2α release in O-DR. SIGNIFICANCE: The present results reveal that chronic losartan administration in O-DR normalizes endothelial function in MRA by correcting the existing COX-2 overexpression and the imbalance between endothelium-derived relaxing and contracting factors. These findings not only support the beneficial effects of AT1 receptor antagonist in O-DR, but also suggest the implication of angiotensin II as a putative mediator of hyperglycemia-programmed vascular dysfunction in rats.

Hyperglycaemia in pregnant rats causes sex-related vascular dysfunction in adult offspring: role of cyclooxygenase-2.

NEW FINDINGS: What is the central question of this study? Hyperglycaemia during pregnancy induces vascular dysfunction and hypertension in male offspring. Given that female offspring from other fetal programming models are protected from the effects of fetal insult, the present study investigated whether there are sex differences in blood pressure and vascular function in hyperglycaemia-programmed offspring. What is the main finding and its importance? We demonstrated that hyperglycaemia in pregnant rats induced vascular dysfunction and hypertension only in male offspring. We found sex differences in oxidative stress and cyclooxygenase-2-derived prostanoid production that might underlie the vascular dysfunction. These differences, particularly in resistance arteries, may in part explain the absence of hypertension in female offspring born to hyperglycaemic dams. Exposure to maternal hyperglycaemia induces hypertension and vascular dysfunction in adult male offspring. Given that female offspring from several fetal programming models are protected from the effects of fetal insult, in this study we analysed possible differences relative to sex in blood pressure and vascular function in hyperglycaemia-programmed offspring. Hyperglycaemia was induced on day 7 of gestation (streptozotocin, 50 mg kg-1 ). Blood pressure, acetylcholine and phenylephrine or noradrenaline responses were analysed in the aorta and mesenteric resistance arteries of 3-, 6- and 12-month-old male and female offspring. Thromboxane A2 release was analysed with commercial kits and superoxide anion (O2- ) production by dihydroethidium-emitted fluorescence. Male but not female offspring of hyperglycaemic dams (O-DR) had higher blood pressure than control animals (O-CR). Contraction in response to phenylephrine increased and relaxation in response to acetylcholine decreased only in the aorta from 12-month-old male O-DR and not in age-matched O-CR. Contractile and vasodilator responses were preserved in both the aorta and mesenteric resistance arteries from female O-DR of all ages. Pre-incubation with tempol, superoxide dismutase, indomethacin, NS-398, furegrelate or SQ29548 decreased contraction in response to phenylephrine and potentiated relaxation in response to acetylcholine in 12-month-old male O-DR aorta. In this artery, thromboxane A2 release and O2- generation were greater in O-DR than O-CR groups. In conclusion, exposure to hyperglycaemia in utero results in sex-specific and age-dependent hypertension. The fact that vascular function is preserved in female O-DR may in part explain the absence of hypertension in this group. In contrast, the peripheral artery dysfunction associated with increased cyclooxygenase-2-derived production of vasoconstrictor prostanoids could underlie the increased blood pressure in male O-DR.