1. Alpha-terpineol is a monoterpene found in the essential oils of several aromatic plant species. In the present study, we investigated the mechanisms underlying the cardiovascular changes induced by alpha-terpineol in rats. 2. In normotensive rats, administration of alpha-terpineol (1, 5, 10, 20 and 30 mg/kg, i.v.) produced a dose-dependent hypotension (-10 +/- 3, -20 +/- 8, -39 +/- 16, -52 +/- 21 and -57 +/- 23 mmHg, respectively; n = 5) followed by tachycardia. The hypotensive responses to 1, 5, 10, 20 and 30 mg/kg, i.v., alpha-terpineol were significantly attenuated following the administration of N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg, i.v.; -2 +/- 1, -5 +/- 2, -7 +/- 3, -22 +/- 9 and -22 +/- 10 mmHg, respectively; P < 0.05; n = 5). 3. In 10 micromol/L phenylephrine (PE)-precontracted mesenteric artery rings, alpha-terpineol (10(-12) to 10(-5) mol/L) caused a concentration-dependent relaxation (maximum relaxation 61 +/- 6%; n = 7). After removal of the endothelium, the vasorelaxation elicited by alpha-terpineol was attenuated (maximum relaxation 20 +/- 1%; P < 0.05; n = 7). In addition, vasorelaxation induced by alpha-terpineol in rings pretreated with 100 or 300 micromol/L l-NAME, 30 micromol/L hydroxocobalamin or 10 micromol/L 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one was attenuated (maximum relaxation 18 +/- 3, 23 +/- 3, 24 +/- 7 and 21 +/- 1%, respectively; n = 6; P < 0.05). 4. Furthermore, in a rabbit aortic endothelial cell line, 10(-6), 10(-5) and 10(-4) mol/L alpha-terpineol induced concentration-dependent increases in nitric oxide (NO) levels (12 +/- 6, 18 +/- 9 and 34 +/- 12%Delta fluorescence, respectively; n = 3). 5. In conclusion, using combined functional and biochemical approaches in the present study, we were able to demonstrate that alpha-terpineol-induced hypotension and vasorelaxation are mediated, at least in part, by the endothelium, most likely via NO release and activation of the NO-cGMP pathway.

Rotundifolone is the major constituent of the essential oil of Mentha x villosa Hudson. In preliminary studies, rotundifolone induced significant hypotensive, bradycardic and vasorelaxant effects in rats. Thus, to gain more insight into the pharmacology of rotundifolone, the aim of this study was to characterize the molecular mechanism of action involved in relaxation produced by rotundifolone. The relaxant effect was investigated in rat superior mesenteric arteries by using isometric tension measurements and whole-cell patch-clamp techniques. Rotundifolone relaxed phenylephrine-induced contractions in a concentration-dependent manner. Pre-treatment with KCl (20 mM), charybdotoxin (10 )7 M) or tetraethylammonium (TEA 10 )3 or 3 · 10 )3 M) significantly attenuated the relaxation effect induced by rotundifolone. Additionally, whole-cell patch-clamp recordings were made in mesenteric smooth muscle cells and showed that rotundifolone significantly increased K + currents, and this effect was abolished by TEA (10 )3 M), suggesting the participation of BK Ca channels. Furthermore, rotundifolone inhibited the vasoconstriction induced by CaCl 2 in depolarizing nominally Ca 2+-free medium and antagonized the contractions elicited by an L-type Ca 2+ channel agonist, S(-)-Bay K 8644 (2 · 10 )7 M), indicating that the vasodilatation involved inhibition of Ca 2+ influx through L-type voltage-dependent calcium channels (Ca v type-L). Additionally, rotundifolone inhibited L-type Ca 2+ currents (I Ca L), affecting the voltage-dependent activation of I Ca L and steady-state inactivation. Our findings suggest that rotundifolone induces vasodilatation through two distinct but complementary mechanisms that clearly depend on the concentration range used. Rotundifolone elicits an increase in the current density of BK Ca channels and causes a shift in the steady-state inactivation relationship for Ca v type-L towards more hyperpolarized membrane potentials.Terpenoids constitute the largest class of plant secondary metabolites and have been used in essential oils for centuries as therapeutically relevant compounds. However, little is known about their mechanism of action [1,2].The monoterpenoids, such as camphor, borneol, citronellol, alpha-terpineol or menthol, compose a group of naturally occurring organic compounds derived from two isoprene units. They are the major components of some essential oils presenting anaesthetic and analgesic activities [3,4] Rotundifolone (C 10 H 14 O 2 ; molecular weight 166) is a naturally occurring monoterpenic ketone of plant origin and an important chemical constituent of the essential oils of many Mentha species (Mentha rotundifolia, M. suaveolens, M. spicata L., M. longifolia and M. x villosa) [19,20]. A previous report from our group showed that rotundifolone induced marked hypotension and bradycardia in non-anaesthetized normotensive rats using an in vivo approach. Those effects were probably due to a decrease in peripheral vascular resistance [21], a hypothesis that was subsequently str...

For many years, nitric oxide (NO) has been studied as an important mediator in the control of vascular tone. Endothelial deficiencies that diminish NO production can result in the development of several future cardiovascular diseases, such as hypertension and arteriosclerosis. In this context, new drugs with potential ability to donate NO have been studied. In this study, 3 aromatic oximes [benzophenone oxime, 4-Cl-benzophenone oxime, and E-cinnamaldehyde oxime (E-CAOx)] induced vasorelaxation in endothelium-denuded and intact superior mesenteric rings precontracted with phenylephrine. E-CAOx demonstrated the most potent effect, and its mechanism of action was evaluated. Vascular reactivity experiments demonstrated that the effect of E-CAOx was reduced by the presence of 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one, and (Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate, suggesting the participation of NO/sGC/PKG pathway. NO donation seems to be mediated through nicatinamide adenine dinucleotide phosphate-dependent reductases because 7-ethoxyresorufin decreased the effect of E-CAOx on vascular reactivity and reduced NO formation as detected by flow cytometry using the NO indicator diaminofluorescein 4,5-diacetate. Further downstream of NO donation, K+ subtype channels were also shown to be involved in the E-CAOx vasorelaxant effect. The present study showed that E-CAOx acts like an NO donor, activating NO/sGC/PKG pathway and thus K+ channels.

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Abstract:The mechanisms underlying the cardiovascular responses evoked by milonine (i.v.), an alkaloid, were investigated in rats. In normotensive rats, milonine injections produced hypotension and tachycardia, which were attenuated after N w -nitro-L-arginine methyl esther (L-NAME; 20 mg ⁄ kg, i.v.). In phenylephrine (10 lM), pre-contracted mesenteric artery rings, milonine (10 )10 M to 3 · 10 )4 M) caused a concentration-dependent relaxation (EC 50 = 1.1 · 10 )6 M, E max = 100 € 0.0%) and this effect was rightward shifted after either removal of the vascular endothelium (EC 50 = 1.6 · 10 )5, p < 0.001), or after L-NAME 100 lM (EC 50 = 6.2 · 10 , p < 0.001). Milonine also reduced CaCl 2 -induced contraction in Ca 2+ -free solution containing KCl (60 mM). In conclusion, using combined functional and biochemical approaches, we demonstrated that the hypotensive and vasorelaxant effects produced by milonine are, at least in part, mediated by the endothelium, likely via nitric oxide release, activation of nitric oxide-cGMP pathway and opening of K + channels.