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Previously, we showed that 1‐nitro‐2‐phenylethene, a nitrostyrene derivative of 1‐nitro‐2‐phenylethane, induced vasorelaxant effects in rat aorta preparations. Here, we studied mechanisms underlying the vasorelaxant effects of its structural analog, trans‐4‐chloro‐β‐nitrostyrene (T4CN), in rat aortic rings. Increasing concentrations of T4CN (0.54‐544.69 µm) fully and similarly relaxed contractions induced by phenylephrine (PHE, 1 µm) or KCl (60 mm) in endothelium‐intact aortic rings with IC50 values of 66.74 [59.66–89.04] and 79.41 [39.92–158.01] µm, respectively. In both electromechanical and pharmacomechanical couplings, the vasorelaxant effects of T4CN remained unaltered by endothelium removal, as evidenced by the IC50 values (108.35 [56.49–207.78] and 65.92 [39.72–109.40] µm, respectively). Pretreatment of endothelium‐intact preparations with L‐NAME, ODQ, glibenclamide, or TEA did not change the vasorelaxant effect of T4CN. Under Ca2+‐free conditions, T4CN significantly reduced the phasic contractions induced by caffeine or PHE, as well as the contractions due to exogenous CaCl2 in aortic preparations stimulated with PHE (in the presence of verapamil). These results suggest that in rat aortic rings, T4CN induced vasorelaxation independently from the activation of soluble guanylate cyclase/cGMP pathway, an effect that may be related to the electrophilicity of the substituted chloro‐nitrostyrene. This vasorelaxation seems to involve inhibition of both calcium influx from the extracellular milieu and calcium mobilization from intracellular stores mediated by IP3 receptors and by ryanodine‐sensitive Ca2+ channels. [ABSTRACT FROM AUTHOR]

A group of nitro compounds contains a benzene ring in a short aliphatic chain with the NO2 group, property that supposedly favors its vasodilator profile. In this study, we evaluated in isolated rat aorta the effects of 1‐nitro‐2‐propylbenzene (NPB), a nitro compound containing the NO2 in the aromatic ring. In aorta precontracted with KCl, NPB (1‐3000 μm) induced full endothelium‐independent relaxation. In endothelium‐intact preparations, phenylephrine‐induced contractions were fully relaxed by NPB, effect unaltered by N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME) or 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ). In the concentration range of 30–300 μm, NPB slightly but significantly potentiated the phenylephrine‐induced contraction. Such potentiation was unaltered by the thromboxane‐prostanoid receptor antagonist seratrodast, but was abolished by endothelium removal or by preincubation of endothelium‐intact preparations with L‐NAME, ODQ or by ruthenium red and HC‐030031, blockers of subtype 1 of ankyrin transient receptor potential (TRPA1) channels. Verapamil exacerbated the potentiating effect of NPB. The potentiating effect was undetectable in preparations precontracted by 9,11‐dideoxy‐11α,9α‐epoxymethanoprostaglandin F2α (U‐46619). Relaxation was reduced by ruthenium red while it was enhanced by HC‐030031. In conclusion, NPB has vasodilator properties but with a mechanism of action distinct from its analogues. Contrary to other nitro compounds, its relaxing effects did not involve recruitment of the guanylyl cyclase pathway. NPB has also endothelium‐dependent potentiating properties on phenylephrine‐induced contractions, a phenomenon that putatively required a role of endothelial TRPA1 channels. The present findings reinforce the notion that the functional group NO2 in the aliphatic chain of these nitro compounds determines favorably their vasodilator properties. [ABSTRACT FROM AUTHOR]

This study investigated the cardiovascular responses to the essential oil of Aniba canelilla (EOAC) and its main constituent 1-nitro-2-phenylethane (NP) in spontaneously hypertensive rats (SHRs). In anesthetized SHRs, intravenous (i.v.) bolus injections of EOAC (1-20 mg/kg) or NP (1-10 mg/kg) elicited dose-dependent hypotensive and bradycardiac effects, which were characterized in two periods (phases 1 and 2). The first rapid component (phase 1) evoked by EOAC and NP both at 10 mg/kg was absent after left ventricle injection, fully abolished by bilateral vagotomy and perineural treatment of both cervical vagus nerves with capsaicin (250 μg/mL) while remained unaltered by i.v. pretreatment with capsazepine (1 mg/kg) or ondansetron (30 μg/kg). In conscious SHRs, NP (5 and 10 mg/kg, i.v.) evoked rapid hypotensive and bradycardiac effects (phase 1) that were fully abolished by methylatropine (1 mg/kg, i.v.) pretreatment. In rat endothelium-containing mesenteric preparations, increasing concentrations (0.1-1000 μg/mL) of EOAC and NP relaxed the phenylephrine-induced contraction in a concentration-dependent manner. It is concluded that NP induces a vago-vagal bradycardiac and depressor reflex (phase 1) that apparently results from the stimulation of vagal pulmonary rather than cardiac C-fiber afferents. This effect does not appear to involve activation of either vanilloid TPRV1 or 5-HT3 receptors located on vagal sensory nerves. The phase 2 hypotensive response to i.v. NP seems to result, at least in part, from its direct vasodilatory effect on the peripheral smooth muscle. All in vivo and in vitro effects of EOAC are mostly attributed to the actions of its main constituent NP. [ABSTRACT FROM AUTHOR]

This study was undertaken to assess the effects of eugenol (EUG) on tracheal muscle (TM) and the putative mechanisms underlying these effects. Cumulatively increasing concentrations (1-1000 μ m) of EUG did not affect the resting tonus of TM. However, EUG (1-2000 μ m) reduced the contractions induced by electrical field stimulation (IC50 = 842.3 ± 52.7 μ m), an effect that was unaltered by either 10 μ m montelukast (IC50 = 816.1 ± 70.1 μ m) or 2 μ m indomethacin (IC50 = 693.1 ± 170.8 μ m). EUG also completely relaxed the sustained contractile responses to 80 mM K+ (IC50 = 597.3 ± 60.6 μ m) and 1 μ m carbamoylcholine (IC50 = 571.3 ± 148.8 μ m), an effect that was unaltered by indomethacin (2 μ m). Under Ca2+-free conditions, EUG reduced the ACh-induced contractions (IC50 = 703.4 ± 256.1 μ m), the CaCl2-induced contractions in preparations pretreated with 60 μ m ACh in the presence of nifedipine, and the Ba2+-induced contractions in preparations depolarized with K+. In tracheal preparations maintained in Ca2+-containing solution, EUG (300-2000 μ m) relaxed the contractile response to phorbol dibutyrate (1 μ m), an activator of protein kinase C. It is concluded that in TM, EUG induces a myogenic antispasmodic effect (not modulated by arachidonic acid derivatives) either through various mechanisms almost with the same pharmacological potency or via an action on a step common to all of them. These mechanisms seem to include blockade of voltage- and receptor-operated Ca2+ channels, IP3-induced Ca2+ release from sarcoplasmic reticulum and reduction of the sensitivity of contractile proteins to Ca2+. [ABSTRACT FROM AUTHOR]

This study investigates the effects of essential oil of Pterodon polygalaeflorus (EOPP) and β-caryophyllene (β-CAR). EOPP and β-CAR relaxed the basal tone of ileum smooth muscle in a concentration-dependent manner (ICs = 394.35 ± 62.12 and 68.65 ± 9.51 μg/mL respectively), an effect that was unaltered by hexamethonium, -nitroarginine methyl ester or indomethacin. Both EOPP and β-CAR evoked a concentration-dependent relaxation of ileum pre-contracted with KCl with an IC value of 107.78 ± 10.47 and 17.35 ± 0.75μg/mL, respectively. EOPP and β-CAR inhibited the contractions induced by acetylcholine (ACh) and by KCl. In ileal preparations, the CaCl-induced contractions were reduced by EOPP (300 μg/mL) and β-CAR (100 μg/mL). Furthermore, CaCl-induced contractions were also reduced by EOPP (300 μg/mL) and β-CAR (100 μg/mL) in ileal preparations pretreated with ACh under Ca-free condition and in the presence of verapamil. EOPP (100 and 300 μg/mL) and β-CAR (30 and 100 μg/mL) reduced the ACh-induced contractions of isolated rat ileum under Ca-free conditions. In the presence of high KCl and Ca-free conditions, EOPP (300 μg/mL) and β-CAR (100 μg/mL) reduced the contractions induced by barium. A similar effect was also observed with verapamil. It is concluded that (i) β-CAR is an important constituent involved in the myorelaxant and antispasmodic effects induced by EOPP; (ii) the inhibitory effect on intestinal contractility is myogenic and seems mainly mediated through an intracellular mechanism. However, the ability of EOPP and β-CAR to decrease Ca influx through cytoplasmic membrane could not be discounted. [ABSTRACT FROM AUTHOR]

Previously, we reported that essential oil of Croton nepetaefolius (EOCN) decreases blood pressure in normotensive rats, an effect that seems resulting from its vasodilatory action directly upon vascular smooth muscle. In the present study, we aimed to study the role of endothelium–nitric oxide pathway in the mediation of vasodilatory effects of EOCN and two of its constituents, methyleugenol and α-terpineol, using rat isolated thoracic aorta and mesenteric vascular bed preparations. EOCN (1–300 μg/mL), in a concentration-dependent manner, relaxed isolated endothelium-intact aortic rings precontracted with KCl 60 mm, with an IC50 value of 26.7 (14.7–48.2) μg/mL. Either pretreatment of the tissue withl-NAME, a nitric oxide synthase inhibitor, or mechanical endothelium removal increased significantly the IC50 value to 66.6 (52.7–84.1) or 105.6 (91.3–122.2) μg/mL, respectively. In endothelium-intact aortic rings precontracted with norepinephrine, EOCN (10–200 μg/mL) produced a vasorelaxant action which was decreased by the pretreatment of the aortic rings with methylene blue, a guanylate cyclase inhibitor. In mesenteric bed preparations perfused under constant pressure, EOCN reverted the reduction of mesenteric flow caused by KCl (60 mm), an effect that was attenuated byl-NAME. Vasodilator responses to EOCN in mesenteric bed preparations were mimicked by methyleugenol and α-terpineol, and were also significantly reduced in the presence ofl-NAME. In conclusion, EOCN has vasorelaxant effects in both a resistance vascular bed and in a conduit artery. They seem attributed, at least in part, to the actions of its main constituents methyleugenol and α-terpineol and appear partially dependent upon the integrity of a functional vascular endothelium. Inhibition of other transduction pathways may be involved in the mediation of these effects. [ABSTRACT FROM AUTHOR]

Phosphodiesterase type-5 (PDE5) specifically cleaves cyclic guanosine monophosphate (cGMP), a key intracellular secondary messenger. The PDE5 inhibitor sildenafil is a well-known vasodilator that also has gastrointestinal myorelaxant properties. In the present study, we further investigated sildenafil-induced myorelaxation in rat isolated duodenum, assessing its interaction with nitric oxide (NO) synthase and K+ channel opening. The spontaneous contractions of duodenal strips were reversibly inhibited by sildenafil (0.1–300 μm) in a concentration-dependent manner [mean (95% confidence interval); EC50 = 6.8 (2.7–17.3) μm]. The sildenafil-induced myorelaxation was significantly decreased by the NO synthase inhibitor N-nitro-l-arginine methyl ester [increasing the EC50 value to 41.9 (26.1–67.3) μm]. Sodium nitroprusside or forskolin pretreatments enhanced the sildenafil-induced myorelaxation. In isolated strips pretreated with BaCl2 (0.2 mm), 4-aminopyridine (4-AP, 3 mm), or glybenclamide (1 μm), the sildenafil-induced EC50 value was significantly increased to 32.8 (19.1–56.4), 27.1 (15.2–48.3) and 20.1 (16.4–24.7) μm, respectively. Minoxidil (50 μm) or diazoxide (100 μm) also significantly attenuated the sildenafil-induced potency. In conclusion, the NO synthase/cyclic nucleotide pathway activation is involved in sildenafil-induced inhibition of spontaneous duodenal contractions. Its pharmacological action seems to be influenced by K+ channel opening, especially the voltage-sensitive ones, being inhibited by 4-AP and KATP channels, sensitive to glybenclamide. [ABSTRACT FROM AUTHOR]

Intravenous (i.v.) treatment of conscious DOCA-salt hypertensive rats with the essential oil of Ocimum gratissimum L. (Labiatae) (EOOG) induced a hypotensive effect that seems related to an active vascular relaxation rather than withdrawal of sympathetic tone. To corroborate this hypothesis, the present study examined the vascular effects of EOOG and its main constituent, eugenol (EUG) and the putative mechanisms underlying these effects. Additionally, the role of the vascular β2-adrenergic mechanism in the mediation of EOOG-induced hypotension has also been investigated. In conscious DOCA-salt hypertensive rats, the EOOG-induced hypotension was reversible and remained unchanged by i.v. pretreatment with propranolol (2 mg/kg). In isolated aorta preparations with intact endothelium from DOCA-salt hypertensive rats, EOOG (1–1000 μg/mL) and EUG (0.006–6 mm) relaxed the phenylephrine-induced contraction similarly with IC50 [geometric mean (95% confidence interval)] values of 226.9 (147.8–348.3) μg/mL and 1.2 (0.6–2.1) mm, respectively. Vasorelaxant effects of EOOG were significantly altered by removal of the vascular endothelium [IC50 = 417.2 (349.5–497.8) μg/mL]. In a calcium-free medium, the CaCl2-induced contractions were significantly reduced and even abolished by EOOG at 300 and 1000 μg/mL, respectively, whereas EOOG (1000 μg/mL) did not have any significant effect on caffeine-induced contractions. Similar results were obtained with EUG (1.8 and 6 mm) on both CaCl2- and caffeine-induced contractions, respectively. The data suggest that hypotensive responses to EOOG in DOCA-salt hypertensive rats are due to an active vascular relaxation, which is partly dependent upon the integrity of the vascular endothelium and seems predominantly mediated through an inhibition of plasmalemmal Ca2+ influx rather than Ca2+-induced Ca2+ release from the sarcoplasmic reticulum. [ABSTRACT FROM AUTHOR]

The effects of essential oil ofCroton nepetaefolius(EOCN) on guinea-pig-isolated ileum were studied. We previously demonstrated that EOCN induced reversible relaxation of ileal tone artificially increased by high [K+] nutrient solution. This study aimed to elucidate whether these effects were caused by indirect, neural, or primarily by myogenic effect. EOCN (40 μg/mL) induced a relaxation of basal tone corresponding to approximately 38% of the reference contraction (K+ 60 mm), and was unaltered by 0.5 mmhexamethonium, 0.5 μmtetrodotoxin, 1 μmindomethacin, and 100 μml-nitroarginine methyl ester (l-NAME). Epinephrine- (100 μm) and EOCN-induced maximal relaxation of ileum pre-contracted with 60 mmKCl represented 16.8 ± 2.3% (n = 10) and 95.0 ± 6.4% (n = 6) of KCl-induced contraction, respectively. EOCN (200 μg/mL) had no effect on the transmembrane resting potential (Em) of ileum in nutrient solutions with normal (5 mm) and high (80 mm) [K+]. EOCN similarly inhibited the contractions induced by KCl, acetylcholine (ACh) and histamine (IC50 values of approximately 18, 28 and 21 μg/mL, respectively). EOCN also inhibited both the nifedipine-insensitive component of ACh-induced contraction and the contraction induced by ACh in Ca2+-free solution. EOCN accelerated the reversal of a KCl-induced tonic contraction upon withdrawal of Ca2+ from the extracellular medium. Our results suggest that EOCN induces relaxation of guinea-pig ileum by a direct action on smooth muscle via a mechanism largely independent of alterations of Em and Ca2+ influx, possibly at the level of the contractile apparatus. [ABSTRACT FROM AUTHOR]