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Trans‐4‐methoxy‐β‐nitrostyrene (T4MN) induced more potent vasorelaxant effects in resistance arteries from hypertensive rats than its parent drug, β‐nitrostyrene 1‐nitro‐2‐phenylethene (NPe). To better understand the influence of insertion of the electron‐releasing methoxy group in the aromatic ring of NPe, we investigated vasorelaxant effects of T4MN in isolated pulmonary artery and compared them with those of NPe in view of the potential interest of T4MN in pulmonary arterial hypertension. T4MN and NPe both caused concentration‐dependent vasorelaxation in pulmonary artery rings pre‐contracted with either phenylephrine (1 µmol/L) or KCl (60 mmol/L), an effect unaffected by endothelium removal. In endothelium‐intact preparations pre‐contracted with phenylephrine, the vasorelaxant effect of T4MN was more potent than that of NPe. However, unlike NPe, this effect was significantly reduced following pretreatment with 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) (10 µmol/L, a guanylate cyclase inhibitor) or tetraethylammonium (5 mmol/L, a potassium channel blocker). T4MN abolished the CaCl2‐induced contractions in pulmonary artery preparations stimulated with phenylephrine (PHE) under Ca2+‐free conditions in the presence of verapamil, to preferentially activate receptor‐operated calcium channels. From these findings, we propose that T4MN evokes endothelium‐independent vasorelaxant effects in isolated rat pulmonary artery, partially by inhibiting Ca2+ influx through L‐type Ca2+ channels, as well as by activating soluble guanylate cyclase and potassium channels. The present results suggest the therapeutic potential of T4MN in treating pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

Summary: β‐Phenylethylamine (β‐PEA) is a trace amine with chemical proximity to biogenic amines and amphetamines. It is an endogenous agonist of trace amine‐associated receptors (TAARs) that acts as a neuromodulator of classic neurotransmitters in the central nervous system. At high concentrations, β‐PEA contracts smooth muscle, and a role for TAARs in these responses has been postulated. The high dietary intake of trace amines has been associated with such symptoms as hypertension and migraine, especially after the intake of foods containing such compounds. In gastrointestinal tissues, TAAR expression was reported, although the effect of β‐PEA on gastric contractile behaviour is unknown. Here, isolated strips that were obtained from the rat gastric fundus were stimulated with high micromolar concentrations of β‐PEA. Under resting tonus, β‐PEA induced contractions. In contrast, when the strips were previously contracted with KCl, a relaxant response to β‐PEA was observed. The contractile effect of β‐PEA was inhibited by 5‐hydroxytryptamine (5‐HT) receptor antagonists (i.e., cyproheptadine and ketanserin) but not by the TAAR1 antagonist EPPTB. In gastric fundus strips that were previously contracted with 80 mmol/L KCl, the relaxant effect of β‐PEA intensified in the presence of 5‐HT receptor antagonists, which was inhibited by EPPTB and the adenylyl cyclase inhibitor MDL‐12,330A. The guanylyl cyclase inhibitor ODQ did not alter the relaxant effects of β‐PEA. In conclusion, β‐PEA exerted dual contractile and relaxant effects on rat gastric fundus. The contractile effect appeared to involve the recruitment of 5‐HT receptors, and the relaxant effect of β‐PEA on KCl‐elicited contractions likely involved TAAR1. [ABSTRACT FROM AUTHOR]

Mechanisms underlying the vasorelaxant effects of trans-4-methyl-β-nitrostyrene (T4MeN) were studied in rat aortic rings. In endothelium-intact preparations, T4MeN fully and similarly relaxed contractions induced by phenylephrine ( PHE) ( IC50 = 61.41 [35.40-87.42] μmol/L) and KCl ( IC50 = 83.50 [56.63-110.50] μmol/L). The vasorelaxant effect of T4MeN was unchanged by endothelium removal, pretreatment with L- NAME, indomethacin, tetraethylammonium, ODQ or MDL-12,330A. Under Ca2+-free conditions, T4MeN significantly reduced with a similar potency: (i) phasic contractions induced by PHE, but not by caffeine; (ii) contractions due to CaCl2 in aortic preparations stimulated with PHE (in the presence of verapamil) or high KCl; (iii) contractions evoked by the restoration of external Ca2+ levels after depletion of intracellular Ca2+ stores in the presence of thapsigargin. In contrast, T4MeN was more potent at inhibiting contractions evoked by the tyrosine phosphatase inhibitor, sodium orthovanadate, than those induced by the activator of PKC, phorbol-12,13-dibutyrate. These results suggest that T4MeN induces an endothelium- independent vasorelaxation that appears to occur intracellularly through the inhibition of contractions that are independent of Ca2+ influx from the extracellular milieu but involve phosphorylation of tyrosine residues. [ABSTRACT FROM AUTHOR]

2-Nitro-1-phenyl-1-propanol ( NPP) is a nitro alcohol that is known as an intermediate in the synthesis of sympathomimetic agents, such as norephedrine. The present study investigated the vasoactive effects of NPP on rat aorta. In endothelium-intact aortic rings, NPP fully relaxed contractions that were induced by phenylephrine, KCl, and U-46619. The relaxant effects of NPP on phenylephrine-elicited contractions remained unaffected by NG-nitro- l-arginine methyl ester ( l-NAME), indomethacin, propranolol, tetraethylammonium, 4-aminopyridine, and glibenclamide. Conversely, pretreatment with 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ), cis- N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine hydrochloride (MDL-12,330A), and N-[2-( P-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89) reduced the ability of NPP to relax contractions that were elicited by phenylephrine. NPP inhibited the vasoconstrictor response that was induced by Ca2+ in aortic rings that were stimulated by pharmacomechanical or electromechanical coupling with phenylephrine and 60 mmol/L KCl, respectively, and after the depletion of intracellular Ca2+ stores. Such effects of NPP were significantly reversed by pretreatment with the guanylyl cyclase inhibitor ODQ and weakly influenced by the adenylyl cyclase inhibitor MDL-12,330A. In Ca2+-free medium, NPP inhibited transient contractions that were induced by phenylephrine but not caffeine. In homogenates of aortic rings, NPP increased cyclic guanosine 3′,5′-monophosphate ( cGMP) and cyclic adenosine 3′-5′-monophosphate levels, but this effect was statistically significant only for cGMP. In conclusion, in contrast to the vasoconstrictor amine norephedrine, NPP is a vasodilator in rat aorta, and its relaxant effects are likely attributable to cGMP production. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the vascular effects of the E-isomer of methyl cinnamate (E- MC) in rat isolated aortic rings and the putative mechanisms underlying these effects. At 1-3000 μmol/L, E- MC concentration-dependently relaxed endothelium-intact aortic preparations that had been precontracted with phenylephrine ( PHE; 1 μmol/L), with an IC50 value (geometric mean) of 877.6 μmol/L (95% confidence interval ( CI) 784.1-982.2 μmol/L). These vasorelaxant effects of E- MC remained unchanged after removal of the vascular endothelium ( IC50 725.5 μmol/L; 95% CI 546.4-963.6 μmol/L) and pretreatment with 100 μmol/L NG-nitro- l-arginine methyl ester ( IC50 749.0 μmol/L; 95% CI 557.8-1005.7 μmol/L) or 10 μmol/L 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one ( IC50 837.2 μmol/L; 95% CI 511.4-1370.5 μmol/L). Over the concentration range 1-3000 μmol/L, E- MC relaxed K+-induced contractions in mesenteric artery preparations ( IC50 314.5 μmol/L; 95% CI 141.9-697.0 μmol/L) with greater potency than in aortic preparations ( IC50 1144.7 μmol/L; 95% CI 823.2-1591.9 μmol/L). In the presence of a saturating contractile concentration of K+ (150 mmol/L) in Ca2+-containing medium combined with 3 μmol/L PHE, 1000 μmol/L E- MC only partially reversed the contractile response. In contrast, under similar conditions, E- MC nearly fully relaxed PHE-induced contractions in aortic rings in a Ba2+-containing medium. In preparations that were maintained under Ca2+-free conditions, 600 and 1000 μmol/L E- MC significantly reduced the contractions induced by exogenous Ca2+ or Ba2+ in KCl-precontracted preparations, but not in PHE-precontracted preparations (in the presence of 1 μmol/L verapamil). In addition, E- MC (1-3000 μmol/L) concentration-dependently relaxed the contractions induced by 2 mmol/L sodium orthovanadate. Based on these observations, E- MC-induced endothelium-independent vasorelaxant effects appear to be preferentially mediated by inhibition of plasmalemmal Ca2+ influx through voltage-dependent Ca2+ channels. However, the involvement of a myogenic mechanism in the effects of E- MC is also possible. [ABSTRACT FROM AUTHOR]

1. 1,8-Cineole is a non-toxic small terpenoid oxide believed to have medicinal properties in folk medicine. It has been shown to have various pharmacological effects, including blockade of the compound action potential (AP). In the present study, using intracellular recording techniques, we investigated the effects of 1,8-cineole on the electrophysiological parameters of neurons of the superior cervical ganglion (SCG) in rats. 2. 1,8-Cineole (0.1–6 mmol/L) showed reversible and concentration-dependent effects on various electrophysiological parameters. At 3 and 6 mmol/L, but not at 0.1 and 1 mmol/L, 1,8-cineole significantly diminished the input resistance (Ri) and altered the resting potential (Em) to more positive values. At 6 mmol/L, 1,8-cineole completely blocked all APs within 2.7 ± 0.6 min ( n = 12). In neurons exposed to 3 and 1 mmol/L 1,8-cineole, the effects regarding excitability varied from complete AP blockade to minor inhibition of AP parameters. The depolarization of Em and the decrease in Ri induced by 6 mmol/L 1,8-cineole were unaltered by 200 µmol/L niflumic acid, a well known blocker of Ca2+-activated Cl− currents. 3. Significant correlations (Pearson correlation test) were found between changes in Em and decreases in AP amplitude ( r = –0.893; P < 0.00282) and maximum ascendant inclination ( r = –0.799; P < 0.0173), but not for maximum descendant inclination ( r = 0.598; P < 0.117). Application of current to restore the transmembrane potential equal to control Em values in the presence of 6 mmol/L 1,8-cineole resulted in the partial recovery of AP. 4. The present study shows that 1,8-cineole effectively blocks the excitability of SCG neurons, probably through various mechanisms, one of which acts indirectly via depolarization of the neuronal cytoplasmatic membrane. [ABSTRACT FROM AUTHOR]

1. 1,8-Cineole is a terpenoid constituent of essential oils with anti-inflammatory properties. It reduces the neural excitability, functions as an antinociceptive agent and has myorelaxant actions in guinea-pig airways. The aim of the present study was to investigate the mechanism underlying the myorelaxant effects of 1,8-cineole in guinea-pig isolated trachea from either naïve guinea-pigs or ovalbumin (OVA)-sensitized animals subjected to antigenic challenge. 2. Isometric recordings were made of the tone of isolated tracheal rings. Rings with an intact epithelium relaxed beyond basal tone in the presence of 1,8-cineole (6.5 × 10−6 to 2 × 10−2 mol/L) in a concentration-dependent manner ( P < 0.001,anova) with a pD2 value of 2.23 (95% confidence interval 2.10–2.37). Removal of the epithelium or pretreatment of intact tissue for 15 min with 50 µmol/L NG-nitro-l-arginine methyl ester, 5 mmol/L tetraethylammonium, 0.5 µmol/L tetrodotoxin or 5 µmol/L propranolol did not alter the potency (pD2) or the maximal myorelaxant effect (Emax) of 1,8-cineole. 3. 1,8-Cineole also significantly decreased the Schultz-Dale contraction induced by OVA, mainly in preparations from OVA-sensitized animals submitted to antigen challenge. 1,8-Cineole decreased tracheal hyperresponsiveness to KCl and carbachol caused by antigen challenge and almost abolished the concentration–response curves to KCl, whereas it had little effect on the concentration–response curves to carbachol. Under Ca2+-free conditions and in the presence of 10−4 mol/L acetylcholine, neither 1,8-cineole (6.5 × 10−3 mol/L) nor verapamil (1 × 10−5 mol/L) affected Ca2+-induced contractions, but they almost abolished Ba2+-induced contractions. 4. In conclusion, the findings of the present study show that 1,8-cineole is a tracheal myorelaxant that acts preferentially on contractile responses elicited electromechanically. [ABSTRACT FROM AUTHOR]

1. Antigenic challenge often induces hyperreactivity in asthmatic airway, although the precise mechanism(s) underlying this increased responsiveness is not entirely known. 2. Tracheae obtained from ovalbumin (OVA)-sensitized saline- or OVA-challenged rats were placed in 10 mL bath chambers for isometric recording of 5-hydroxytryptamine (5-HT)-induced contractions. 3. 5-Hydroxytryptamine induced a stronger contraction compared with control in antigen-challenged trachea under normal or Ca2+-free conditions. 4. In tracheae pretreated with the L-type Ca2+ channel blocker nifedipine (10−6 mol/L) or the Ca2+-activated Cl– channel blocker niflumic acid (10−4 mol/L), this hyperresponsiveness was not developed in either normal or Ca2+-free medium. 5. The increased contractile response to 5-HT in allergic rat isolated trachea may be related to a greater ionic (Ca2+ and Cl–) channel involvement. [ABSTRACT FROM AUTHOR]

1. Sildenafil citrate (Viagra™; Pfizer, Sandwich, Kent, UK), a phosphodiesterase 5 inhibitor, rises cGMP levels in smooth muscle cells. It relaxes both vascular and visceral smooth muscle. In order to assess the intestinal effects of sildenafil, we decided to investigate its actions on rat duodenal motor activityin vitro.2. In isolated duodenal segments maintained in Tyrode's solution, sildenafil exhibited a concentration-dependent antispasmodic effect on acetylcholine (ACh)-induced phasic contractions, with an IC50 value of 26.7 µmol/L (95% confidence interval (CI) 2.0–55.3 µmol/L).3. Sildenafil also relaxed the carbamylcholine (CCh)-induced sustained contraction with an IC50 of 16.2 µmol/L (95% CI 9.5–27.6 µmol/L). Sildenafil produced significant additional relaxation of 25.2 ± 8.1% of the CCh-induced contraction, beyond basal tone.4. Sildenafil reduced the amplitude of spontaneous duodenal contractions with an EC50 of 9.6 µmol/L (95% CI 5.7–16.2 µmol/L). This effect was significantly more potent than the effects of zaprinast and papaverine, which also reduced duodenal contractions with EC50 values of 91.6 µmol/L (95% CI 46.0–182.2 µmol/L) and 78.5 µmol/L (95% CI 37.1–166.3 µmol/L), respectively.5. In preparations treated previously with methylene blue (10 μmol/L) or 1H-[1,2,4]oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 µmol/L), the EC50 values for the sildenafil effect were significantly increased to 39.0 µmol/L (95% CI 23.9–63.4 µmol/L) and 43.8 µmol/L (95% CI 24.5–78.3 µmol/L), respectively. These values were significantly greater than those obtained with sildenafil alone.6. In conclusion, sildenafil has myorelaxant and antispasmodic effects on rat duodenal segmentsin vitro.The contractile inhibitory effect of sildenafil on rat isolated duodenum is probably due to intracellular cGMP accumulation as a result of its decreased degradation. [ABSTRACT FROM AUTHOR]