Moving together: K⁺ channel openersand ATP-sensitive K⁺ channels

Flavonoid galetin 3,6-dimethyl ether (FGAL) has been isolated from the aerial parts of Piptadenia stipulaceae and has shown a spasmolytic effect in guinea pig ileum. Thus, we aimed to characterize its relaxant mechanism of action. FGAL exhibited a higher relaxant effect on ileum pre-contracted by histamine (EC₅₀=1.9±0.4×10⁻⁷ M) than by KCl (EC₅₀=2.6±0.5×10⁻⁶ M) or carbachol (EC₅₀=1.8±0.4×10⁻⁶ M). The flavonoid inhibited the cumulative contractions to histamine, as well as to CaCl₂ in depolarizing medium nominally Ca²⁺-free. The flavonoid relaxed the ileum pre-contracted by S-(–)-Bay K8644 (EC₅₀=9.5±1.9×10⁻⁶ M) but less potently pre-contracted by KCl or histamine. CsCl attenuated the relaxant effect of FGAL (EC₅₀=1.1±0.3×10⁻⁶ M), but apamin or tetraethylammonium (1 mM) had no effect (EC₅₀=2.6±0.2×10⁻⁷ and 1.6±0.3×10⁻⁷ M, respectively), ruling out the involvement of small and big conductance Ca²⁺-activated K⁺ channels (SK_Ca and BK_Ca, respectively). Either 4-aminopyridine or glibenclamide attenuated the relaxant effect of FGAL (EC₅₀=1.8±0.2×10⁻⁶ and 1.5±0.5×10⁻⁶ M, respectively), indicating the involvement of voltage- and ATP-sensitive K⁺ channels (K_V and K_ATP, respectively). FGAL did not alter the viability of intestinal myocytes in the MTT assay and decreased (88%) Fluo-4 fluorescence, indicating a decrease in cytosolic Ca²⁺ concentration. Therefore, the relaxant mechanism of FGAL involves pseudo-irreversible noncompetitive antagonism of histaminergic receptors, K_V and K_ATP activation and blockade of Ca_V1, thus leading to a reduction in cytosolic Ca²⁺ levels.

This study was planned to assess pharmacological basis for the medicinal use of Flaxseed in constipation and diarrhea.

The oil and mucilage of Flaxseeds were studied for their laxative, and antidiarrheal activities in mice. The mechanisms of laxative and antidiarrheal activities were further studied using the isolated tissue preparations (rabbit jejunum and guinea-pig ileum) immersed in Tyrode׳s solution maintained at 37 °C and aerated with carbogen gas. Isotonic responses were measured on spontaneously contracting isolated jejunum and guinea-pig ileum preparations.

Oral administration of Flaxseed oil (30 and 70 mg/kg, orally) and mucilage (1 and 2.5 g/kg, orally) caused dose-dependent increase in wet feces in mice. The spasmogenic effect of Flaxseed oil was partially blocked by pyrilamine (p<0.05) and atropine (p<0.01) in isolated rabbit jejunum whereas atropine completely blocked the effect of Flaxseed mucilage on isolated guinea-pig ileum. When studied for its antidiarrheal effect, Flaxseed oil reduced the castor oil-induced diarrheal score by 49.35% and 84.41% and intestinal secretions by 19% and 33.62% at the oral doses of 100 and 300 mg/kg respectively. In isolated rabbit jejunum preparations, Flaxseed oil produced a dose-dependent inhibition of both spontaneous and low K⁺ (25 mM) -induced contractions in rabbit jejunum. The inhibitory effect against low K⁺ was most sensitive to tetra-ethylammonium chloride, a non-specific K⁺ channel blocker, followed by glibenclamide, a partial ATP-dependent K⁺ channels blocker and 4-Aminopyridine, a voltage gated K⁺-channel blocker.

Our results indicate that Flaxseed oil and mucilage exhibit laxative activity, mediated primarily through cholinergic pathway with weak histaminergic effect component evident in Flaxseed oil, which also showed antidiarrheal activity, mediated possibly through K⁺ channels activation. Thus this study rationalizes the medicinal use of Flaxseed in both the constipation and diarrhea with sound mechanistic basis.

Flavonols, and specially quercetin, are widely distributed in plants and are present in considerable amounts in fruits and vegetables. In addition to their anti-oxidant effect, flavonols interfere with a large number of biochemical signaling pathways and, therefore, physiological and pathological processes. There is solid evidence that, in vitro, quercetin and related flavonols exert endothelium-independent vasodilator effects, protective effect on nitric oxide and endothelial function under conditions of oxidative stress, platelet antiaggregant effects, inhibition of LDL oxidation, reduction of adhesion molecules and other inflammatory markers and prevention of neuronal oxidative and inflammatory damage. The metabolites of quercetin show partial protective effects on endothelial function and LDL oxidation. Quercetin produces undisputed antihypertensive and antiatherogenic effects, prevents endothelial dysfunction and protects the myocardium from ischemic damage. It has no clear effects on serum lipid profile and on insulin resistance. Human intervention trials with isolated flavonols demonstrate an antihypertensive effect. The meta-analysis of epidemiological studies show an inverse association between flavonol (together with flavone) intake and coronary heart disease and stroke. Therefore, although there is no solid proof yet, a substantial body of evidence suggests that quercetin may prevent the most common forms of cardiovascular disease contributing to the protective effects afforded by fruits and vegetables.

Sulfonylureas are a class of drugs widely used to promote …

The cardioprotective effects of KR-31761, a newly synthesized K⁺_ATP opener, were evaluated in rat models of ischemia/reperfusion (I/R) heart injury. In isolated rat hearts subjected to 30-min global ischemia/30-min reperfusion, KR-31761 perfused prior to ischemia significantly increased both the left ventricular developed pressure (% of predrug LVDP: 17.8, 45.1, 54.2, and 62.6 for the control, 1 μM, 3 μM, and 10 μM, respectively) and double product (DP: heart rate × LVDP; % of predrug DP: 17.5, 44.9, 56.2, and 64.5 for the control, 1 μM, 3 μM, and 10 μM, respectively) at 30-min reperfusion while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31761 (10 μM) significantly increased the time to contracture during the ischemic period, whereas it concentration-dependently decreased the lactate dehydrogenase release during reperfusion. All these parameters were significantly reversed by 5-hydroxydecanoate (5-HD, 100 μM) and glyburide (1 μM), selective and nonselective blockers of the mitochondrial K⁺_ATP (mitoK⁺_ATP) channel and K⁺_ATP channel, respectively. In anesthetized rats subjected to 30-min occlusion of left anterior descending coronary artery/2.5-h reperfusion, KR-31761 administered 15 min before the onset of ischemia significantly decreased the infarct size (72.2%, 55.1%, and 47.1% for the control, 0.3 mg/kg, i.v., and 1.0 mg/kg, i.v., respectively); and these effects were completely and almost completely abolished by 5-HD (10 mg/kg, i.v.) and HMR-1098, a selective blocker of sarcolemmal K⁺_ATP (sarcK⁺_ATP) channel (6 mg/kg, i.v.) administered 5 min prior to KR-31761 (72.3% and 67.9%, respectively). KR-31761 only slightly relaxed methoxamine-precontracted rat aorta (IC₅₀: >30.0 μM). These results suggest that KR-31761 exerts potent cardioprotective effects through the opening of both mitoK⁺_ATP and sarcK⁺_ATP channels in rat hearts with a minimal vasorelaxant effect.

The ripe dried fruit of Ficus carica Linn. (Moraceae) commonly known as “Fig” has medicinal value in traditional system of medicine for its use in gastrointestinal and inflammatory disorders.

To rationalize the medicinal use of Fig (Ficus carica) in gastrointestinal and inflammatory disorders.

The aqueous-ethanolic extract of Ficus carica (Fc.Cr) was studied for antispasmodic effect on the isolated rabbit jejunum preparations and for antiplatelet effect using ex vivo model of human platelets.

Fc.Cr tested positive for alkaloids, flavonoids, coumarins, saponins, sterols and terpenes. When tested in isolated rabbit jejunum, Fc.Cr (0.1–3.0 mg/mL) produced relaxation of spontaneous and low K⁺ (25 mM)-induced contractions with negligible effect on high K⁺ (80 mM) similar to that caused by cromakalim. Pretreatment of the tissue with glibenclamide caused rightward shift in the curves of low K⁺-induced contractions. Similarly, cromakalim inhibited the contractions induced by low K⁺, but not of high K⁺, while verapamil equally inhibited the contractions of K⁺ at both concentrations. Fc.Cr (0.6 and 0.12 mg/mL) inhibited the adenosine 5′-diphosphate and adrenaline-induced human platelet aggregation.

This study showed the presence of spasmolytic activity in the ripe dried fruit of Ficus carica possibly mediated through the activation of K⁺_ATP channels along with antiplatelet activity which provides sound pharmacological basis for its medicinal use in the gut motility and inflammatory disorders.