Positive inotropic activity induced by a dehydroisoandrosterone derivative in isolated rat heart model

Experimental studies indicate that some steroid derivatives have inotropic activity; nevertheless, there is scarce information about the effects of the dehydroisoandrosterone and its derivatives at cardiovascular level. In addition, to date the cellular site and mechanism of action of dehydroisoandrosterone at cardiovascular level is very confusing. In order, to clarify those phenomena in this study, a dehydroisoandrosterone derivative was synthesized with the objective of to evaluate its activity on perfusion pressure and coronary resistance and compare this phenomenon with the effect exerted by dehydroisoandrosterone. The Langendorff technique was used to measure changes on perfusion pressure and coronary resistance in an isolated rat heart model in absence or presence of dehydroisoandrosterone and its derivative. Additionally, to characterize the molecular mechanism involved in the inotropic activity induced by dehydroisoandrosterone derivative was evaluated by measuring left ventricular pressure in absence or presence of following compounds; flutamide, prazosin, metoprolol and nifedipine. The results showed that dehydroisoandrosterone derivative significantly increased the perfusion pressure and coronary resistance in comparison with the control conditions and dehydroisoandrosterone. Additionally, other data indicate that dehydroisoandrosterone derivative increase left ventricular pressure in a dose-dependent manner [1 × 10^?9–1 × 10^?4 mmol]; nevertheless, this phenomenon was significantly inhibited by nifedipine at a dose of 1 × 10^?6 mmol. In conclusion, these data suggest that dehydroisoandrosterone derivative induces positive inotropic activity through of activation the L-type calcium channel.     

Anti-inflammatory activity of sugiol, a diterpene isolated from Calocedrus formosana bark

Sugiol is a diterpene which was isolated and purified from alcohol extracts of the bark of Calocedrus formosana Florin (Cupressaceae). Although sugiol has low inhibitory activity against the DPPH radical, it could effectively reduce intracellular reactive oxygen species (ROS) production in lipopolysaccharide (LPS)-stimulated macrophages. The present study investigated the potential anti-inflammatory activity of sugiol, and the relationship between signal transduction and inflammatory cytokines in vitro. A dose of 30 microM of sugiol was effectively inhibitory for proIL-1beta, IL-1beta and TNF-alpha production, suggesting that sugiol is bioactive against inflammation. Moreover, sugiol reveals a capacity for suppressing the activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) activated by LPS-stimulation in J774A.1 murine macrophages. A low dosage of 10 microM of sugiol completely inhibited ERK1/2 phosphorylation, while 30 microM effectively inhibited JNK1/2 and p38 phosphorylation in LPS-stimulated macrophages. In addition, sugiol significantly inhibited LPS-induced ROS production. Our studies suggest that sugiol's efficacy in inhibiting the inflammatory cytokines of IL-1beta and TNF-alpha could be attributed to a reduction of the ROS that leads to a decrease in the phosphorylation of MAPKs.     

The antihypertensive and positive inotropic diterpene forskolin: effects of structural modifications on its activity

Four naturally occurring analogues of forskolin were isolated. Forty-nine semisynthetic derivatives were prepared, incorporating structural alterations at the 1-, 6-, 7-, 9-, 11-, and 14/15-positions. Blood pressure lowering properties of 53 compounds were assessed in anesthetized normotensive cats and of 31 compounds in conscious spontaneously hypertensive (SH) rats. The positive inotropic properties of 25 compounds were investigated in an isolated guinea pig atrial preparation. Forskolin was unique among the compounds in its hypotensive activity in cats and in its positive inotropic properties. Although several derivatives displayed oral antihypertensive activity in the SH rats, none was significantly more potent than forskolin. The optimal structural requirements for activity are apparent, since they are found in forskolin itself.     

Vascular activity of a natural diterpene isolated from Croton zambesicus and of a structurally similar synthetic trachylobane

The aim of this study was to determine the vasorelaxant activity of a natural diterpene extracted from Croton zambesicus, ent-18-hydroxy-trachyloban-3-one (DT6), and a synthetic diterpene of similar structure, ent-trachyloban-14,15-dione (DT10) in rat aorta. DT6 and DT10 inhibited aorta contraction in a concentration-dependent manner. Both were more potent inhibitors of KCl-evoked contraction than noradrenaline-evoked contraction. Nitric oxide (NO) synthase inhibition did not significantly affect DT6 effect whereas it significantly decreased DT10 inhibitory potency. In fura-2 loaded aorta rings, DT10 simultaneously inhibited KCl-evoked contraction and cytosolic calcium increase in a concentration-dependent manner. Furthermore, DT10 significantly inhibited calcium channel current recorded by the patch-clamp technique in human neuroblastoma cells SH-SY5Y. However, despite potentiation of 8-bromo-cGMP-response, DT6 and DT10 as verapamil depressed acetylcholine-evoked relaxation, DT6 being the most potent, while only DT6 and DT10 depressed SNAP-evoked relaxation. In conclusion, these data suggest that vasorelaxant activity of diterpenes (DT) is associated with the blockade of L-type voltage-operated calcium channels. Inhibition of NO-dependent relaxation by DT could be related to a decrease in NO availability.     

Synthesis and blood pressure lowering activity of benzylic ethers of 2-diethylaminoethanol and a related diamine.

Based upon the unpublished finding that 3'-hydroxy-4'-(beta-diethylaminoethoxy)-3',4'-dihydroseselin possessed a potent blood pressure lowering effect in the cat at a dose of 1 mg/kg, the present study examined the activities of several related compounds. These compounds were derived by dissection of the parent compound to give four benzylic ethers of 2-diethylaminoethanol and a diamine, derived by replacing the ether oxygen of the parent compound with an N--CH3 function. The simplest compounds were the benzyl and 2,6-dimethoxybenzyl ethers of the aminoalcohol. Closely related to the benzyl compound was a congener with a hydroxymethyl group on the benzylic carbon. The beta-diethylaminoethyl ether of 4-chromanol was the most complex of the ethers. The blood pressure measurements were carried out on male cats and compared to papaverine hydrochloride as a standard. In all cases, the most potent blood pressure lowering activity resided in the parent compound, which was not greatly superior to the diamine but substantially more active than the other compounds.     

Positive inotropic effect of cycloprotobuxine-A on isolated guinea pig myocardium

Cycloprotobuxine-A (CPB-A) 0.1-100 mumoles/L produced positive inotropic effects in left and right atria in a concentration-dependent manner. CPB-A 30 mumoles/L enhanced post-rest contraction, augmented the response of left atrium to increase in stimulating frequency, and increased the developing tension evoked by paired pulse stimulation. By taking simultaneous recordings of action potentials and contractile force of papillary muscles, it was found that CPB-A 30 mumoles/L increased the contractile force and prolonged the action potential duration at 50% of depolarization. It is concluded that the positive inotropic effect of CPB-A on myocardium may be associated with an increase in transsarcolemmal influx of calcium as well as an augmentation of the amount of calcium released from intracellular stores.     

Positive inotropic action of saponins on isolated atrial and papillary muscles from the guinea-pig.

The effects of several saponins of animal and plant origin on the contractile activity of atrial and papillary muscles of the guinea-pig were tested. In a concentration of 1 X 10(-5)M, holothurin-A (HL-A), holothurin-B, echinoside-A, echinoside-B and sakuraso-saponin (Saku) exhibited positive inotropic and chronotropic actions whereas desacyl-jego-saponin and ginsenoside-Rd did not. Saponins having a positive inotropic action caused haemolysis of rabbit erythrocytes whereas those without inotropic action did not cause haemolysis. The positive inotropic action of saponins was not affected by practolol, chlorpheniramine, cimetidine and indomethacin. Verapamil (10(-6)M) inhibited the inotropic actions due to HL-A and isoprenaline (10(-8)M) to the same extent but had a small effect on those due to ouabain (10(-7)M). In high K+ (30 mM K+) medium where the action potential and the contraction were depressed, HL-A, Saku and isoprenaline restored the action potential and the contraction of the 'slow response' type whereas ouabain failed to do so. In normal medium HL-A and Saku reduced the resting membrane potential by 15-20 mV. These results suggest that modification of the Ca channel is involved in the positive inotropic action of saponins.     

甲基葡糖苷对豚鼠离体心房的正性肌力作用

目的　观察甲基葡糖苷对豚鼠离体心房的正性肌力作用 ,并探讨其作用机制。方法　采用豚鼠离体左右心房 ,测定药物对心房肌收缩力、右心房心率 ,以及对静息后收缩和正阶梯现象的影响 ,并测定大鼠心肌细胞膜Na+ K+ ATP酶活性。结果　甲基葡糖苷显著增强心房肌收缩力 ,减慢右心房心率 ,且呈剂量依赖性 ;能明显增强左心房静息后收缩和正阶梯现象 ,并能显著抑制大鼠心肌细胞膜Na+ K+ ATP酶活性。结论　甲基葡糖苷具有加强心房肌收缩力 ,降低右心房心率的作用 ,其正性变力作用可能与抑制心肌细胞膜Na+ K+ ATP酶活性 ,促进心肌细胞外钙内流和内钙释放有关     

Forskolin: a specific stimulator of adenylyl cyclase or a diterpene with multiple sites of action?

Forskolin, a naturally occurring diterpene, directly stimulates adenylyl cyclase and has been used extensively to increase cAMP and to elicit cAMP-dependent physiological responses. More recently, forskolin has been shown to inhibit a number of membrane transport proteins and channel proteins through a mechanism that does not involve the production of cAMP. Many of these channel proteins are predicted to have similar topographies in the membrane bilayer and it is tempting to speculate that forskolin may be binding at structurally homologous sites. Kenneth Seamon and colleagues discuss the cAMP-independent effects of forskolin and the structural similarity between forskolin and other physiologically important substances such as hexoses and steroids with respect to potential forskolin binding sites.     

Anti-inflammatory activity of abietic acid, a diterpene isolated from Pimenta racemosa var. grissea.

The anti-inflammatory activity of abietic acid, a diterpene isolated from Pimenta racemosa var. grissea (Myrtaceae), was evaluated in-vivo and in-vitro. This compound significantly inhibited rat paw oedema induced by carrageenan in a time- and dose-dependent manner, and mouse ear oedema induced by 12-O-tetradecanoylphorbol acetate, after oral or topical administration. The inhibition of myeloperoxidase enzyme showed that its topical activity was influenced by neutrophil infiltration into the inflamed tissues (ears). In addition, the effect of abietic acid on some macrophage functions was analysed in-vitro. Non-toxic concentrations of abietic acid inhibited prostaglandin E2 (PGE2) production in lipopolysaccharide-treated macrophages, whereas nitrite, tumour necrosis factor alpha and interleukin-1beta production were only weakly affected by this diterpene. PGE2 production from A23187-stimulated macrophages was only inhibited at high doses (100 microM) and it failed to modify leukotriene C4 production. These results indicate that abietic acid exerts in-vivo anti-inflammatory activity after oral or topical administration and has partial ability to prevent the production of some inflammatory mediators.     

Positive inotropic and vasodilating effects of amrinone and milrinone in isolated canine heart

The question has been raised whether the in vivo positive inotropic effect of amrinone and milrinone is a primary effect or secondary to vasodilation. The effects of each drug on isolated trabeculae and resistance vessels obtained from the same dog hearts were determined separately. The positive inotropic and vasodilatory effects coincided over the same concentration range for amrinone. The active isometric force of trabeculae and resistance vessels was increased, and respectively decreased by 20% at comparable concentrations of amrinone--20% ED (effective dose) ranging between 9.5 and 18 microM. By contrast, the vasodilatory properties of milrinone (20% ED, 15-34 microM) appeared only at concentrations at which milrinone had already evoked a maximal positive inotropic response in trabecular muscle (20% ED, 0.36-0.38 microM). Based on the present experiments and their limitations, it would thus appear that, in the intact heart and at therapeutic doses, positive inotropic and vasodilatory effects may be equally present for amrinone, whereas, for milrinone, the positive inotropic effect would largely predominate the vasodilatory effect.     

Evaluation of the gastroprotective activity of cordatin, a diterpene isolated from Aparisthmium cordatum (Euphorbiaceae)

Aparisthmium cordatum (Juss.) BAIL. (Euphorbiaceae) is a medium sized tree native to the North Brazilian coastal region, which is known in the State of Pará as "ariquena queimosa." To our knowledge it has no popular use. Phytochemical studies of the benzene extract of the bark of A. cordatum yielded a furan diterpene with a clerodane skeleton, called cordatin. Recently, we reported the antiulcerogenic activity of trans-dehydrocrotonin (DHC), another furan diterpene isolated from Croton cajucara bark, in different ulcerogenic models in mice and rats. The aim of the present study was to assess the possible antiulcerogenic activity of cordatin, another compound of the clerodane diterpene group present in A. cordatum bark. When previously administered (p.o.) at the dose of 100 mg/kg, cordatin significantly reduced (p<0.01) gastric injury induced by the indomethacin/bethanechol (78%), ethanol (76%), and hypothermic restraint-stress models (66%) and by pylorus ligature (50%) in mice and rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 250 mg/kg, cordatin from A. cordatum significantly reduced (p<0.001) the formation of gastric lesions by 70% and 77%, respectively, when compared to the control. In the pylorus-ligature model, cordatin (p.o.) only decreased the volume of gastric juice compared to the control (p<0.001). When cordatin (100 mg/kg) was administered intraduodenally to mice, significant modifications were found, such as a decrease in gastric acidity compared to the control (p<0.05). In the animals pre-treated with cordatin, free mucus production was not altered when compared with the control group. The results suggest that cordatin from A. cordatum presents a significant anti-ulcer effect when assessed in these induced ulcer models. Although the mechanism underlying this antiulcerogenic effect remains unknown, it seems to be related to an anti-secretory property but the involvement of mucosal defensive mechanisms are not to be ignored. The good yield of cordatin obtained from A. cordatum, as well as its antiulcerogenic activity, suggest that this compound should be submitted to pharmacological research as a potential new antiulcerogenic drug.     

Positive chronotropic and inotropic responses to guanosine in the isolated dog atrium.

The effects of guanosine on chronotropism and inotropism in isolated dog atria were studied in spontaneously beating preparations which were suspended in a bath perfused with arterial blood from a carotid artery of a heparinized support dog. Guanosine administered into the cannulated sinus node artery in a dose range of 30 microgram to 3 mg produced a dose-related positive inotropic and chronotropic effect. The positive responses to guanosine were not inhibited by treatment with propranolol or a non-depressant beta-blocker, carteolol, in doses which blocked responses to norepinephrine. From these results, it is concluded that guanosine has a direct effect on atrial rate and contractility.     

Anti-inflammatory activity of a new sphingosine derivative and cembrenoid diterpene (lobohedleolide) isolated from marine soft corals of Sinularia crassa TIXIER-DURIVAULT and Lobophytum species of the Andaman and Nicobar Islands

The aim of this study is to determine the anti-inflammatory activity of a new sphingosine derivative (1) and cembrenoid diterpene (lobohedleolide) (2) isolated from the soft corals of Sinularia crassa and Lobophytum species respectively, collected on the coasts of Andaman and Nicobar Islands. The anti-inflammatory activity was evaluated using carrageenin-induced rat hind paw edema model for acute inflammation and cotton pellet granuloma model for chronic inflammation. Indomethacin was used as a standard drug in this study. Both the sphingosine derivative (1) and the cembrenoid diterpene (2) produced the maximum effect at a dose of 10 mg/kg and this is comparable to that of indomethacin (2 mg/kg, p<0.001). The observed anti-inflammatory activity is almost identical in both the types of experimental inflammation.     

Positive inotropic and negative chronotropic effects of proton pump inhibitors in isolated rat atrium

The effects of three specific H+/K+-ATPase inhibitors (omeprazole, lansoprazole and SCH 28080 (2-methyl-8-(phenylmethoxy)-imidazo[1,2-a] pyridine-3-acetonitrile)) were investigated on the mechanical and electrophysiological properties of rat atrium, in vitro. Omeprazole (100-300 microM), lansoprazole (100-300 microM) and SCH 28080 (10-100 microM) increased the amplitude of contractions and decreased the beating rate. These effects are reversible, reproducible and correlated with their order of potency as gastric H+/K+-ATPase inhibitors; SCH 28080 > omeprazole = lansoprazole. Cardiac effects of proton pump inhibitors were not inhibited with phentolamine (5 microM), propranolol (15 microM), atropine (1 microM), ouabain (2 microM), theophylline (300 microM) and milrinone (100 microM). Ouabain-induced increase in beating rate and contracture development were antagonized by H+/K+-ATPase inhibitors. Ouabain increased the positive inotropic effect of H+/K+-ATPase inhibitors. Lansoprazole (300 microM) significantly prolonged the duration of action potentials in rat atrial cells. H+/K+-ATPase may play a crucial role in the mechanical and electrophysiological properties of rat atrial myocardium.     

Positive inotropic agents: modelling, synthesis and SAR

Five non steroidal cardiotonics have been studied for the search of a common pharmacophore with the aid of the SYBYL computer modelling programme. On the basis of the model thus obtained a series of pyridylquinolones have been prepared and some structure activity relationships examined. The compounds were evaluated for positive inotropic and vasodilatory activities in vitro and in vivo animal models. Several substances displayed activities higher than that of classical references, and might be beneficial in patients with congestive heart failure.     

从嗜线虫杆菌分离的吲哚衍生物抗肿瘤活性的研究

目的研究嗜线虫杆菌次级代谢产物吲哚衍生物的抗肿瘤活性.方法用有机溶剂萃取和硅胶柱层析对嗜线虫杆菌发酵液进行提取和分离,获得吲哚衍生物,用MTT法测定其体外杀肿瘤细胞作用,利用裸鼠接种人HeLa细胞模型检测其体内抗肿瘤活性.结果从发酵液粗提物中分离得到5个组分,从有抗肿瘤活性的组分中再分离得到化合物3-吲哚乙基(3'-甲基-2'-酮)戊酰胺,其对HepG2,HeLa,HT-29,BGC-823和K562的IC50分别为(0.12±0.01),(1 83±0.02),(6.16±0.52),(1.45±0.12),(5.90±1.17)μg.mL-1,对正常人肺成纤维细胞MRC-5和正常人肝细胞L-02生长的影响很小.接种HeLa肿瘤细胞裸鼠连续灌服上述吲哚衍生物(2,4和8mg.kg-1)7d,抑瘤率分别为48.1%,56.5%和72.2%.结论嗜线虫杆菌发酵液来源的3-吲哚乙基(3'-甲基-2'-酮)戊酰胺具有较强的抗肿瘤活性.