Quantitative structure-inotropy relationship applied to substituted grayanotoxins.

Nine 14 beta-O-acylated grayanotoxins were synthesized by ozonolysis of 14,16-alkylidenegrayanotoxin III. The correlation between positive inotropic potency (PIE) in guinea pigs and physicochemical parameters (Vw, Mw, and Rm50) in 14 14-substituted grayanotoxins were quantitatively analyzed. It became clear that a parabolic relation existed between the bulkiness of the 14-substituents and PIE and that some electronic factor and the hydrophilic-hydrophobic balance would be related to the development of PIE.

Protective effects of dimethyl amiloride against postischemic myocardial dysfunction in rabbit hearts: phosphorus 31-nuclear magnetic resonance measurements of intracellular pH and cellular energy.

The effects of 5-(N,N-dimethyl)amiloride, a potent and specific Na(+)-H+ exchange inhibitor, were investigated in isolated perfused rabbit hearts subjected to ischemia and reperfusion. Phosphorus 31-nuclear magnetic resonance spectroscopy was used to monitor intracellular pH, creatine phosphate, beta-adenosine triphosphate, and inorganic phosphate. After cardioplegic arrest with St. Thomas' Hospital solution, normothermic (37 degrees C) global ischemia was induced for 45 minutes, and the hearts were reperfused for 50 minutes. Dimethyl amiloride at 10 mumol/L, which has minimal inotropic and chronotropic effects on the nonischemic heart, was added to the cardioplegic solution. Treatment with dimethyl amiloride reduced the elevation of left ventricular end-diastolic pressure during and after the ischemia and improved the postischemic recovery of developed pressure from 76% +/- 3.2% at 30 minutes of reperfusion in control hearts (n = 6) up to 99% +/- 1.9% in hearts treated with dimethyl amiloride (n = 8). Dimethyl amiloride did not affect the decline in intracellular pH during ischemia for up to 30 minutes but enhanced the intracellular acidosis thereafter. The intracellular pH at the end of ischemia was 6.21 +/- 0.05 in control hearts compared with 5.24 +/- 0.17 in hearts treated with dimethyl amiloride (p < 0.05). During reperfusion, intracellular pH of hearts treated with dimethyl amiloride was less than control for 5 minutes, but subsequent recovery of intracellular pH was similar to control. Treatment with dimethyl amiloride did not affect creatine phosphate breakdown, inorganic phosphate accumulation, and beta-adenosine triphosphate depletion during 45 minutes of ischemia. The creatine phosphate resynthesis and inorganic phosphate reduction during reperfusion were also unaffected. These findings suggest that Na(+)-H+ exchange plays an important role not only during reperfusion but also during ischemia for the development of postischemic cardiac dysfunction most likely by inducing primary Na+ and secondary Ca2+ overload. Specific Na(+)-H+ exchange inhibitors like dimethyl amiloride would have a potential therapeutic profile in cardiac surgery, especially if added before ischemia.

Triphasic inotropic response of guinea-pig papillary muscle to murrayaquinone-A isolated from Rutaceae.

Murrayaquinone-A, a carbazole alkaloid, was found to produce a triphasic inotropic response (first positive, second negative and third positive phases) of guinea-pig papillary muscle that normally paced at a slow rate of 0.2 Hz in Krebs-Henseleit solution at 30 degrees C. Murrayaquinone-A produced a concentration-dependent (10(-6) M-10(-4) M) positive inotropic effect (pD2 value 5.27 evaluated at the first phase). The triphasic pattern of inotropism of murrayaquinone-A was unaffected by reserpine, metoprolol or cimetidine treatment. Murrayaquinone-A increased the initial upstroke and the duration of the slow action potential in partially depolarized muscle (external K+ = 30 mEq). Murrayaquinone-A did not cause any positive inotropy under anoxic conditions and in the presence of 2,4-dinitrophenol and dicumarol. These results indicated that the triphasic inotropic effect of murrayaquinone-A is not mediated through a receptor mechanism but through a novel mechanism involving mitochondrial ATP production, thereby increasing the slow inward calcium current across the cardiac cell membrane via cyclic AMP converted from mitochondrial ATP.

Different effects of isoproterenol and dihydroouabain on cardiac Ca2+ transients.

Cytosolic fura-2 Ca2+ transient signals (TCa) and the left ventricular pressure or contraction of myocardium under the positive inotropic effects of the beta-adrenoceptor agonist, isoproterenol, and the cardiac glycoside, dihydroouabain, were measured simultaneously and the results were compared. TCa was observed preceding the onset of force development and showed a steeper rise and slower decay than did the contraction curve of papillary muscle. Isoproterenol increased the steepness and the amplitude of TCa, reflecting the speed and peak force of contraction, and clearly biphasic TCa were observed with biphasic contractions developed at low frequency. Ryanodine reduced not only the early component of the contraction but also TCa, without affecting the diastolic Ca2+ level. These effects of isoproterenol were attributed to the enhanced uptake of Ca2+ by the sarcoplasmic reticulum. In contrast, dihydroouabain elevated the Ca2+ level at diastole without any change in the amplitude of TCa, suggesting that dihydroouabain inhibits the membrane Na pump thereby increasing the intracellular Ca2+ via Na(+)-Ca2+ exchange. Furthermore, a comparison of the time course of the isometric twitch curve with that of TCa in rested state contraction indicated that there are distinct differences between the mechanisms of the positive inotropic effects of isoproterenol and of dihydroouabain.

Cyclic octapeptides from Stellaria dichotoma var. lanceolata.

Two new cyclic octapeptides, dichotomin H, cyclo(-Ala-Pro-Thr-Phe-Tyr-P ro-Leu-Ile-), and dichotomin I, cyclo(-Val-Pro-Thr-Phe-Tyr-Pro-Leu-Ile-) have been isolated from the roots of Stellaria dichotoma L. var lanceolata Bge., and their structures were elucidated by extensive two-dimensional NMR methods and chemical degradation.

Two antitumour bicyclic hexapeptides from Rubia cordifolia.

Two novel antitumour bicyclic hexapeptides, named RA-XV and -XVI, were isolated from Rubia cordifolia and their structures were characterized by spectroscopic and chemical means.

Sesquiterpenoids and iridoid glycosides from Valeriana fauriei.

A new guaiane sesquiterpenoid glycoside together with known sesquiterpenoids and iridoid glycosides have been isolated from the rhizomes and roots of Valeriana fauriei. The 13C NMR assignments of the isolated compounds are presented.

Eucalyptone from Eucalyptus globulus.

A new cariostatic compound named eucalyptone was isolated from the leaves of Eucalyptus globulus. The structure of this compound was elucidated by spectroscopic methods.

Cytotoxic azadirachtin-type limonoids from Melia azedarach.

Four new limonoids, 1-tigloyl-3,20-diacetyl-11-methoxymeliacarpinin, 3-tigloyl-1,20-diacetyl-11-methoxymeliacarpinin, 1-cinnamoyl-3-hydroxy-11-methoxymeliacarpinin, and 1-deoxy-3-methacrylyl-11-methoxymeliacarpinin, together with a known limonoid, 1-cinnamoyl-3-acetyl-11-methoxymeliacarpinin, were isolated from the extract of the root bark of Melia azedarach. The structures were elucidated by spectroscopy.

Cytotoxic flavonoids from Vitex agnus-castus.

Four new flavonoids, luteolin 6-C-(4"-methyl-6"-O-trans-caffeoylglucoside), luteolin 6-C-(6"-O-trans-caffeoylglucoside), luteolin 6-C-(2"-O-trans-caffeoylglucoside), and luteolin 7-O-(6"-p-benzoylglucoside), together with four known ones 5, 4'-dihydroxy-3,6,7,3'-tetramethoxyflavone, luteolin, artemetin and isorhamnetin, were isolated from the root bark of Vitex agnus-castus. The structures were elucidated by spectroscopic means.

A cyclic heptapeptide from Vaccaria segetalis.

A new cyclic heptapeptide, segetalin E, cyclo(-Gly-Tyr-Val-Pro-Leu-Trp-Pro-), has been isolated from the seeds of Vaccaria segetalis and the structure elucidated by extensive two-dimensional NMR methods and chemical degradation.

Cyclolinopeptides F-I, cyclic peptides from linseed.

Four cyclic peptides, cyclolinopeptides F-I, were isolated from seeds of Linum usitatissimum. Their structures were elucidated by extensive 2D NMR spectroscopic methods and by chemical degradation. Further, their immunosuppressive activity is examined.

Steroidal saponins from the leaves of Cestrum sendtenerianum.

Five steroidal saponins were isolated from the EtOH extract of Cestrium sendtenerianum (Solanaceae), as confirmed by detailed analysis of their 1H, 13C, and two-dimensional NMR spectral data, and by the results of hydrolytic cleavage. The saponins were revealed to contain three hydroxyl groups at the C-1beta, C-2alpha, and C-3beta positions in the spirostanol skeleton, and to bear a di- or triglycoside at C-3 as the common structural features. One of the compounds, a spirostanol triglycoside, showed weak cytotoxic activity on HL-60 human promyelocytic leukemia cells, with an IC50 value of 7.7 microg/ml.

Antibacterial trichorabdal diterpenes from Rabdosia trichocarpa.

Four antibacterial diterpenes, trichorabdals A, B, C and H were isolated from the leaves of Rabdosia trichocarpa and the relationship between their conformations analysed by spectroscopic and computational methods. Their antibacterial activity is discussed.

Ester-type cephalotaxus alkaloids from Cephalotaxus harringtonia var. drupacea.

Three alkaloids, neoharringtonine, homoneoharringtonine and 3'S-hydroxyneoharringtonine, were isolated from the leaves and stems of Cephalotaxus harringtonia var. drupacea. Their structures were established by spectroscopic methods, including two-dimensional NMR and CD spectra, and their antileukaemic activity was evaluated using P-388 leukaemia cells.

Triterpenoid saponin from Vaccaria segetalis.

A new triterpenoid saponin, vaccaroid B, has been isolated from the seeds of Vaccaria segetalis and its structure was elucidated to be 3beta-hydroxyolean-12-en-23, 28-dioic acid-28-O-beta-D-glucopyranosyl-(1-->3)- beta-D-glucopyranosyl-(1-->6)-[6- O-(3-hydroxy-3-methylglutaryl)-beta-D-glucopyranosyl-(1-->2)]- beta-D-glucopyranoside by spectroscopic methods.

Cytotoxic triterpenes from Cleome africana.

Eighteen dammarane-type triterpenes were obtained from the whole plant of Cleome africana by means of cytotoxic bioassay-directed fractionation. Twelve of them were novel compounds whose structures were elucidated by various spectroscopic methods.

Anthraquinones from the polar fractions of Galium sinaicum.

The new anthraquinones, 6,7-dimethoxy xanthopurpurin, 6-hydroxy-7-methoxy rubiadin, 5-hydroxy-6-hydroxymethyl anthragallol 1, 3-dimethyl ether, 7-carboxy anthragallol 1,3-dimethyl ether, anthragallol 1-methyl ether 3-O-beta-D-glucopyranoside, anthragallol 1-methyl ether 3-O-rutinoside, anthragallol 3-O-rutinoside and alizarin 1-methyl ether 2-O-primeveroside were isolated from the CH2Cl2 and n-BuOH extracts of Galium sinaicum roots and their structures were established by various spectroscopic techniques. In addition, two known anthraquinones were also isolated and fully characterized.

The specificity of potentiating effect of glutathione on the actions of bradykinin.

Potentiating effects of GSH, a physiologic kininase inhibitor on the bradykinin actions on (a) blood pressure responses of rabbits, (b) acute inflammatory response in rat's hind paws and (c) the isolated guinea-pig ileum contractions were examined among the combinations between various active agents and thiols. The potentiation of the hypotensive response to bradykinin by GSH was highly specific compared with the other experimental models (B and C). Throughout these three experiments, specific relation between GSH and bradykinin was consistently observed.

Structure-activity relationship of cardiotonic flavonoids in guinea-pig papillary muscle.

Sixteen flavonoids were tested for a positive inotropic effect (PIE) on guinea-pig papillary muscle paced at 0.2 Hz in a Krebs-Henseleit solution at 30 degrees C. The structure-activity relationship was investigated by determining both the pD2 value and the intrinsic activity in the case of ten flavonols, three flavones, one flavanone and two catechins. Quercetin showed the most potent intrinsic activity, and produced the strongest inotropic responses among the 16 compounds. The relative order of potency of the tested flavonoids was quercetin > morin = kaempferol = HEPTA > luteolin = apigenin > natsudaidain = fisetin = galangin. Those that did not produce any PIE were 3-hydroxyflavone, flavone, glycosides of quercetin (rutin and hyperin), flavanones (naringenin) and catechins. With respect to the essential flavonoid nucleus for PIE development, the presence of a hydroxy group at C-4', an alpha, beta-unsaturated ketone on the C-ring and a reasonable lipophilic moiety in the molecule are required. Pharmacological analyses suggest that there is a common mechanism for the PIE and it is cyclic AMP dependent.