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At least 505 records · Page 28Linked to original sources
PubMed1980

Singlet oxygen and aging in Drosophila.

There was little or no improvement in the median survival times of Drosophila melanogaster fruit flies when fed high concentrations of the singlet oxygen quenchers, beta-carotene and 1,4-diazabicyclo(2.2.2)octane. Singlet oxygen was presumably generated endogenously by inactivating catalse with 3-amino-1,2,4-triazole and feeding NaOCl. This treatment caused reduction in median life span of from 14.3 to 25% depending upon the NaOCl concentration used. beta-Carotene and 1,4-diazabicyclo(2.2.2)octane gave partial protection against the singlet oxygen generated by NaOCl. These data are interpreted to mean that normally occurring singlet oxygen does not contribute to senescence in Drosophila but that artificially produced singlet oxygen accelerates the rate of aging.

Aging↗
PubMed1994

Augmented responses to intrathecal nicotinic agonists in spontaneous hypertension.

Abnormal central cholinergic activity has been reported to be responsible in part for the pathogenesis of high blood pressure in spontaneously hypertensive rats (SHR). Administration of cholinergic agonists in brain and spinal cord results in exaggerated pressor responses in SHR. Studies to date have focused largely on the muscarinic cholinergic system. Recently, we demonstrated that intrathecal administration of nicotinic agonists results in pressor, tachycardic, and irritation responses. In the present study we examine the cardiovascular and behavioral responses to nicotine and cytisine administered intrathecally in La Jolla strain (LJ) SHRLJ and age-matched Wistar-Kyoto (WKYLJ) rats. Nicotinic agonists produced augmented pressor, heart rate, and irritation responses in SHRLJ compared with normotensive rats. In both SHRLJ and WKYLJ rats, cytisine elicited a greater nociceptive response and greater spinobulbar component to the pressor response than nicotine. SHRLJ and WKYLJ rats also differ in that the SHRLJ strain shows a diminished tendency for desensitization to cytisine. As in Sprague-Dawley rats, in SHRLJ and WKYLJ rats the cardiovascular and behavioral responses to intrathecal nicotine were significantly inhibited by mecamylamine, dihydro-beta-erthyroidine, and methyllycaconitine. However, methyllycaconitine, which effectively blocked cytisine-elicited cardiovascular and behavioral responses in Sprague-Dawley and WKYLJ rats, was unable to inhibit the maximal rise in cystine-elicited blood pressure, heart rate, and irritation responses in SHRLJ. In contrast to the heightened cardiovascular and behavioral responses, the number of nicotinic binding sites in spinal cord membranes was significantly decreased in the hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Aconitine↗
PubMed1997

Differential effects of the Ca2+ sensitizers caffeine and CGP 48506 on the relaxation rate of rat skinned cardiac trabeculae.

During heart failure, force production by the heart decreases. This may be overcome by Ca2+-sensitizing drugs, which increase myofibril Ca2+ sensitivity without necessarily altering intracellular Ca2+ concentration. However, Ca2+ sensitizers slow the relaxation of intact cardiac muscle. We used diazo-2, a caged chelator of Ca2+, to study the effects of the Ca2+ sensitizers caffeine and CGP 48506 on the intrinsic relaxation rate of cardiac myofibrils. Trabeculae from rat right ventricles were skinned by 1% Triton X-100 and were activated in a 10-microL bath. In steady state experiments, CGP 48506 (10 micromol/L) shifted the force-pCa curve leftward by 0.41+/-0.03 pCa units (mean+/-SEM, n=6). An identical shift was induced by caffeine (20 mmol/L). Photolysis of diazo-2 by a flash of light (160 mJ, 310 to 400 nm) caused an immediate decrease in Ca2+-activated force produced by the trabeculae. Relaxation was fitted by a double-exponential decay, and the rate constants were found to be independent of force and preflash Ca2+ concentration. The initial fast rate, corresponding to myofibrillar relaxation, was increased from 17.3+/-2.0 to 30.9+/-3.7 s(-1) (n=4) by caffeine but was unaffected by CGP 48506 (16.6+/-1.7 and 14.4+/-2.3 s(-1) in the absence and presence of drug, respectively; n=5). Thus, myofibril relaxation need not be slowed by Ca2+-sensitizing agents but can even be accelerated. Despite similarities in their effects on myofibril Ca2+ sensitivity, caffeine and CGP 48506 affect the myofibrils at least partly via different mechanisms.

Animals↗
PubMed2003

Activity of opioid ligands in cells expressing cloned mu opioid receptors.

BACKGROUND: The aim of the present study was to describe the activity of a set of opioid drugs, including partial agonists, in a cell system expressing only mu opioid receptors. Receptor activation was assessed by measuring the inhibition of forskolin-stimulated cyclic adenosine mono phosphate (cAMP) production. Efficacies and potencies of these ligands were determined relative to the endogenous ligand beta-endorphin and the common mu agonist, morphine. RESULTS: Among the ligands studied naltrexone, WIN 44,441 and SKF 10047, were classified as antagonists, while the remaining ligands were agonists. Agonist efficacy was assessed by determining the extent of inhibition of forskolin-stimulated cAMP production. The rank order of efficacy of the agonists was fentanyl = hydromorphone = beta-endorphin > etorphine = lofentanil = butorphanol = morphine = nalbuphine = nalorphine > cyclazocine = dezocine = metazocine >or= xorphanol. The rank order of potency of these ligands was different from that of their efficacies; etorphine > hydromorphone > dezocine > xorphanol = nalorphine = butorphanol = lofentanil > metazocine > nalbuphine > cyclazocine > fentanyl > morphine >>>> beta-endorphin. CONCLUSION: These results elucidate the relative activities of a set of opioid ligands at mu opioid receptor and can serve as the initial step in a systematic study leading to understanding of the mode of action of opioid ligands at this receptor. Furthermore, these results can assist in understanding the physiological effect of many opioid ligands acting through mu opioid receptors.

Azocines↗
PubMed1985

Opiate antagonist WIN44,441-3 stereospecifically improves neurologic recovery after ischemic spinal injury.

In the unanesthetized rabbit, temporary aortic occlusion results in predictable patterns of spinal cord injury. We use this "spinal stroke" model to assess the potential role of opiate antagonists in treating CNS ischemia. WIN44,441-3 (WIN(-], an opiate antagonist with enhanced activity at the kappa-receptor, reduced motor dysfunction after ischemic spinal cord injury. The effect was stereospecific and dose-related; beneficial actions were seen at doses as low as 40 micrograms/kg. Opiate receptor antagonists may be therapeutically useful in ischemic CNS injury, and the beneficial actions of these compounds may be at the kappa-receptor site.

Animals↗
PubMed1995

Application of [125I] (S)-5-iodonicotine, a new radioiodinated ligand, in the assay of nicotinic acetylcholine receptor binding in the brain.

[125I](S)-5-Iodonicotine was prepared and its application in the assay of nicotinic acetylcholine receptor binding in the brain was studied. [125I](S)-5-Iodonicotine bound to the rat cortical membrane with high affinity (Kd, 15.0 nm). Various nicotinic cholinergic compounds showed competition with [125I](S)-5-iodonicotine for the binding sites in the rats cortical membrane, and the specificity of its binding was correlated well with that of [H3] cytisine (r = 0.98). These findings suggest that [125I](S)-5-iodonicotine binds to the same sites as [H3] cytisine and indicate that [125I](S)-5-iodonicotine can be applied as a brain nicotine receptor binding assay.

Alkaloids↗
PubMed1998

Pharmacological characterization of a novel long-acting histamine H1 receptor antagonist, KAA-276.

The pharmacological profile of a newly synthesized histamine H1 receptor antagonist, KAA-276 (1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-12-[4-( 2-carboxyethyl)-phenyl]ethyl]-1,5-diazacyclooctane sulfate), was characterized. In a H1 receptor binding assay in vitro, KAA-276 inhibited [3H]mepyramine binding to guinea pig cerebellar membrane preparations with an IC50 of 0.66 nM. The inhibitory potency of KAA-276 was greater than that of terfenadine, but similar to that of astemizole and ketotifen. KAA-276 antagonized the histamine-induced constriction of ileum and trachea isolated from guinea pigs in a dose-dependent manner with a concomitant reduction in the maximum response. Furthermore, the inhibitory effect of KAA-276 on histamine induced contraction was potentiated depending on the duration of preincubation time and revealed an irreversible property. KAA-276 given orally, intraduodenally, and by inhalation significantly inhibited histamine-induced bronchoconstriction dose-dependently in guinea pigs. Inhalation of KAA-276 exhibited inhibitory activity with a rapid onset and long duration, while intraduodenal administration resulted in action with a slow onset. Therefore, KAA-276, an irreversible and selective histamine H1 receptor antagonist, was shown to be a useful drug for therapeutic strategies against bronchial asthma when administered by the aerosol route.

Administration, Inhalation↗
PubMed1993

Synthesis and pharmacological activities of novel cyclic disulfide and cyclic sulfide derivatives as hepatoprotective agents.

In order to search for anti-hepatitis drugs, we synthesized a series of eight- and nine-membered cyclic disulfides (1) and six- and seven-membered cyclic sulfides (2) and evaluated them for ability to reduce mortality in the model of acute hepatic failure induced by Propionibacterium acnes-lipopolysaccharide in mice. Compounds 1 were synthesized by oxidative cyclization of the corresponding dithiol derivatives (3) with diethyl bromomalonate or iodine. Compounds 2 were prepared from the methyl esters of 1 by desulfurization with tris(diethylamino)phosphine followed by deprotection. Compounds 1 were generally found to be more active than compounds 2. Compound 1b (SA3443) was found to exhibit potent protective activity. The synthesis and structure-activity relationships are discussed.

Animals↗