Activity of clinafloxacin, compared with six other quinolones, against Acinetobacter baumannii clinical isolates.
(73/855)
The in vitro activity of clinafloxacin was studied in comparison with ciprofloxacin, levofloxacin, moxifloxacin, nalidixic acid, sparfloxacin and trovafloxacin against Acinetobacter baumannii clinical isolates. Clinafloxacin showed a MIC(90) of 4 mg/L, whereas the remaining quinolones showed a MIC(90) equal to or higher than 16 mg/L. MIC(50) determination in the presence of reserpine resulted in a two-fold decrease, except for trovafloxacin, which decreased four-fold, and for moxifloxacin and nalidixic acid, which did not change. The effect of reserpine was most pronounced among strains with a low level of resistance to quinolones. The MIC of clinafloxacin for strains with no mutation in either gyrA or parC genes ranged from 0.008 to 0.25 mg/L. In strains with a single mutation at amino acid codon Ser83 of the gyrA gene, the MIC of clinafloxacin ranged from 0.12 to 1 mg/L, whereas strains with a double mutation, one in the gyrA gene and another in the parC gene, showed a range of MIC of clinafloxacin from 1 to 8 mg/L. Therefore, clinafloxacin shows good activity against strains carrying a single mutation in the gyrA gene, and hence a second mutation is required for the microorganism to express resistance. (+info)
Depressed transient outward potassium current density in catecholamine-depleted rat ventricular myocytes.
(74/855)
The effect of catecholamine depletion (induced by prior treatment with reserpine) was studied in Wistar rat ventricular myocytes using whole cell voltage-clamp methods. Two calcium-independent outward currents, the transient outward potassium current (I(to)) and the sustained outward potassium current (I(sus)), were measured. Reserpine treatment decreased tissue norepinephrine content by 97%. Action potential duration in the isolated perfused heart was significantly increased in reserpine-treated hearts. In isolated ventricular myocytes, I(to) density was decreased by 49% in reserpine-treated rats. This treatment had no effect on I(sus). The I(to) steady-state inactivation-voltage relationship and recovery from inactivation remained unchanged, whereas the conductance-voltage activation curve for reserpine-treated rats was significantly shifted (6.7 mV) toward negative potentials. The incubation of myocytes with 10 microM norepinephrine for 7-10 h restored I(to), an effect that was abolished by the presence of actinomycin D. Norepinephrine (0.5 microM) had no effect on I(to). However, in the presence of both 0.5 microM norepinephrine and neuropeptide Y (0.1 microM), I(to) density was restored to its control value. These results suggest that the sympathetic nervous system is involved in I(to) regulation. Sympathetic norepinephrine depletion decreased the number of functional channels via an effect on the alpha-adrenergic cascade and norepinephrine is able to restore expression of I(to) channels. (+info)
The atypical 5-HT2 receptor mediating tachycardia in pithed rats: pharmacological correlation with the 5-HT2A receptor subtype.
(75/855)
1. In pithed rats, 5-HT mediates tachycardia both directly (by 5-HT(2) receptors) and indirectly (by a tyramine-like effect). The receptor mediating tachycardia directly has been classified as an 'atypical' 5-HT(2) receptor since it was 'weakly' blocked by ketanserin. Moreover, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2) agonist, failed to mimic 5-HT-induced tachycardia. Since 5-HT(2) receptors consist of 5-HT(2A), 5-HT(2B) and 5-HT(2C) subtypes, this study investigated if these subtypes mediate the above response. 2. In pithed rats, intraperitoneally (i.p.) pre-treated with reserpine (5 mg kg(-1)), intravenous (i.v.) administration of 5-HT, 5-methoxytryptamine (5-MeO-T), 1-(3-chlorophenyl) piperazine (mCPP) and 5-carboxamidotryptamine (5-CT) (10, 30, 100 and 300 microg kg(-1) each), produced dose-dependent tachycardic responses. Interestingly, DOI (10 - 1000 microg kg(-1), i.v.) induced only slight, dose-unrelated, tachycardic responses, whilst the 5-HT(2C) agonist, Ro 60-0175 (10 - 1000 microg kg(-1), i.v.), produced a slight tachycardia only at 300 and 1000 microg kg(-1). In contrast, sumatriptan and 1-(m-trifluoromethylphenyl)- piperazine (TFMPP) were inactive. The rank order of potency was: 5-HT > or =5-MeO-T> mCPP > or =5-CT > or =DOI > Ro 60-0175. 3. The tachycardic responses to 5-HT, which remained unaffected after i.v. saline (0.3 and 1 ml kg(-1)) or propranolol (3 mg kg(-1)), were selectively blocked by the 5-HT(2A) antagonists ketanserin (30 and 100 microg kg(-1)) or spiperone (10 and 30 microg kg(-1)) as well as by the non-selective 5-HT(2) antagonists, ritanserin (10 and 30 microg kg(-1)) or mesulergine (100 microg kg(-1)). Remarkably, these responses were unaffected by the antagonists rauwolscine (5-HT(2B)), SB204741 (5-HT(2B/2C)) or Ro 04-6790 (5-ht(6)) (300 and 1000 microg kg(-1) each). 4. These results suggest that the 'atypical' 5-HT(2) receptors mediating tachycardia in reserpinized pithed rats are pharmacologically similar to the 5-HT(2A) receptor subtype. (+info)
Alterations in responses of ventral pallidal neurons to excitatory amino acids after long-term dopamine depletion.
(76/855)
The present study explored the possibility that excitatory amino acid (EAA) sensitivity within the ventral pallidum (VP) is altered by long-term removal of dopamine (DA). Electrophysiological experiments were conducted in chloral hydrate-anesthetized rats 21 to 28 days after they received unilateral substantia nigra injections of the dopaminergic toxin 6-hydroxydopamine (6-OHDA). VP neurons increased firing at low microiontophoretic ejection currents of the EAA agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA); however, high currents decreased action potential amplitude and rapidly caused cessation of neuronal firing. These responses likely reflected the induction of depolarization block for they were reversed by coiontophoresis of the hyperpolarizing transmitter gamma-aminobutyric acid (GABA) at ejection current levels that normally suppressed firing. The ability of NMDA and AMPA to induce such inactivation was greater in the VP of 6-OHDA-lesioned hemispheres, but unchanged in reserpinized rats, verifying that the alterations in responding to NMDA were the result of chronic, rather than acute, DA removal. The adaptations do not appear to be the consequence of a diminished GABAergic tone for the ability of bicuculline to increase firing (due to blocking a tonic GABAergic input) was not changed. However, low ejection currents of GABA that were insufficient to alter firing rate greatly attenuated the ability of NMDA to induce an apparent depolarization inactivation when coiontophoresed with NMDA onto VP neurons of the lesioned, but not the unlesioned, hemisphere. These studies show that chronic DA removal altered the EAA-induced amplitude-decreasing (i.e., the apparent depolarization inactivation) effects in VP neurons in the absence of a decrease in GABAergic tone. (+info)
Alpha-1 adrenoceptor up-regulation induced by prazosin but not KMD-3213 or reserpine in rats.
(77/855)
1. We have investigated the effects of chronic administration of prazosin (a subtype-nonspecific alpha-1 AR antagonist), KMD-3213 (an alpha-1A AR subtype-specific antagonist) and reserpine (a catecholamine depletor) on the density of alpha-1 AR subtypes in various rat tissues (liver, kidney, submaxillary gland, heart and spleen). 2. Administration of prazosin (2 mg kg(-1) day(-1), i.p.) for 2 weeks did not affect K(D) values for [(3)H]-prazosin or [(3)H]-KMD-3213 of alpha-1 ARs in five rat tissues tested. However, it caused 52% up-regulation of alpha-1B AR in the spleen, and 84% and 107% up-regulation of alpha-1A- and alpha-1B ARs, respectively, in the heart. Although major subtypes of alpha-1 AR are alpha-1A AR in the submaxillary gland, alpha-1B AR in the liver, and alpha-1A and alpha-1B ARs in the kidney, these tissues showed no up-regulation. The mRNA levels of alpha-1 AR subtypes were not affected by prazosin administration in any tissue tested. 3. Neither administration of KMD-3213 (2 mg kg(-1) day(-1), i.p.) nor reserpine (0.5 - 1 mg kg(-1) day(-1), i.p.) for 2 weeks caused any change in either the binding affinity for [(3)H]-prazosin or [(3)H]-KMD-3213 or the density of the alpha-1 AR subtypes in the five rat tissues. 4. Neither prazosin nor KMD-3213 treatment reduced the noradrenaline content in the five rat tissues, in contrast to reserpine treatment, which markedly reduced it. 5. The findings of the present study demonstrated that up-regulation of alpha-1 AR is selectively caused by prazosin treatment in some tissues but neither by KMD-3213 treatment nor by chemical denervation with reserpine. These results suggest that up-regulation of alpha-1 ARs is not caused by a simple blockade of sympathetic tone. (+info)
Synthesis, 5-HT1A and 5-HT2A receptor activity of new 1-phenylpiperazinylpropyl derivatives with arylalkyl substituents in position 7 of purine-2,6-dione.
(78/855)
A series of new 1,3-dimethyl-7-phenylalkyl-8-[3-(4-phenyl-1-piperazinyl)propylamino]-purine-2,6-d ione derivatives (10-16) was synthesized and their 5-HTIA and 5-HT2A receptor affinities were determined. It was found that compounds with the phenylpropyl substituent in position 7 of purine-2,6-dione (12, 14 and 16), or with phenylmethyl in position 7 and 2-OCH3 in the phenylpiperazine part (13) showed a distinct affinity for 5-HTIA receptors (Ki = 8-50 nM). No structural modifications resulted in 5-HT2A ligands, since the affinity of 10-16 for those receptors was insignificant (Ki = 115-550 nM). The new 5-HT1A receptor ligands (12-14, 16) were investigated in vivo to determine their functional activity at those receptors. In behavioral studies, 12-14 and 16 behaved like postsynaptic 5-HTIA receptor antagonists, since they reduced lower lip retraction and the behavioral syndrome induced by 8-OH-DPAT (5-HT1A receptor agonist) in rats. When given alone, none of the compounds investigated in vivo, mimicked 8-OH-DPAT activity in those tests. Derivative 12 did not affect the body temperature in mice, whereas 13, 14 and 16 decreased it. Furthermore, 12 did not change the hypothermia induced by 8-OH-DPAT, and the decrease in body temperature in mice induced by 13, 14 or 16 was not antagonized by WAY 100635 (5-HT1A receptor antagonist); hence in that model neither 12, 13, 14 nor 16 acted as antagonists or agonists, respectively, at presynaptic 5-HT1A receptors. (+info)
Substitution mode of the amide fragment in some new N-[omega-[4-(2-methoxyphenyl)piperazin-1-yl]alkyl]pyrid-2(1H)-ones and their 5-HT1A/5-HT2A activity.
(79/855)
A series of omega-[4-(2-methoxyphenyl)piperazin-1-yl]alkyl derivatives with terminal pyrid-2(1H)-one fragments was synthesized and evaluated for their 5-HTIA and 5-HT2A activity. Enlargement of the aromatic amide system by its substitution with phenyl and/or p-methoxyphenyl in positions 4, 5 and/or 6, as well as modification of an aliphatic spacer allowed us to better understand structure-activity relationships in that group of compounds. The results of in vitro and in vivo experiments showed that only unsubstituted (1b) and monosubstituted (2b-4b) derivatives with the tetramethylene spacer demonstrated high 5-HTIA receptor affinity (Ki = 15-40 nM) and 5-HT1A/5-HT2A selectivity; they exhibited features of 5-HTIA antagonists. Those results suggested that the mode of substitution of the terminal amide moiety in the tested tetramethylene arylpiperazines was not significant for their 5-HTIA receptor activity. Conformational analysis calculations indicated that despite its great capacity for adaptation at 5-HTIA receptor site, an aryl substituent in position 4 in the pyrid-2(1H)-one ring destabilized the ligand-5-HT1A receptor complex formation in the case of trimethylene derivatives. Diarylsubstituted derivatives (5a-8a and 5b-8b) were characterized by a low 5-HT2A affinity (Ki > 446 nM) regardless of the spacer length, while those with the tetramethylene aliphatic chain had a higher 5-HT2A affinity than the remaining investigated compounds. (+info)
Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats.
(80/855)
Ischemic preconditioning (PC) has been proposed as an endogenous form of protection against-ischemia reperfusion injury. We have shown that PC does not prevent postischemic dysfunction in the aging heart. This phenomenon could be due to the reduction of cardiac norepinephrine release, and it has also been previously demonstrated that age-related decrease of norepinephrine release from cardiac adrenergic nerves may be restored by caloric restriction. We investigated the effects on mechanical parameters of PC against 20 min of global ischemia followed by 40 min of reperfusion in isolated hearts from adult (6 mo) and "ad libitum"-fed and food-restricted senescent (24 mo) rats. Norepinephrine release in coronary effluent was determined by high-performance liquid chromatography. Final recovery of percent developed pressure was significantly improved after PC in adult hearts versus unconditioned controls (85.2 +/- 19% vs. 51.5 +/- 10%, P < 0.01). The effect of PC on developed pressure recovery was absent in ad libitum-fed rats, but it was restored in food-restricted senescent hearts (66.6 +/- 13% vs. 38.3 +/- 11%, P < 0.05). Accordingly, norepinephrine release significantly increased after PC in both adult and in food-restricted senescent hearts, and depletion of myocardial norepinephrine stores by reserpine abolished the PC effect in both adult and in food-restricted senescent hearts. We conclude that PC reduces postischemic dysfunction in the hearts from adult and food-restricted but not in ad libitum-fed senescent rats. Despite the possibility of multiple age-related mechanisms, the protection afforded by PC was correlated with increased norepinephrine release, and it was blocked by reserpine in both adult and food-restricted senescent hearts. Thus caloric restriction may restore PC in the aging heart probably via increased norepinephrine release. (+info)