Carteolol hydrochloride reduces visible light-induced retinal damage in vivo and BSO/glutamate-induced oxidative stress in vitro.

The purpose of this study was to determine whether carteolol eye drops, a ß-adrenoceptor antagonist used as an intraocular hypotensive agent, has protective effects against the light-induced oxidative stress in retina. Dark-adapted pigmented rats were pre-treated with topical carteolol ophthalmic solution or saline and then exposed to visible light. The effects on electroretinogram (ERG), morphology, oxidative stress, and expression of mRNAs in the retinas were determined. The l-buthionine-(S,R)-sulfoximine (BSO)/glutamate-induced oxidative stress in 661 W cells, a murine photoreceptor cell line, was evaluated by cell death assays, production of reactive oxygen species (ROS), and activation of caspase. In vivo studies showed that exposure to light caused a decrease in the amplitudes of ERGs and the outer nuclear layer (ONL) thickness and an increase of the 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells in the ONL. These changes were significantly reduced by pre-treatment with carteolol. Carteolol also significantly up-regulated the mRNA levels of thioredoxin 1 and glutathione peroxidase 1 compared to saline-treated group. Moreover, carteolol and timolol, another ß-adrenoceptor antagonist, significantly inhibited BSO/glutamate-induced cell death and reduced caspase-3/7 activity and ROS production in vitro. Therefore, carteolol could protect retina from light-induced damage with multiple effects such as enhancing the antioxidative potential and decreasing the intracellular ROS production.

Enhancement in Corneal Permeability of Dissolved Carteolol by Its Combination with Magnesium Hydroxide Nanoparticles.

We prepared magnesium hydroxide (MH) nanoparticles, and investigated their effect when combined with dissolved carteolol on the bioavailability and intraocular pressure (IOP)-reducing effect of carteolol. The carteolol was solved in saline containing additives (0.5% methylcellulose, 0.001% benzalkonium chloride, 0.5% mannitol; CRT-solution). MH nanoparticles were prepared by a bead mill method with additives. Then carteolol/MH microparticle and carteolol/MH nanoparticle fixed combinations (mCMFC and nCMFC) were prepared by mixing the CRT-solution and MH particles. The transcorneal penetration and IOP-reducing effect of carteolol was evaluated in rabbits. The mean particle size of mCMFC was 7.2 µm, and the particle size was reduced to 73.5-113.5 nm by the bead mill treatment. The MH particles in nCMFC remained in the nano size range for 8 days after preparation, and the amounts of lacrimal fluid and corneal damage were unchanged by repetitive instillation of nCMFC (twice a day for 4 weeks). The transcorneal penetration of carteolol was enhanced by the combination with MH nanoparticles, and the IOP-reducing effect of nCMFC was significantly higher than that of CRT-solution or mCMFC. In conclusion, we designed nCMFC, and showed that the high levels of dissolved carteolol can be delivered into the aqueous humor by the instillation of nCMFC. Combination with MH nanoparticles may achieve an enhancement of corneal penetration for water-soluble drugs. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.

[Long-acting carteolol hydrochloride 2% ophthalmic solution phase IV study--investigation of the effectiveness, safety and plasma concentration].

PURPOSE: We investigated the effectiveness, safety and plasma concentration of long-acting carteolol hydrochloride 2% ophthalmic solution (LA) as compared with the original carteolol hydrochloride 2% ophthalmic solution(CA). METHODS: Patients with primary open angle glaucoma and ocular hypertension were randomized to 62 patients of LA group (LA once a day) and 62 patients of CA group (CA twice a day) in this multicenter, open-label trial. The intraocular pressure (IOP), pulse rate, blood pressure and plasma concentration were examined for 8 weeks. RESULTS: The IOP reduction and reduction rate were not significant at any point between the two groups. Systolic blood pressure decreased significantly in both groups, however, diastolic blood pressure decreased only in the CA group. The plasma concentration of the LA group was significantly lower than that of the CA group. CONCLUSIONS: The IOP reduction effect of the LA group was the same as the CA group. This study suggests that long-acting treatment with alginic acid can be useful for reducing systemic side effects.

[Effect of anti-glaucoma drugs on inflammatory cytokine production by human and murine peripheral blood mononuclear cells].

OBJECTIVE: We investigated both human and murine peripheral blood mononuclear cells to find which of the anti-glaucoma drugs used to lower intraocular pressure drug also suppresses inflammation. SUBJECTS & METHODS: Peripheral blood mononuclear cells (PBMCs) prepared from healthy men and from BALB/c mice were suspended in RPMI 1640 culture medium containing 10% FBS. Each test drug was added to the cells, and they were cultured in a CO2 incubator (set to 37 degrees C and 5% CO2) for 30 minutes. Lipopolysaccharide (LPS) was added to the same cells and they were cultured again for a given period of time, after which either tumor necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6) levels in the culture medium were determined by ELISA. RESULTS: Carteolol inhibited production of both TNF-alpha and IL-6 from PBMCs. The other test agents had no inhibitory effect. The carbonic anhydrase inhibitor (CAI) dorzolamide, isopropyl unoprostone and latanoprost had almost no effect on the production of inflammatory cytokines. CONCLUSIONS: We demonstrated that carteolol exhibits an inhibitory action on the production of inflammatory cytokines from PBMCs because of its intrinsic sympathomimetic action. We also showed that CAI and PG drugs had almost no effect on inflammatory cytokine production.

Phosphorus dendrimers as powerful nanoplatforms for drug delivery, as fluorescent probes and for liposome interaction studies: A concise overview.

Gene therapy is a new and promising tool to treat many severe diseases and the silencing of proteins is the safest and the most efficient tool to treat diseases because it does not induce changes in human genome and avoids a huge problem encompassing insertional mutagenesis. Using small RNAs to switch on/off target proteins is limited due to existence of some barriers for them in the human body (blood RNAses, serum albumins, cell walls, etc). For therapeutic applications they need the efficient and non-toxic carrier which will deliver them into cell cytoplasm. Within the huge range of carriers available, dendrimers can be underlined as new promising efficient carriers. This review summarizes several findings in phosphorus dendrimers based on in vitro and in vivo studies. As a result, we can conclude that advantages of phosphorus dendrimers are strong interaction with siRNA/DNA and formation of small and compact positively charged complexes of high and fast penetration into cells; efficient release of siRNA/pDNA in endosomes due to "proton sponge" effect; possibility of their modification including addition of fluorescent probes - in this case fluorescent dendrimer can be used both as a gene carrier and a tracer of delivery into cells. Additional benefit of using fluorescent phosphorus dendrimers is their ability to monitor the macrophage physiological status in vitro and in vivo.

Insidious-onset, non-wheezing carteolol-induced asthma in an atopic patient without asthma history.

Carteolol, a non-selective beta-antagonist with a potential risk of severe bronchial constriction in patients with asthma, is one of the most commonly prescribed medication for managing ocular pressure in glaucoma. We present a case of a 24-year-old woman with a history of atopy but no known asthma who presented an insidious onset of clinical manifestations compatible with drug-induced asthma after the initiation of carteolol for ocular hypertension control. The patient developed progressive chest tightness and dyspnoea for 2 months before the pulmonary function test revealed a positive bronchoprovocation response. She reported significant improvement of respiratory symptoms within 2 weeks after the discontinuation of carteolol, and a negative provocation response was later confirmed by repeat pulmonary function test. In conclusion, eye drops with non-selective beta-antagonising effect can induce asthmatic symptoms in patients without a previous diagnosis of asthma and should be administered with caution in patients with associated risk factors.

Efficacy and safety of the fixed combinations of tafluprost/timolol and latanoprost/carteolol.

In this study, we made a comparative efficacy and safety assessment of two different fixed combinations of drugs, viz., tafluprost/timolol (TAF/TIM) and latanoprost/carteolol (LAT/CAR), by determining their effects on intraocular pressure (IOP) in ocular normotensive monkeys and examining their toxic effects on ocular surface using human corneal epithelial cells. TAF/TIM was found to be more effective in lowering IOP for a longer duration compared to LAT/CAR. We found that the difference in the intensity of IOP-lowering effect was because of the differences in the strength of timolol compared with that of carteolol as a beta-adrenergic antagonist and strength of tafluprost compared with that of latanoprost as a prostaglandin analogue. In addition, TAF/TIM showed much less cytotoxic effects compared to LAT/CAR on the human corneal epithelial cells. Our findings showed that TAF/TIM is better than LAT/CAR with regard to the IOP-lowering effect in monkeys and toxicity on ocular surface.

Carteolol, a non-conventional partial agonist of beta(1)-adrenoceptors, relaxes phenylephrine-constricted rat aorta through antagonism at alpha(1)-adrenoceptors.

This in vitro study was designed to investigate whether carteolol, a non-conventional partial agonists of beta(1)-adrenoceptors, relaxes phenylephrine-constricted rat aorta through activation of the low-affinity state of beta(1)-adrenoceptors or antagonist effect at alpha(1)-adrenoceptors. Carteolol-induced complete concentration-dependent relaxation of phenylephrine-contracted aorta (pD(2)=3.65+/-0.04), this effect not being modified by endothelium removal and not antagonised by NO-synthase inhibitor N(G)-nitro-l-arginine methyl ester (100 microM) or cyclo-oxygenase inhibitor indomethacin (10 microM). The effect of carteolol was unaffected by the non-selective beta-adrenoceptor antagonist propranolol (1 microM), or the beta(2)-adrenoceptor selective antagonist (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551, 1 microM). Increasing concentrations of carteolol produced a parallel rightward shift of the concentration-response curves for phenylephrine-induced contraction, exhibiting a pK(B) of 4.28+/-0.07. Carteolol affinity for alpha(1)-adrenoceptors was evaluated by means of competition experiments carried out in BHK-21 cell membranes expressing rat recombinant alpha(1D)-adrenoceptor, the alpha(1)-adrenoceptor subtype mainly present in rat aorta. Carteolol competed monophasically with [(3)H]prazosin, exhibiting a pK(i) value (3.39+/-0.31) similar to its pD(2) and not very far from its pK(B). In conclusion, this study indicates that carteolol relaxes phenylephrine-contracted aorta through its alpha(1)-adrenoceptor antagonist properties, excluding the possibility that the relaxant effect is due to the activation of beta-adrenoceptors, particularly of the low-affinity state of beta(1)-adrenoceptors, by the drug.

Effects of switching from topical beta-blockers to latanoprost on intraocular pressure in patients with normal-tension glaucoma.

AIMS: The effects of switching from topical beta-blockers (beta) to latanoprost (LA) on intraocular pressure (IOP) and IOP-reduction rate (IOP-RR) in patients with normal-tension glaucoma (NTG) were investigated. SUBJECTS AND METHODS: Sixty (60) NTG patients (60 eyes) were divided into three equal groups receiving carteolol hydrochloride (group A), nipradilol (group B), and betaxolol hydrochloride (group C) twice-daily for 3 months. The drugs were changed to topical LA administered once-daily for the next 3 months. RESULTS: Baseline IOP was 14.4 +/- 0.9, 14.6 +/- 0.6, and 14.6 +/- 0.9 mmHg in groups A, B, and C, respectively. At 3 months, IOP was 12.4 +/- 0.6, 13.4 +/- 0.6, and 12.9 +/- 0.8 mmHg and 10.5 +/- 0.5, 11.1 +/- 0.8, and 11.7 +/- 0.8 mmHg at 6 months in groups A, B, and C, respectively. At 3 months, IOP-RR was 10.4 +/- 5.5, 9.5 +/- 2.6, and 10.8 +/- 4.7% and 24.1 +/- 4.3, 22.9 +/- 5.9, and 19.4 +/- 3.8% at 6 months in groups A, B, and C, respectively. The groups did not significantly differ in the first 3 months regarding IOP and IOP-RR. Switching to LA significantly decreased IOP and increased IOP-RR in all groups. CONCLUSION: In NTG patients, LA reduced IOP more effectively than the beta tested.

Efficacy of the combination of carteolol hydrochloride + latanoprost in the treatment of glaucoma and ocular hypertension.

INTRODUCTION: The only evidence-based mechanism for prevention and treatment of glaucomatous optic neuropathy is decreasing the intraocular pressure (IOP). Prescribing multiple ocular hypotensive agents, such as the combination of carteolol and latanoprost, may synergistically improve IOP; however, doing so may increase the complexity of a medication regimen, in turn, impairing patient adherence. Fixed-combination glaucoma medications offer convenience and effectiveness. New to this class of glaucoma medication is fixed combination carteolol-latanoprost (FCCL). Area covered: This review intends to give the reader a better understanding of the efficacy of the combination of carteolol and latanoprost separately, and where FCCL fits into the vast medical arsenal of IOP drops. Furthermore, it outlines the particular pharmacologic mechanisms targeted, the pharmacokinetics, effectiveness, the advantages of fixed-combination administration, and tolerability. Expert opinion: The combination of carteolol and latanoprost, separately or in a fixed-combination, is more effective than either drug alone. Given the early stage in development of FCCL, it has yet to be determined how FCCL compares to other fixed-combination medications. However, pending further approval, fixed-combination carteolol-latanoprost may represent a reasonable alternative for a patient whose IOP is inadequately controlled on a prostaglandin analog alone and for whom a simplified combination is preferred.

[Ocular hypotensive effect of 1% carteolol long-acting eye drops--a double-masked, randomized phase III study in ocular hypertension or primary open-angle glaucoma patients comparing long-acting carteolol eye drops vs. current product].

PURPOSE: To compare the ocular hypotensive activity and safety profile of long-acting 1% carteolol hydrochloride eye drops (long-acting formulation) to those of 1% carteolol hydrochloride eye drops(currently prescribed drug) for reduction of intraocular pressure. SUBJECTS AND METHODS: Patients with primary open-angle glaucoma or ocular hypertension (146 cases) were assigned randomly to the long-acting drug group (74 cases) and the currently-prescribed drug group (72 cases). Long-acting eye drops were instilled once a day in the morning (along with one drop of placebo at night), and currently-prescribed eye drops were instilled twice a day in the morning and at night. Eye drops were administered for 8 weeks. Intraocular pressure was monitored at 2, 4, and 8 weeks after the initiation of drug instillation for evaluation of equivalence. RESULTS: Intraocular pressure was significantly reduced during the entire follow-up period in both groups. In the long-acting drug group, the reduction of intraocular pressure was--3.5 +/- 0.2,--4.3 +/- 0.2 and--4.6 +/- 0.3 mmHg at 2, 4, and 8 weeks, respectively (paired t test). In the currently-prescribed drug group, the reduction of intraocular pressure was--4.1 +/- 0.2,--4.4 +/- 0.3 and--4.6 +/- 0.2 mmHg at 2, 4, and 8 weeks(paired t test). The safety profile was similar in both groups, and the tolerance for the long-acting eye drops was as good as for the currently-prescribed eye drops. CONCLUSION: Because the efficacy of both drugs was equivalent, with an identical safety profile, the long-acting eye drops seem to be an efficacious formulation for clinical use in Japanese glaucoma patients.

Carteolol hydrochloride protects human corneal epithelial cells from UVB-induced damage in vitro.

PURPOSE: To investigate whether carteolol hydrochloride has protective effects against ultraviolet B (UVB)-induced damage in human corneal epithelial cells (HCECs). METHODS: Cultured HCECs were exposed to a single dose of UVB 300 mJ/cm, and the cell viability was measured 12 hours after the UVB irradiation using a cell-counting kit. Test samples at 0.01-1.0 mmol/L (carteolol hydrochloride, timolol maleate, betaxolol hydrochloride, levobunolol hydrochloride, or nipradilol) were added to the HCECs before, during, or after UVB irradiation. UV absorption spectra for each drug sample were determined using a spectrophotometer. Hydrogen peroxide (H2O2) and carteolol hydrochloride were simultaneously added to the HCECs for 10 minutes, and the cell viability was measured 12 hours later. The ability of carteolol hydrochloride to scavenge superoxide anion (O2) and singlet oxygen (O2) was investigated using the MCLA chemiluminescence method. RESULTS: UVB irradiation decreased the number of viable HCECs in a dose-dependent manner. Carteolol hydrochloride at 1 mmol/L attenuated the UVB-induced cell damage when added before, during, or after UVB irradiation (P<0.01). Levobunolol hydrochloride at 1 mmol/L (P<0.01) added during or after irradiation and timolol maleate at 0.1 mmol/L or higher (P<0.05) added during irradiation attenuated the UVB-induced cell damage. Betaxolol hydrochloride and nipradilol had no effect. The UV absorption spectra of timolol maleate and levobunolol hydrochloride overlapped with the UVB wavelength spectrum, while carteolol hydrochloride, betaxolol hydrochloride, and nipradilol showed a partial overlap. Carteolol hydrochloride at 1 mmol/L (P<0.05) significantly inhibited H2O2-induced cell damage and was able to scavenge O2 (EC50 value: 48 mmol/L). CONCLUSIONS: These data strongly suggest that carteolol hydrochloride has a protective action against UVB-induced HCEC damage, and its radical scavenging ability may be an important basis for this effect.

Beta-blocking effect of single oral doses of carteolol.

Carteolol is a nonselective beta-adrenergic blocking agent with intrinsic sympathomimetic activity. The duration of beta blockade after single oral doses of carteolol was studied in normal men for 72 hr by determining the heart rate response to an external stimulus, bolus intravenous isoproterenol, and an internal stimulus (graded treadmill exercise designed to achieve 85% of the subjects' maximal heart rate in 12 min). Each subject first received 5 mg of carteolol and then, at 3-wk intervals, 2.5, 15, and 60 mg carteolol and placebo in a randomized, double-blind fashion. Beta blockade was maximal 1 to 2 hr after dosing and the heart rate response to isoproterenol and exercise remained less (P less than 0.05) than placebo responses for the 72 hr after each dose of carteolol. The double product (maximal exercise heart rate x systolic blood pressure during the twelfth minute of exercise) was below (P less than 0.05) baseline values for 24 hr after all doses, for 48 hr after 15 mg, and for 72 hr after 60 mg of carteolol.

Systemic effects of three beta-blocker eyedrops: comparison in healthy volunteers of beta 1- and beta 2-adrenoreceptor inhibition.

The beta 1- and beta 2-adrenoreceptor blockade by means of the systemic diffusion of three beta-blocker eyedrops--timolol, carteolol, and betaxolol--was evaluated in a randomized, single-blind, three-way crossover study in 18 volunteers. The blockade was evaluated by analyzing the variations of the beta 1- and beta 2-blockade effects of isoproterenol before and after instillation of one drop in each eye. The beta 1-blockade effect was judged on the variation of heart rate, and the beta 2-blockade effect was judged on the change in peripheral blood flow measured by veno-occlusive plethysmography. Comparison of the blockade by these drops showed that carteolol and timolol totally inhibited the beta 1 and beta 2 effects of a dose of isoproterenol able to increase heart rate by 50% (placebo eyedrops were used as a control). Betaxolol differ significantly because it allowed the same effects with the same dose of isoproterenol. Intensity of the blockade was measured by comparison of the effective doses of isoproterenol. Carteolol and timolol were shown to be four times more inhibitory.

Comparative long-term vasoactive effects of atenolol and carteolol on the properties of the small and large arteries of the upper extremities in human essential hypertension.

The long-term effects of selective (atenolol) and nonselective (carteolol) beta-blockers on brachial artery diameter velocity and flow and on vascular resistance (pulsed Doppler) were compared in two groups of 10 hypertensive patients at respective daily doses of 100 and 20 mg. The drugs decreased mean blood pressure (p less than 0.01) with similar magnitude, although systolic blood pressure was decreased more by atenolol than by carteolol (p less than 0.05). Heart rate was decreased by atenolol (p less than 0.01) but was unchanged by carteolol. The drugs did not change brachial circulation when the hand circulation was present. During hand exclusion (wrist occlusion) comparison from baseline showed that atenolol decreased velocity and flow (p less than 0.01, p less than 0.05) and increased resistance (p less than 0.05), whereas carteolol decreased resistance (p less than 0.05); after 3 months of treatment, velocity and flow were higher (p less than 0.01, p less than 0.001) and resistance was lower (p less than 0.01) with carteolol than with atenolol. Thus, hand exclusion demonstrated opposite drug effects on arterioles--dilation for carteolol and constriction for atenolol.

A single dose of three different ophthalmic beta-blockers antagonizes the chronotropic effect of isoproterenol in healthy volunteers.

The systemic effect of three beta-blocking eyedrops was compared in a placebo-controlled, double-blind trial in 12 healthy male volunteers. Each subject received successively each treatment in random order at weekly intervals. The eyedrops administered were as follows: 0.5% timolol, 2% carteolol, 0.6% metipranolol, and placebo. We evaluated the intraocular pressure and systemic beta-blockade 3 hours after a single administration of one eyedrop in each eye. The systemic beta-blocking effect was evaluated by the isoproterenol sensitivity test, that is the dose of isoproterenol required to increase resting heart rate by 25 bpm (I25). Each beta-blocking eyedrop antagonized the chronotropic effect of isoproterenol. I25 for placebo was 3.1 +/- 0.5 micrograms, for metipranolol 5.2 +/- 0.9 micrograms (P less than 0.005), for timolol 10.9 +/- 1.9 micrograms (P less than 0.001), and for carteolol 39.6 +/- 5.4 micrograms (P less than 0.0005). Each treatment significantly decreased the intraocular pressure: metipranolol 3.6 +/- 0.4 mm Hg (P less than 0.001), timolol 2.44 +/- 0.4 mm Hg (P less than 0.01), and carteolol 2.38 +/- 0.48 mm Hg (P less than 0.01) compared with placebo. The resting heart rate and blood pressure were not influenced by the treatments. Even though the results might be different in the case of an earlier or a later time of evaluation or chronic administration, we believe that the isoproterenol sensitivity test may be used to evaluate the systemic effect of beta-blocking eyedrops.

Effect of topical carteolol on the normal human retinal circulation.

The effect of topical carteolol 1%, a beta-adrenergic blocker with intrinsic sympathomimetic activity, on the retinal circulation was investigated in 15 normal subjects using laser Doppler velocimetry and monochromatic fundus photography. In a double-masked randomized design, one eye received one drop of carteolol 1% and the fellow eye one drop of placebo. Vessel diameter, maximum erythrocyte velocity, and volumetric blood flow rate were determined in a major temporal vein of each eye just before instillation of the drops and then 120 min later. No significant changes in heart rate or mean brachial artery blood pressure were detected after treatment. Intraocular pressure decreased by 28% in the carteolol-treated eye (P less than 0.0001) and by 15% in the placebo-treated eye (P less than 0.001). No significant changes in vessel diameter, maximum erythrocyte velocity, and volumetric blood flow rate were observed in the carteolol-treated eyes (0.3%, 4.3%, and 3.6%, respectively) or the placebo-treated eyes (0.5%, 5.8%, and 6.7%, respectively).

Mitochondrial activity and glutathione injury in apoptosis induced by unpreserved and preserved beta-blockers on Chang conjunctival cells.

PURPOSE: Quaternary ammonium ions have been demonstrated to induce apoptosis correlated with superoxide anion production in vitro. The purpose of this study was to further investigate the mechanisms of benzalkonium chloride (BAC), unpreserved and preserved beta-blocker eye-drops-induced programmed cell death, with special attention to the roles of mitochondrial transmembrane potential and intracellular reduced glutathione. METHODS: Chang conjunctival cells were incubated with different concentrations of unpreserved or preserved timolol (0.1%, 0.25%, and 0.4%), or carteolol (1% and 2%), or BAC (0.0001% to 0.01%) for 15 minutes, or for 15 minutes with a 24-hour recovery period in normal medium. Cellular viability (neutral red test), mitochondrial activity (rhodamine 123 test), intracellular reduced glutathione (monochlorobimane test), DNA condensation (Hoechst 33342 test), and reactive oxygen species (ROS) production (dichlorofluorescein diacetate and hydroethidine tests) were evaluated using microplate cold-light cytofluorometry. RESULTS: A significant, concentration-dependent decrease in cellular viability was found with preserved beta-blockers and with BAC alone, whereas unpreserved preparations did not show any toxicity. Only preserved beta-blockers induced chromatin condensation associated with an alteration of mitochondrial activity and a decrease of glutathione, suggesting an apoptotic phenomenon. BAC increased glutathione after 15 minutes, whereas a decrease was observed after a recovery period. ROS production was found with preserved formulations at significantly higher levels than those observed with unpreserved drugs. CONCLUSIONS: This in vitro study demonstrates that oxidative stress, evidenced by enhanced ROS production and mitochondrial injury rather than by cellular glutathione depletion, is a mechanism involved in apoptosis induced by preservative-containing eye-drops.

Developmental disappearance of excitatory alpha 1-adrenoceptor function in the oesophagus of chick embryo.

1. Developmental change in the response to noradrenaline (NA) and 5-hydroxytryptamine (5-HT) was investigated in the chick oesophagus between 9 and 21 days of incubation and 4 days after hatching. 2. NA (5 microM) produced a significant contraction in the oesophagus at 9 days of incubation. The NA-induced contraction progressively decreased with development and changed to an inhibition of spontaneous contraction or a small relaxation by 17 days of incubation. 3. The NA-induced contractile response was inhibited by phentolamine (2.7 microM) and prazosin (0.55 microM). Phenylephrine (5 microM) but not clonidine (5-50 microM), also induced a contraction at early stages. The relaxation response to NA was sensitive to the beta-receptor blocker, carteolol (3.4 microM). 4. Pretreatment with carteolol unmasked the contractile responses to NA in preparations at 17-19 days of incubation. However, even in the presence of carteolol, the contraction produced by NA decreased and disappeared by the time of hatching. This change in response to NA is accompanied by a decline in the pD2 value. The response to phenylephrine (5 microM) followed the same pattern as that to NA. 5. The maximum binding sites of [3H]-dihydroergocryptine to the crude membrane preparation from oesophagus changed little at 13, 17 and 21 days of incubation. 6. Isoprenaline (Iso, 0.01-20 microM) caused a carteolol-sensitive relaxation in the carbachol-contracted oesophagus after 13 days of incubation. The sensitivity (pD2 value) to Iso decreased slightly up to 17 days of incubation. 7. 5-HT (10 microM) caused a contraction in the oesophagus after 13 days of incubation and the amplitudem of the response increased up to 17 days of incubation. The response to 5-HT was abolished by methysergide (1 microM) but not by tetrodotoxin (0.78 microM) or atropine (1 microM) at every stage tested. 8. These results suggest that the response to NA changed from an alpha-adrenoceptor-mediated contraction to a beta-receptor-mediated relaxation during the embryonic period, resulting partly from the decline and disappearance of excitatory alpha-receptor function in the chick oesophagus.

Betaxolol, a beta(1)-adrenoceptor antagonist, reduces Na(+) influx into cortical synaptosomes by direct interaction with Na(+) channels: comparison with other beta-adrenoceptor antagonists.

Betaxolol, a beta(1)-adrenoceptor antagonist used for the treatment of glaucoma, is known to be neuroprotective in paradigms of ischaemia/excitotoxicity. In this study, we examined whether betaxolol and other beta-adrenoceptor antagonists interact directly with neurotoxin binding to sites 1 and 2 of the voltage-sensitive sodium channel (Na(+) channel) in rat cerebrocortical synaptosomes. Betaxolol inhibited specific [(3)H]-batrachotoxinin-A 20-alpha-benzoate ([(3)H]-BTX-B) binding to neurotoxin site 2 in a concentration-dependent manner with an IC(50) value of 9.8 microM. Comparison of all the beta-adrenoceptor antagonists tested revealed a potency order of propranolol>betaxolol approximately levobetaxolol>levobunolol approximately carteolol>/=timolol>atenolol. None of the drugs caused a significant inhibition of [(3)H]-saxitoxin binding to neurotoxin receptor site 1, even at concentrations as high as 250 microM. Saturation experiments showed that betaxolol increased the K(D) of [(3)H]-BTX-B binding but had no effect on the B(max). The association kinetics of [(3)H]-BTX-B were unaffected by betaxolol, but the drug significantly accelerated the dissociation rate of the radioligand. These findings argue for a competitive, indirect, allosteric mode of inhibition of [(3)H]-BTX-B binding by betaxolol. Betaxolol inhibited veratridine-stimulated Na(+) influx in rat cortical synaptosomes with an IC(50) value of 28. 3 microM. Carteolol, levobunolol, timolol and atenolol were significantly less effective than betaxolol at reducing veratridine-evoked Na(+) influx. The ability of betaxolol to interact with neurotoxin site 2 of the Na(+) channel and inhibit Na(+) influx may have a role in its neuroprotective action in paradigms of excitotoxicity/ischaemia and in its therapeutic effect in glaucoma.