Metipranolol promotes structure and function of retinal photoreceptors in the rd10 mouse model of human retinitis pigmentosa.

Metipranolol is a ß-adrenergic receptor antagonist that is given orally for the treatment of hypertension and also applied topically to the cornea for treating glaucoma. It also inhibits nitrosative stress which has previously been shown to be the cause of cone photoreceptor death in retinitis pigmentosa. In this study, we tested the hypothesis that metipranolol protects photoreceptor structure and function in the mouse model rd10. At P35, compared with vehicle-treated rd10 mice in which rod degeneration was nearly complete, rd10 mice given daily subcutaneous injections of 40 mg/kg of metipranolol had reduction in markers of nitrosative stress, fewer TUNEL-positive cells, increased outer nuclear layer thickness, and substantially more staining for rhodopsin. This was accompanied by significantly higher mean scotopic and photopic electroretinogram b-wave amplitudes indicating improved photoreceptor function. At P50, metipranolol-treated rd10 mice had decreased 3-nitrotyrosine staining in the retina, increased immunostaining for cone arrestin, a marker for cone photoreceptors, and significantly higher scotopic and photopic b-wave amplitudes at the highest stimulus intensity compared with vehicle-treated mice. At P65, cone density was significantly higher in metipranolol-treated versus vehicle-injected rd10 mice. Metipranolol applied as eye drops promoted cone photoreceptor function in retinas of rd10 mice greater than subcutaneously injected metipranolol. The reduced nitrosative damage and rescue of functional loss of photoreceptors in rd10 mice suggests that metipranolol, a drug with established ocular safety and tolerability, may have potential for treating patients with retinitis pigmentosa.

Pharmacophore modeling, homology modeling, and in silico screening reveal mammalian target of rapamycin inhibitory activities for sotalol, glyburide, metipranolol, sulfamethizole, glipizide, and pioglitazone.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and member of the PI3K-related kinase (PIKK) family. It plays a central role in integrating signals from metabolism, energy homeostasis, cell cycle, and stress response. Aberrant PI3K/mTOR activation is commonly observed in diseases such as cancer, diabetes and Alzheimer's disease. Accordingly, we developed common feature binding hypotheses for a set of 6 potent mTOR antagonists. The generated models were validated using receiver operating characteristic (ROC) curve analyses. To gain better insight into ligand-mTOR interactions, a homology model for the kinase domain of mTOR was built using the crystallographic structure of PI3Kγ as template. The optimal pharmacophore model was further improved based on detailed docking studies of potent training compound in the homology model. The modified binding model was employed as 3D search query to screen our in-house-built database of established drugs. Subsequent in vitro screening of captured hits showed that six of them have submicromolar to low micromolar bioactivities, namely, glyburide, metipranolol, sulfamethizole, glipizide, pioglitazone, and sotalol.

Alteration of the cardiac sympathetic innervation is modulated by duration of diabetes in female rats.

To evaluate the sympathetic innervation of the female diabetic heart, resting heart rate and sympathetic tone were assessed in vivo, and effect of tyramine on spontaneous beating rate, norepinephrine atrial concentrations, uptake, and release were determined in vitro in streptozotocin- (STZ-) treated rats and respective controls aged 3 months to 2 years. Resting bradycardia, decreased sympathetic tone, deceleration of spontaneous beating rate, and slightly declining carrier-mediated, but preserved exocytotic norepinephrine release from the atria were found in younger diabetic rats while the reactivity of the right atria to tyramine was not affected with age and disease duration. Diabetic two-year-old animals displayed symptoms of partial spontaneous recovery including normoglycemia, increased plasma insulin concentrations, fully recovered sympathetic tone, but putative change, in releasable norepinephrine tissue stores. Our data suggested that female diabetic heart exposed to long-lasting diabetic conditions seems to be more resistant to alteration in sympathetic innervation than the male one.

Cardiovascular parameters in rat model of chronic renal failure induced by subtotal nephrectomy.

Chronic renal failure (CRF) is associated with high incidence of cardiovascular complications. To clarify pathogenesis of CRF numerous animal models have been developed. The aim of our work was to describe methodology of subtotal surgical renal ablation in rat and to characterize some biochemical and cardiovascular parameters of this animal model. Male rats underwent 5/6 surgical nephrectomy or sham operations in two steps. The following parameters were measured on day 10 and in week 10 after the surgery: plasma concentrations of creatinine and urea, blood pressure, resting heart rate, chronotropic response to atropine and metipranol, heart ventricles weight, contraction parameters and action potential duration in the left ventricle. Increased serum concentrations of creatinine and urea, decreased creatinine clearance, polyuria and alteration of the remnant kidney tissue were found in CRF rats. Changes in cardiovascular parameters identified after subtotal nephrectomy resembled alterations of cardiovascular system in uremic patients and included hypertension, elevated resting heart rate, diminished parasympathetic cardiac tone, hypertrophy of the left ventricle associated with weakened force of contraction, prolonged contraction and relaxation and shortening of action potential duration. These data suggest that the present model can be a useful tool in the study of CRF and its cardiovascular complications.

Parasympathetic regulation of heart rate in rats after 5/6 nephrectomy is impaired despite functionally intact cardiac vagal innervation.

BACKGROUND: Chronic renal failure is frequently associated with a high risk of sudden cardiac death due to dysfunction of the autonomic nervous system. The pathogenic mechanisms underlying the parasympathetic cardiac dysautonomia are not fully elucidated yet. METHODS: Chronic renal failure was induced in rats by 5/6 nephrectomy. Blood pressure, resting heart rate and plasma levels of creatinine, urea and asymmetric dimethylarginine (ADMA) were measured. To characterize the parasympathetic innervation of the heart, chronotropic responses to atropine, metipranolol and to vagal stimulation in the absence or presence of ADMA were investigated in vivo. In vitro, chronotropic and inotropic effects of carbachol and ADMA and mRNA expression of muscarinic M2 receptors, high affinity choline transporter (CHT1), vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) were assessed in the isolated cardiac tissues. RESULTS: In 5/6 nephrectomy rats, the resting heart rate was significantly higher and the parasympathetic tone, measured as the effect of atropine after administration of metipranolol was significantly lower than in control animals. Plasma ADMA levels were significantly elevated in the uraemic rats and significantly inversely correlated with the effect of atropine on the heart rate. No differences were revealed in the plasma norepinephrine concentrations, negative chronotropic responses to stimulation of the vagus nerves, chronotropic and inotropic responses to carbachol and the relative expression of M2 receptors, CHT1, VAChT and ChAT. CONCLUSION: The data suggest that cardioacceleration in chronic renal failure is caused by a diminished cardiac parasympathetic tone in the presence of a functionally intact intrinsic cardiac cholinergic signalling system.

Chronic atropine administration diminishes the contribution of vasoactive intestinal polypeptide to heart rate regulation.

Vasoactive intestinal polypeptide (VIP) is implicated in the modulation of vagal effects on the heart rate. In this study, the impact of acute and chronic atropine administration on VIP levels in rat heart atria was investigated in relation to heart rate in the course of vagus nerves stimulation. Anaesthetised control and atropinised (10 mg/kg/day for 10 days) rats pretreated with metipranolol and phentolamine that were either given or not a single dose of atropine were subjected to bilateral vagus nerve stimulation (30 min: 0.7 mA, 20 Hz, 0.2 ms). VIP concentrations in the atria were determined after each stimulation protocol. In control rats with or without single atropine administration, the heart rate upon vagal stimulation was higher than in atropinised animals with or without single atropine dose, respectively. VIP concentrations in the control atria were significantly decreased after the stimulation; the decrease was comparable both in the absence and presence of a single dose of atropine. Compared to controls, VIP levels were significantly decreased after chronic atropine treatment and they were not further reduced by vagal stimulation and single atropine administration. Administration of VIP antagonist completely abolished the differences in the heart rate upon vagal stimulation between control and atropinised groups. In conclusion, the data indicate that chronic atropine administration affects VIP synthesis in rat heart atria and consequently it modifies the heart rate regulation.

The beta-adrenergic receptor antagonist metipranolol blunts zinc-induced photoreceptor and RPE apoptosis.

PURPOSE: To determine the effect of zinc on retinal cells at concentrations at which it is known to cause oxidative stress. Furthermore, the effects of metipranolol, known to prevent retinal damage, and of other antiglaucoma drugs were determined on zinc-injured retinal cells. METHODS: Lipid peroxidation assays were conducted on rat brain and bovine retina-retinal pigment epithelial (RPE) membrane preparations. Immunohistochemistry, immunoblot analysis and the terminal-deoxynucleotidyl transferase dUTP-linked nick-end labeling (TUNEL) procedure determined the effects of zinc with or without trolox or metipranolol on photoreceptor death in situ. The effect of treatments on cultured RPE cells was analyzed using cell viability assays, immunoblot analysis, and the TUNEL procedure. RESULTS: Zinc-induced lipid peroxidation of rat brain and bovine retina-RPE membranes, although the effect of the latter was of a (twofold) greater magnitude. Both effects, however, were similarly attenuated by metipranolol, desacetylmetipranolol, and trolox. Antiglaucoma drugs other than metipranolol had no effect. Intraocular injection of 150 microM zinc and treatment of cultured RPE cells with zinc led to mainly photoreceptor apoptosis and apoptotic death of RPE cells (50% death at 18 microM rising to 10% at 50 microM), respectively. Zinc-induced apoptosis of cultured RPE cells and photoreceptors were attenuated only by metipranolol and trolox. CONCLUSIONS: The combined data suggest that oxidative injury to RPE cells and photoreceptors may be caused by elevated levels of zinc in diseases such as age-related macular degeneration (AMD) and that metipranolol may act as an efficacious antioxidant to blunt this process.

Metipranolol blunts nitric oxide-induced lipid peroxidation and death of retinal photoreceptors: a comparison with other anti-glaucoma drugs.

PURPOSE: To determine the effect of the nitric oxide donor sodium nitroprusside (SNP) on rat retinas and to see whether detrimental changes could be attenuated by known antiglaucoma drugs. METHODS: SNP was injected into the rat eye and retinas were analyzed by the terminal-deoxynucleotidyl transferase dUTP-linked nick end labeling (TUNEL) procedure and by immunohistochemistry. In some instances, retinal homogenates were analyzed by immunoblot for proteins associated with either photoreceptors or with cell death. Analysis of lipid peroxidation in retinal homogenates was by the thiobarbituric acid reactive species (TBARS) formation RESULTS: SNP caused an increase in the number of retinal photoreceptors labeled for DNA breakdown by the TUNEL procedure and for caspase-3 and Bcl-2. After intravitreal injection of SNP, breakdown of poly(ADP-ribose) polymerase and an increase in the level of active forms of caspase-3 and Bcl-2 were detected. Furthermore, photoreceptor-specific rhodopsin kinase was reduced. SNP also stimulated formation of TBARS in retinal homogenates, occurring to a greater extent in retinas from young Royal College of Surgeons rats lacking photoreceptor degeneration. This supports the view that the photoreceptors are the prime target for SNP. Significantly, of several antiglaucoma drugs tested only metipranolol and its active metabolite, desacetylmetipranolol, blunted the SNP-induced retinal changes. CONCLUSIONS: Of all antiglaucoma drugs tested, only metipranolol was able to attenuate SNP-induced lipid peroxidation and activation of apoptosis in photoreceptors. Because oxidative injury has been implicated in the pathogenesis of certain ocular diseases, these findings could prove to be of clinical significance.

Metipranolol attenuates lipid peroxidation in rat brain: a comparative study with other antiglaucoma drugs.

BACKGROUND: Free radical production seems to be involved in the pathogenesis of a number of ocular diseases. Certain beta-adrenoceptor antagonists display antioxidant properties, but these have not been ascribed to any of the presently used ophthalmic beta-adrenoceptor antagonists. Therefore, we examined the influence of ophthalmic beta-adrenoceptor antagonists and other antiglaucoma drugs on stimulated lipid peroxidation in rat brain homogenates. METHODS: Lipid peroxidation in rat brain homogenates was stimulated by iron/ascorbate or sodium nitroprusside. Lipid peroxidation was assessed by the formation of thiobarbituric acid reactive species (TBARS). RESULTS: Of the antiglaucoma drugs tested (brimonidine, carteolol, dorzolamide, latanoprost, levobetaxolol, levobunolol, metipranolol, pilocarpine, timolol, travoprost and unoprostone), only metipranolol and its active metabolite, desacetylmetipranolol, were found to significantly reduce iron/ascorbate-induced lipid peroxidation in rat brain homogenates with IC50 values of 6.9 and 1.1 microM, respectively. Metipranolol and desacetylmetipranolol also concentration-dependently inhibited sodium nitroprusside-stimulated lipid peroxidation in rat brain homogenates, displaying IC50 values of 25.1 and 2.6 microM, respectively. CONCLUSION: These data indicate that metipranolol and desacetylmetipranolol exhibit remarkable antioxidant properties, with an effect not dissimilar from the reference antioxidant trolox.

Inhibition of neutrophil migration and oxygen free radical release by metipranolol and timolol.

Propanolol and metoprolol exert adrenoceptor-independent effects including scavenging of free radicals and inhibition of protein kinase C leading to inhibition of leukocyte migration and radical release as a consequence. Whether topically used metipranolol and timolol exert such effects is unknown. Neutrophil chemotaxis was tested using modified Boyden microchemotaxis chambers. Respiratory burst activity of neutrophils was detected fluorometrically. Radical scavenging properties were tested using 2',7'-dichlorofluorescein diacetate. Metipranolol and timolol inhibited neutrophil chemotaxis at doses in the micromolar range, oxygen free radical production triggered with formyl-Met-Leu-Phe was inhibited at higher concentration. Protein kinase C involvement, suggested to trigger free radical production with phorbol myristate acetate, was antagonized. A direct radical scavenging effect of the beta-blockers was also seen. Inhibition of neutrophil chemotaxis and free radical production is a novel mode of action of metipranolol and timolol that may be relevant for beneficial effects in the topical treatment of eye disease.

The beta-adrenoceptor antagonists metipranolol and timolol are retinal neuroprotectants: comparison with betaxolol.

beta-adrenoceptor antagonists are used clinically to reduce elevated intraocular pressure in glaucoma which is characterised by a loss of retinal ganglion cells. Previous studies have shown that the beta(1)-selective adrenoceptor antagonist, betaxolol, is additionally able to protect retinal neurones in vitro and ganglion cells in vivo from the detrimental effects of either ischemia-reperfusion or from excitotoxicity, after topical application. The neuroprotective effect of betaxolol is thought not to be elicited through an interaction with beta-adrenoceptors, but by its ability to reduce influx of sodium and calcium through voltage-sensitive calcium and sodium channels. In the present study it is shown that the non-selective beta-adrenoceptor antagonists, metipranolol and timolol behave like betaxolol. When topically applied they all attenuate the detrimental effect of ischemia-reperfusion. Protection of the retina was determined by evaluating changes in the electroretinogram and by assessing the loss of mRNA for Thy-1, which is expressed in retinal ganglion cells. In addition, studies conducted on neurones in mixed retinal cultures demonstrated that metipranolol, betaxolol and timolol were all able to partially counteract anoxia-induced cell loss and viability reduction. The influence of timolol was, however, not significant. Within the confines of these investigations, an order of neuroprotective efficacy was delineated for the three beta-adrenoceptor antagonists: betaxolol>metipranolol>timolol. The ability of the beta-adrenoceptor antagonists to attenuate ligand-induced stimulation of calcium and sodium entry into neuronal preparations showed a similar order of effectiveness. In conclusion, the ability to confer neuroprotection to retinal neurones is a common feature of three ophthalmic beta-adrenoceptor antagonists (betaxolol, metipranolol and timolol). A comparison of the effectiveness of the individual compounds in protecting retinal cells in vivo was not possible in these studies. However, in vitro studies show that the capacity of the individual beta-adrenoceptor antagonists to act as neuroprotectants appears to relate to their capacity to attenuate neuronal calcium and sodium influx.

Cationic amphiphilic drugs and platelet phospholipase A(2) (cPLA(2)).

The aim of the study was to verify and compare the effect of cationic amphiphilic drugs (CAD) from different pharmacological groups on activation of platelet phospholipase A2 (PLA2)--the essential enzyme of arachidonic pathway in blood platelets. Beta-adrenoceptor-blocking (BAB) drugs inhibited platelet aggregation in the rank order of potency: propranolol>alprenolol>metipranolol>atenolol. The higher the inhibition of arachidonic acid (AA) liberation by BAB drugs, the higher the inhibition of aggregation. Similarly did the H1-histamine antagonists bromadryl (BRO) and dithiaden (DIT) as well as the antimalarial chloroquine (CQ) show antiplatelet effect in vitro in the rank order of potency: DIT>BRO>CQ. Dose-dependent inhibition of aggregation was followed by the inhibition of AA liberation from membrane phospholipids of platelets stimulated either at the receptor site (thrombin) or by a stimulus bypassing membrane receptors (Ca2+ ionophore A23187). The rank order potency for inhibition of stimulated 3H-AA liberation from membrane phospholipids was: (a) for BAB drugs: propranolol>alprenolol>metipranolol, (b) for other drugs: DIT>BRO>CQ. The investigated drugs' interference with stimulated liberation of AA showed nonspecific inhibition of platelet cytosolic PLA2 (cPLA2) by these drugs at intracellular level. The results revealed that besides the inhibition of cyclooxygenase pathway and receptors for adenosine diphosphate (ADP) and glycoproteins Gp IIbIIIa, the interaction of drugs with cPLA2 may represent a further site for antiplatelet action.

Topical ophthalmic beta blockers may cause release of histamine through cytotoxic effects on inflammatory cells.

AIM: To evaluate the effects of beta blockers used in ophthalmology on the release of histamine from mixed cell preparations containing human leucocytes and basophils. METHODS: A mixed leucocyte and basophil preparation was obtained from venous blood of healthy non-atopic volunteers. Cell preparations were then incubated with betaxolol, metipranolol, timolol, or carteolol. After incubation for 1 hour the histamine content of the supernatant was analysed by automated fluorometric analysis. Cell viability was tested by measuring lactate dehydrogenase (LDH) concentrations. RESULTS: Betaxolol and metipranolol in concentrations between 10(-2) M and 10(-3) M liberated histamine from human blood cells in a dose dependent manner. Carteolol and timolol had no effect on histamine at these concentrations. At the same concentrations LDH was also detected in the supernatants of cell suspensions incubated with metipranolol or betaxolol. CONCLUSIONS: Betaxolol and metipranolol induce substantial histamine release from human leucocytes, probably as a result of their cytotoxic effect.

[Measuring retinal circulation with the Heidelberg retinal flowmeter: reproducibility of data and no effect of metipranolol in normal probands]. / Messung der retinalen Durchblutung mit dem Heidelberg Retina Flowmeter: Reproduzierbarkeit der Daten und kein Einfluss von Metipranolol an Normalpersonen.

PURPOSE: We wanted to know whether topical Metipranolol has any effect on ocular blood flow. Before starting this investigation using the Heidelberg Retina Flowmeter, we studied the reproducibility of this device. METHOD: Retinal blood flow was determined in 15 healthy volunteers. Altogether, each volunteer was measured 20 times (4 different days with 5 pictures each). Coefficients of variation were calculated for both, the short term fluctuation and the long term fluctuation. After that, the effect of metipranolol was tested in 14 of the 15 volunteers mentioned above. This was done in a randomized, placebo controlled, double masked and crossover designed study. RESULTS: The mean coefficients of variation were 21% for the short term fluctuation and 13% for the long term fluctuation. There was a significant effect of learning, i.e. coefficients of variation decreased with increasing experience of the investigator (MVR). Blood flow values did not differ significantly between metipranolol and placebo. CONCLUSIONS: 1. The reproducibility of blood flow values measured with the Heidelberg Retina flowmeter are sufficient, at least if the device is used in clinical studies. When performing those studies, the learning curve of the investigator should be taken into account. 2. The topical application of metipranolol does not alter the retinal blood flow in healthy volunteers.

Acute effect of metipranolol on the retinal circulation.

AIM: To assess the effect of topical and systemic application of a beta adrenergic receptor blocker on retinal haemodynamics. METHODS: 24 healthy subjects were included in this double masked, randomised, placebo controlled crossover study. Metipranolol, a non-selective beta adrenergic receptor blocking agent was used as test drug. In all subjects arm-retina time, arteriovenous passage time, arterial mean dye velocity, the arterial vessel diameters, and capillary flow velocity were quantified from digital video fluorescein angiograms. RESULTS: A significant effect was observed on the arteriovenous passage time (p < 0.05), the arterial mean dye bolus velocity (p < 0.05), and capillary blood velocity (p < 0.05), but not on the arterial vessel diameter. The arterial mean dye bolus velocity and capillary blood velocity increased after application of the test drug (topical and systemic). In tandem with this a decrease of the arteriovenous passage time was observed. The perfusion pressure increased after topical application and remained unchanged after systemic application of metipranolol. CONCLUSIONS: This study shows that systemic as well as topical application of metipranolol leads to increased retinal blood flow velocities. The implications of these results for treatment with beta adrenergic receptor blockers is not clear. However, in view of these data it is very unlikely that treatment with metipranolol has a negative effect on retinal blood flow.

Effects of beta-blockers association with pilocarpine on rabbit intraocular pressure and heart rate.

The effect of 7-days BID (twice in a day) or TID (three times in a day) administration of the eye-drop combinations of timolol and pilocarpine (0.5% and 2%, respectively), metipranolol and pilocarpine (0.1% and 2%, respectively) or placebo on intraocular pressure (IOP) and heart rate (HR) of conscious rabbits were studied in order to assess the pharmacological potency of the combinations and their heart side effects. TID administration of both pharmacological combinations was followed by similar decrease of IOP as measured over 24 h (at 4.00 and 20.00 h). After the BID administration, a reduction in IOP was observed only twice with the timolol-pilocarpine combination. In contrast, a constant reduction in IOP was seen with the metipranolol-pilocarpine combination. Furthermore, the TID administration of the timolol-pilocarpine combination exerted a decrease of IOP that appeared to be more pronounced than that observed after the BID administration of the same combination, while no difference was found between the TID and BID administration of the metipranolol-pilocarpine treatment. Heart rate, when measured after 7 days of treatment, appeared to be constantly decreased only in the group of animals which received the TID administration of timolol-pilocarpine combination. The present results suggest that the BID or TID administration of metipranolol-pilocarpine combination was fully effective in reducing IOP without influencing HR. The timolol-pilocarpine association appeared to be fully active in reducing IOP only under the TID administration schedule. However, this rate of administration was followed by a constant reduction of HR. Thus, on a dose basis the metipranolol-pilocarpine combination appeared to be more effective in reducing IOP and less effective in inducing bradycardia than the timolol-pilocarpine association.

Electrophysiological properties of cultured human trabecular meshwork cells.

Previous studies using cultured bovine trabecular meshwork cells demonstrated at least two different cell types which were distinguishable morphologically and electrophysiologically. The purpose of the present study was to evaluate the electrical membrane properties of cultured human trabecular meshwork cells. Seven different human trabecular meshwork cell lines were grown from four different donors. One trabecular meshwork cell line was transformed by microinjection with SV40 DNA. The electrochemical properties of these TM cells were determined by micropuncture with glass microelectrodes. The mean membrane voltage at resting conditions differed between the cell lines (-33.3 to -58.7 mV). Application of 10-mmol l-1 Ba2+ induced repetitive voltage spikes in all cell lines. The voltage transients similar to action potentials were inhibited by nifedipine, but insensitive to tetrodotoxin. Acetylcholine evoked depolarizations in three cell lines which were blocked by atropine. In one cell line isoproterenol caused sustained depolarizations sensitive to metipranolol. All three of the cell lines tested depolarized upon application of the vasoactive peptide endothelin-1. All untransformed cell lines showed voltage spikes typical for smooth muscle cells and functional receptors for endothelin-1 and cholinergic agonists. One out of three cell lines tested possessed beta-adrenergic receptors influencing the membrane voltage.

The effect of preservatives and antiglaucomatous medication on the histopathology of the conjunctiva.

BACKGROUND: Topical medication applied chronically for the treatment of glaucoma changes the cellular profile of the conjunctiva. We wanted to determine the role of preservatives, which are usually combined with the drugs, on this effect. METHODS: We applied metipranolol 0.3% and pilocarpine 2% with and without benzalkonium chloride 0.01% and cetrimonium chloride 0.004%, respectively. Twenty-four rabbits, divided into four groups, were treated for 3 months. The complete globes and the adherent bulbar conjunctiva were examined histopathologically and immunohistochemically. RESULTS: With special stains for collagen, a slight increase of the thickness of subepithelial collagen of the conjunctiva was present in both groups treated with medication and preservative compared with eyes treated with medication alone. This effect was also true for special antibodies for collagen type IV and alpha-smooth muscle actin in the eyes treated with pilocarpine, but not in the eyes treated with metipranolol. CONCLUSION: The results suggest that preservatives may have an additional adverse effect on the conjunctiva in addition to the effects of the medications alone.

Ocular macro- and microcirculation after topical application of clonidine and metipranolol.

We investigated the effect of clonidine (Isoglaucon, an alpha-agonist) and metipranolol (Betamann, a beta-antagonist) on the blood flow in the ophthalmic artery and the anterior uvea of 40 young, healthy volunteers (mean age, 23.5 +/- 2 years) in a prospective, randomized simple blind study. The blood flow in the iris and ciliary body was detected by laser-Doppler flowmetry (bpm, 403a; TSI; wavelength, 780 nm; power, < 1.6 mW). The blood flow in the ophthalmic artery was measured by pulsed Doppler sonography (4 MHz, EME). The blood pressure, pulse respiration, and intraocular pressure (IOP) were recorded. Vascular resistance (RF) was calculated by the equation RF = (RRmean--IOP)/blood flow. Group 1 was treated with a single drop of Betamann (3 mg/ml) applied topically, and group 2 was treated with Isoglaucon (2.5 mg/ml). Measurements were made before and 30 min after application. Both drugs significantly lowered the IOP by about 7% (P = 0.01). Clonidine did not affect the blood velocity in the ophthalmic artery. In group 2 (metipranolol) we found a significant increase in the blood velocity in the ophthalmic artery during the diastolic period (from 11.0 +/- 3.7 to 11.9 +/- 2.2 cm/s, P = 0.05). Both clonidine and metipranolol decreased the iridal blood flow [clonidine, from 9.3 +/- 3.9 to 7.6 +/- 3.1 (flux), P = 0.05; metipranolol, from 7.5 +/- 2.9 to 6.5 +/- 2.6 (flux), P = 0.05]. Vascular resistance in the iris increased under the effect of clonidine (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the new beta-adrenolytic compound propyl-3-acetyl-4-[(2-hydroxy-3-isopropylamino) propoxy]carbanylate hydrochloride on isolated heart muscle.

The effect of the new beta-adrenolytic drug Bl 343 Ac (propyl-3-acetyl-4-[(2-hydroxy-3-isopropylamino) propoxy] carbanylate hydrochloride) was tested in preparations of the guinea-pig atrium and compared with the effects of propranolol and metipranolol. BL 343 Ac has an affinity to beta-adrenergic receptors, expressed as the pA2 value, which is comparable to those of propranolol and metipranolol. To achieve the slope of the Schild plot not different from unity, it was necessary to prolong incubation of the drug with the tissue to 75 min. At the concentrations of 10(-5) and 10(-4) mol/l and higher, BL 343 Ac was found to have negative chronotropic and inotropic effects, respectively. IN atria isolated from guinea-pigs and rats premedicated with reserpine, application of 10(-8) and 10(-7) mol/l of Bl 343 Ac exhibited a slightly stimulatory effect on the chronotropy. A positive inotropic effect of Bl 343 Ac was observed on the left guinea-pig atria after prolongation of the incubation time of the drug with the tissue up to 75 min. This inotropic effect of Bl 343 Ac may be associated with an increased concentration of cyclic adenosine monophosphate (cAMP), observed after 1-h incubation with the drug (from 0.78 +/- 0.05 to 1.13 +/- 0.09 pmol/mg w.w. cAMP). Bl 343 Ac, similarly to propranolol and metipranolol, prolonged the refractory period in the atrial preparations starting with the concentration of 10(-6) mol/l. In the ventricular preparations, Bl 343 Ac shortened the refractory period up to the concentration of 10(-5) mol/l, similarly to propranolol.