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Biomedical subjects

B P Vogh

Publications and source records attributed to B P Vogh.

At least 19 recordsLinked to original sources
PubMed1997

Timolol decreases aqueous humor flow but not Na+ movement from plasma to aqueous.

PURPOSE: To determine whether the well-known effect of timolol in reducing ocular pressure and aqueous humor (AH) flow is a function of reduced Na+ movement from plasma to aqueous. Previously, the authors have shown this to be the case for carbonic anhydrase inhibitors. METHODS: The rate of appearance of 22Na in rabbit posterior aqueous was measured 1 to 3 minutes after the intravenous injection (time T) of the isotope. One hour before this, the animals received one of the following: two drops of 0.5% timolol, two drops of 3.5% pilocarpine, or 25 mg/kg intravenous methazolamide. At 1 minute (T + 1), a posterior chamber sample was taken; 2 minutes later (T + 3) a second sample was removed from the fellow eye. The rate constant of sodium accession is simply the difference between the two counts/2 minutes. Aqueous flow was measured by dilution of sulfacetamide marker as described previously. RESULTS: The rate constant (k(in)) for sodium entering the posterior chamber was 0.036 +/- 0.004 minute-1 (n = 17). Corresponding to previous findings, methazolamide (25 mg/kg intravenous) reduced this to 0.023 +/- 0.003 minute-1 (n = 14). Conversely, timolol (two drops of 0.5% solution) had no effect on kin, which measured 0.037 +/- 0.004 minute-1 (n = 12). Similarly, as expected, pilocarpine had no effect on k(in) (0.035 +/- 0.003 minute-1). Control flow was 3.9 microliters/minute +/- 0.4; after timolol, 2.5 microliters/minute +/-0.1; after methazolamide, 2.4 microliters/minute +/-0.2; after pilocarpine, 3.6 microliters/minute +/- 0.2. These are converted to rate constants by dividing by volume of posterior aqueous (60 microliters). The control rate constant for fluid entry was 0.065 minute-1, 1.8-fold higher than for sodium. CONCLUSIONS: A central dogma of the formation of AH (and cerebrospinal fluid) is that fluid moves isotonically from plasma to AH or cerebrospinal fluid and, therefore, that rate constant k(in) for fluid and for sodium are approximately the same. In the authors' hands, the fluid constant was modestly higher than for sodium. This holds for normal function and also for the reduced k(in) for fluid and sodium after carbonic anhydrase inhibition. The k(in) for neither flow nor sodium was affected by pilocarpine. Surprisingly, however timolol, which reduces flow, had no effect on Na+ entry.

Adrenergic beta-Antagonists↗
PubMed1989

Measurement of aqueous humor flow following scleral injection of sulfacetamide as marker: effect of methazolamide, timolol, and pilocarpine.

A simple technique for rapid determination of the flow of aqueous humor (AH) in rabbits is described. Data from control eyes and eyes treated with known inhibitors of aqueous humor production are presented as evidence of the suitability of the technique for comparing the influence of other drugs on aqueous flow. The flow measurement depends on marker dilution by fluid turnover during the first 30 min after 5 microliters marker solution is delivered to the anterior chamber. This is done by passing a needle through the sclera and behind the iris. The advantage of this route is that it permits withdrawal of the needle after delivery without leakage of marker or aqueous humor. Sulfacetamide (SAC), a sulfonamide with low lipid solubility and pKa 5.4, is the marker of flow used here. Control flow data from SAC, fluorescein (FL), reactive blue-2, and 14C-inulin as markers were compared. The control flow measured with SAC in two independent groups is 3.91 and 3.40 microliters/min or 3.69 +/- 0.37 S.E. overall. The data show that inhibition of carbonic anhydrase (CA) in ciliary processes by systemic methazolamide reduces flow 38%. Topical timolol reduces flow 35%. Pilocarpine, which is known to decrease IOP largely by increasing outflow facility, did not significantly reduce flow. This system for measuring AH flow allows rapid accumulation of data for topical, intracameral or systemic treatments.

Animals↗
PubMed1989

Effects of inhibition of angiotensin converting enzyme and carbonic anhydrase on fluid production by ciliary process, choroid plexus, and pancreas.

Inhibitors of angiotensin converting enzyme (ACE) (1) and of carbonic anhydrase (CA) (2,3) decrease intraocular pressure (IOP) in conscious rabbits. We asked whether ACE inhibition decreases IOP through effects on CA-dependent flow of aqueous humor (AH) and whether ACE inhibitors decrease other CA-dependent secretions. We show in anesthetized rabbits (a) that topical inhibitors of ACE decrease both IOP and AH flow as much as systemic inhibitors of CA; (b) that the maximal effects of ACE and CA inhibition are not additive, therefore these treatments may affect one or more components of a single system for fluid production; and that (c) ACE inhibitors do not work through inhibition of CA. Looking at other fluid production systems, we find (d) that cerebrospinal fluid (CSF) production is increased after ventriculocisternal perfusion with a potent ACE inhibitor and (e) that flow of pancreatic juice (PJ) is increased after systemic ACE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Effect of AlCl3 and other acids on cerebrospinal fluid production: a correction.

Our earlier report that perfusion of Al and Ga salts through rat brain ventricles abolished cerebrospinal fluid (CSF) production is incorrect. We now realize there are three conditions which, when simultaneously present, will give a false reading of the events taking place. These are: metal salts, low pH with subsequent rise in pH during perfusion and use of blue dextran as the marker. When we perfused 10 mM AlCl3 or GaCl3 in vivo, all three conditions were provided, and led to the misinterpretation that all CSF production had been eliminated. In doing experiments that prevented the subsequent rise in pH during perfusion, or in using [14C]dextran as the marker in vivo, we found that Al and Ga (acting as Lewis acids at pH 4.7 and below), and also hydrochloric, phosphoric and acetic acids of the same pH, reduce CSF production by approximately 33%. We attribute this to the lowering of pH eliminating the uncatalyzed reaction OH- + CO2----HCO3- in secretory cells of choroid plexus. Acetazolamide blocks the HCO3- formation catalyzed by carbonic anhydrase, and reduces CSF production 42%. These mechanisms are additive in that, when acetazolamide and either Al or acetic acid are given together, there is a total reduction of 64%. Therefore, at least 64% of CSF production is dependent on formation of HCO3-. The mechanisms accounting for the balance of CSF production are not yet defined clearly. A significant portion of this production is expected to relate to transport of Cl-.

Acetates↗
PubMed1985

Timolol plus acetazolamide: effect on formation of cerebrospinal fluid in cats and rats.

Administration iv of 50 mg X kg-1 acetazolamide (A) and 3 mg X kg-1 timolol (T) causes the formation of cerebrospinal fluid (f-CSF) to be reduced to 43.7% of the control rate compared with a reduction to 82.5% of control by T alone and to 52.6% of control by A alone. The effect of combined drugs is the same when A is combined with T initially, when A is added to T after studying T alone, or when T is added to A after studying A alone. In contrast, in rats f-CSF is not influenced by T, either alone or when in combination with A. The rate in rats is reduced to 55% of control by treatments with A or A and T. Decrease in formation of cerebrospinal fluid by A occurs through inhibition of carbonic anhydrase, but the means whereby T (a known blocker of beta-adrenergic receptors) causes a reduction in f-CSF is not established; it is known that it does not inhibit carbonic anhydrase. Control of f-CSF by the sympathetic nervous system is discussed.

Acetazolamide↗
PubMed1985

Aluminum and gallium arrest formation of cerebrospinal fluid by the mechanism of OH- depletion.

AlCl3 or GaCl3 was added to artificial cerebrospinal fluid and perfused through the cerebral ventricles of the rat. Depending on the metal and its concentration (1-10 mM) the pH of the perfusate ranged from 7.2 to 3.5. At 10 mM metal chloride, yielding pH 4.7 (Al) or 3.5 (Ga), formation of cerebrospinal fluid was suppressed 100%. The effect was reversed as soon as control cerebrospinal fluid (pH 7.35) was introduced. There was no effect at pH greater than 6 in the presence of metal ions nor was the effect mimicked by cerebrospinal fluid acidified with HCl or phosphate buffer to pH 4.7. HCl and phosphate at pH 4.7 had partial effects (25-30%). Inhibition of carbonic anhydrase is well known to have a partial effect (approximately 50%), the remainder of normal flow being dependent on the uncatalyzed formation of HCO3- and the corresponding movement of Na+. The complete cessation of flow after exposure to Al or Ga ions appears to occur when these ions are perfused at pH where they are partly hydrolyzed. Under these circumstances they form very powerful proton generating systems (as shown by titration data), which could lower [OH-] at the secretory border of choroid plexus cells. As a result, both the catalyzed and the uncatalyzed processes for formation of HCO3- from CO2 are abolished and secretion stops. This mechanism may also account for the antiperspirant action of Al salts. Using metal ion hydrolysis to probe other secretory systems will also be of interest.

Acetazolamide↗
PubMed1984

Addition of the effects of norepinephrine and acetazolamide to decrease formation of cerebrospinal fluid.

In a system for ventriculocisternal perfusion of the choroid plexus, the rate of formation of new cerebrospinal fluid was measured by changes in dilution of an impermeant dye in the perfusate. Norepinephrine added to the perfusate decreased formation of cerebrospinal fluid in rats as was previously demonstrated in rabbits. The dose-response relationship for rats was determined. The formation rate was decreased 42% by 10(-3) M norepinephrine. Acetazolamide, 50 mg/kg i.v., caused a decrease of 46%. Given together, these drugs decreased formation 79%, demonstrating essentially full addition between the regulatory mechanisms involved. Addition of equal magnitude occurred when intraventricular nialamide, an inhibitor of monoamine oxidase, and i.v. acetazolamide were given together. This demonstrates addition between acetazolamide and endogenous norepinephrine (or other catecholamines present) in which metabolic breakdown is prevented by the inhibitor. The degree of reduction in cerebrospinal fluid formation seen in these experiments exceeds that reported for numerous other trials of single drugs.

Acetazolamide↗
PubMed1982

Cerebrospinal fluid formation in rats and cats during treatment with timolol.

The influence of timolol upon cerebrospinal fluid formation rate has been examined in rats by the measurement of 22Na+ entry into this fluid after 10, 100, or 1000 micrograms x kg-1 i.v. and in cats by the dye-dilution measurement of new fluid formation after 30, or 3000 microgram x kg-1 i.v., or 250 micrograms x mL-1 in ventricular perfusate. In rats no change from control rates occurred. In the cats there appeared to be no effect of intraventricular timolol; however, a significant decrease of approximately 25% in the mean flow rate was seen after 40 min when drug was given i.v. at either dose level. A time study showed that no further decrease occurred within 5 h and that the observed decrease continued for at least 3 h. These findings are of interest in view of the ability of topical, intraocular, and i.v. timolol to reduce aqueous humor formation rate.

Animals↗
PubMed1981

The effect of furosemide and bumetanide on cerebrospinal fluid formation.

Complete inhibition of carbonic anhydrase maximally reduces CSF flow 40-60%. We have confirmed that CSF flow in rabbits may be maximally decreased in this way by acetazolamide 30 mg/kg i.v., but have found only about 20% reduction from control after furosemide at 50 mg/kg i.v. This effect of furosemide is consistent with specific but partial inhibition of carbonic anhydrase of choroid plexus (and perhaps other sites of CSF secretion) based on the affinity of furosemide for carbonic anhydrase. Bumetanide, with 7 times lower affinity for carbonic anhydrase and 14-40 times higher inhibition of renal electrolyte transport processes than furosemide, did not decrease CSF flow.

Acetazolamide↗
PubMed1981

The effect of carbonic anhydrase inhibitors and other drugs on sodium entry to cerebrospinal fluid.

Single cerebrospinal fluid (CSF) samples, taken 7 min after the i.v. administration of tracer 22Na+, provided data for calculation of rate constants for entry of Na+ into CSF from plasma. Four carbonic anhydrase (CA) inhibitors and certain other drugs were studied in terms of 1) ability to reduce the entry of Na+ into CSF and 2) level of drug in plasma. Dose-response curves were generated for the CA inhibitors. Complete CA inhibition in this system is defined by kin 0.017 to 0.019 min-1, a reduction of about 35% from the control kin for Na+. Acetazolamide, ethoxzolamide and methazolamide were fully inhibitory at 20 mg/kg. Significant decreases, approximately 19%, were caused by 2 mg/kg of acetazolamide or ethoxzolamide; methazolamide unaccountably was less effective at this dose. Benzolamide was relatively inactive, but gave full effect at 150 mg/kg. The diuretics furosemide and bumetanide and the steroid dexamethasone showed no activity against Na+ entry. In considering these responses, attention is given to drug affinity for CA and to properties affecting access of inhibitors to CSF-secreting sites. There is a well recognized correlation between the movement of Na+ from plasma into CSF and the secretion of CSF. These data may, therefore, be taken as indicators of the relative ability of the drugs to decrease CSF flow.

Animals↗
PubMed1980

The relation of choroid plexus carbonic anhydrase activity to cerebrospinal fluid formation: study of three inhibitors in cat with extrapolation to man.

Drugs which inhibit carbonic anhydrase (CA) reduce cerebrospinal fluid (CSF) flow. This study relates the inhibition of CSF flow in cats after 1 to 30 mg/kg of methazolamide, acetazolamide or benzolamide (inhibitors of differing pharmacokinetic properties) to plasma and choroid plexus levels of these drugs. From plasma concentrations of unbound drug and the dissociation constants for the interaction of drugs with choroid plexus CA, it is shown that the concentration of residual active CA in choroid plexus of cats must be reduced from approximately 22 microM to the range of 5 to 10 nM to reduce CSF flow significantly. This represents at least 99.95% inhibition of CA of choroid plexus. This level of inhibition was achieved by an i.v. dose of 30 mg/kg of methazolamide, acetazolamide or benzolamide, whereas doses of 10 mg/kg of methazolamide or acetazolamide did not significantly decrease mean residual CSF flow. The data suggest that it is the residual flow after inhibition, not the absolute or percentage of decrease in flow, which should be used to evaluate the effectiveness of CA inhibition, because of the variability in individual control rates. Maximal effects of CA inhibition in cat reduce flow to 9 to 11 microliter/min from a mean of 21.7 microliter/min. In choroid plexus of man, the CA concentration is, at most, 40% that of cat. An attempt has been made to use CA concentration, drug binding data and other pharmacokinetic factors in predicting appropriate choices of drug and dose for man, extrapolating from the data for cats. These predictions are compared to existing data for plasma levels or CSF effects of CA inhibitors in man.

Acetazolamide↗
PubMed1979

Some measurements of autonomic nervous system influence on production of cerebrospinal fluid in the cat.

The effects on cerebrospinal fluid (CSF) production of specific agonists and antagonists for the autonomic nervous system were studied during ventriculocisternal perfusion in cats. Both carbachol and phenylephrine increased the rate of CSF formation 11 microliter/min from control rates of 17 and 11 microliter/min, resepctively; albuterol increased formation 6 microliter/min above the control 16 microliter/min. Atropine or phentolamine administered alone caused slight but significant decreases in CSF production; propranolol had no effect. All three antagonists reduced the changes in fluid formation elicited by their respective agonists. Atropine also blocked the action of phenylephrine. Hemicholinium-3, which reduced the synthesis of acetylcholine, sharply attenuated the increase caused by phenylephrine. These observations were taken to indicate that phenylephrine increased CSF production by stimulating a cholinergic pathway to the choroid plexus. Bilateral electrical stimulation of the cervical sympathetic trunks decreased CSF formation. Agents which increased CSF production caused no significant changes in cerebral or choroid plexus blood flow, possibly indicating that their effect is a direct action on the choroid plexus secretory mechanisms.

Animals↗
PubMed1976

The effect of acetazolamide on the movements of anions into the posterior chamber of the dog eye.

The rate of entry of bicarbonate and chloride ions the posterior chamber of the dog, a species that has both HCO3- and Cl- concentrations in excess of plasma in this chamber, was measured in order to clarify the mechanisms involved in the produciton of aqueous humor. Four animals were given H14CO3- and 36Cl- intravenously first in a control series and then after pretreatment with acetazolamide, (50 mg/kg), a carbonci anhydrase inhibitor. Samples were taken from arterial blood and the posterior chamber. Acetazolamide did not affect chloride entry into the posterior chamber but bicarbonate entry was decreased about 50%. It is concluded that in this species, bicarbonate is the key anion for the decrease of aqueous humor production caused by the administration of acetazolamide.

Acetazolamide↗
PubMed1976

The effect of acetazolamide on the movement of sodium into the posterior chamber of the dog eye.

The rate of appearance (entry) of 22Na into the posterior chamber of the eye was determined in eight dogs under control conditions and again after pretreatment with acetazolamide, 50 mg/kg i.v. In comparison with the paired controls, pretreatment with acetazolamide decreased the average rate of entry of 22Na by 29% during the first 3 minutes after the intravenous administration of a tracer dose of the isotope. In separate experiments, the volumes of the chambers of the dog eye and the rate of aqueous humor formation were determined for the purpose of calculating nascent fluid ion concentrations. Comparisons of sodium data with the previously reported anion data are made. Results support the suggestion that reduction of intraocular pressure caused by acetazolamide is partially, if not wholly, the result of the action of the drug to reduce the secretion of aqueous humor.

Acetazolamide↗
PubMed1975

Sodium, chloride, and bicarbonate movement from plasma to cerebrospinal fluid in cats.

Rate constants have been determined for the entry of 22Na+, 36Cl minus, and H14CO3- into CSF from plasma in cats during changes in Pco2 with and without inhibition of carbonic anhydrase. The application of these rate constants to movement of unlabeled electrolytes suggests that Na+ and Cl minus enter CSF by a one-way flux into newly formed fluid, but that entering HCO3-is involved both in net accumulation in new fluid and in rapid exchange with existing HCO3-. The entering HCO3-ions are not transferred from plasma but are formed in secretory cells from dissolved CO2. The exchange component of HCO3-entry is Pco2-dependent; entry of Na+ and Cl minus is not; hence net rate of HCO3-formation estimated by difference between Na+ and Cl minus is not Pco2 dependent. The net rate of HCO3-formation lies within the availability of CO2 from blood flow to choroid plexus but is not necessarily limited to this tissue. When carbonic anhydrase is inhibited, the net rate of formation of HCO3-is close to the calculated uncatalyzed rate expected for choroid plexus. The entry of all three ions is reduced by carbonic anhydrase inhibition, but the enzyme does not seem to provide the primary signal for alteration of CSF acid-base status. Regulation of CSF pH appears to be achieved through changes in HCO3-concentration that occur subsequent to the secretion of HCO3--rich new fluid.

Acetazolamide↗