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Biomedical subjects

M K Menon

Publications and source records attributed to M K Menon.

At least 19 recordsLinked to original sources
PubMed2001

Long-term blood pressure control in a cohort of peritoneal dialysis patients and its association with residual renal function.

BACKGROUND: Hypertension is the prime contributor for cardiovascular mortality in the dialysis population. Peritoneal dialysis (PD) has been thought to improve blood pressure (BP) control in the short term, but the long-term benefits are not conclusively proven. We aimed to evaluate the degree of BP control in PD patients in the long term and analyse the factors associated with poor control. METHODS: Data of all patients who were initiated on PD at one centre between July 1994 and July 1998 and completed at least 1 year of PD were analysed retrospectively at initiation of PD, at 6 months, and annually thereafter until 5 years or until discontinuation of therapy. Hypertension was defined as per WHO/ISH criteria. A 'Blood Pressure Control Index' was empirically defined to account for the effect of antihypertensives on measured BP. Factors associated with poor BP control were analysed. RESULTS: Out of 207 patients (age 57.0+/-16.0 years, 103 male, 104 female) 91.3% were hypertensive at the start of PD. About 33.8% had diabetic nephropathy. Systolic and mean arterial pressure index improved in early phase reaching a nadir between 6 months and 1 year followed by steady progressive worsening through out the rest of follow up. On multiple linear regression analysis age (P<0.001), duration of hypertension prior to dialysis (P<0.001), and declining residual renal function, expressed as both average of urea and creatinine clearance (P=0.002) and residual urine output (P<0.001) were independently associated with poor BP control. Diabetes (P=0.836), peritoneal transport (D/P 4 of creatinine at start) (P=0.218), peripheral oedema (P=0.479) and dose of erythropoetin (P=0.488) were not associated. CONCLUSIONS: Initiation of PD results in early improvement of hypertension in end-stage renal disease (ESRD). BP control thereafter deteriorates steadily with time and this is associated with age, duration of hypertension, and declining residual renal function. This suggests that hypertension in ESRD patients is a progressive disease primarily related to falling glomerular filtration rate, the preservation of which might improve BP control and possibly modify cardiovascular risk.

Adult↗
PubMed2000

Determination of effective protein charge by capillary electrophoresis: effects of charge regulation in the analysis of charge ladders.

Protein charge ladders are an effective tool for measuring protein charge and studying electrostatic interactions. However, previous analyses have neglected the effects of charge regulation, the alteration in the extent of amino acid ionization associated with differences between the pH at the protein surface and in the bulk solution. Experimental data were obtained with charge ladders constructed from bovine carbonic anhydrase. The protein charge for each element in the ladder was calculated from the protein electrophoretic mobility as measured by capillary electrophoresis using the hindrance factor for a hard sphere with equivalent hydrodynamic radius. The protein charge was also evaluated theoretically from the amino acid sequence by assuming a Boltzmann distribution in the hydrogen ion concentration. The calculations were in excellent agreement with the data, demonstrating the importance of charge regulation on the net protein charge. These results have important implications for the use of charge ladders to evaluate effective protein charge in solution.

Animals↗
PubMed1999

Effect of ion binding on protein transport through ultrafiltration membranes.

Electrostatic interactions can have a significant impact on protein transmission through semipermeable membranes. Experimental data for the transport of bovine serum albumin (BSA) through a polyethersulfone ultrafiltration membrane were obtained in different salt solutions over a range of pH and salt concentrations. Net BSA charge under the same conditions was evaluated from mobility data measured by capillary electrophoresis. The results show that specific ionic composition, in addition to solution pH and ionic strength, can strongly affect the rate of protein transport through semipermeable ultrafiltration membranes. The effects of different ions on BSA sieving are due primarily to differences in ion binding to the protein, which leads to significant differences in the net protein charge at a given pH and ionic strength. This effect could be described in terms of an effective protein radius, which accounts for the electrostatic exclusion of the charged protein from the membrane pores. These results provide important insights into the nature of the electrostatic interactions in membrane systems.

Animals↗
PubMed1998

Measurement of protein charge and ion binding using capillary electrophoresis.

A new technique is described for the rapid and accurate measurement of electrophoretic mobilities of proteins in different solution environments using capillary electrophoresis. Data were obtained at different pH using surface-modified capillaries to reduce nonspecific protein adsorption and using hydrodynamic mobilization to improve reproducibility and overall accuracy. The net protein charge and extent of anion binding were evaluated from the mobility data obtained in different pH and ionic environments for bovine serum albumin. The results were in good agreement with titration data obtained using ion-selective electrodes and mobility data obtained using free solution electrophoresis. The method requires extremely small amounts of protein (picogram quantities and nanoliter volumes) and is easily automated, making it very suitable for protein characterization and for initial screening of possible separation techniques.

Adsorption↗
PubMed1990

Antagonism of the hypothermic effect of clozapine in mice by centrally-active alpha 2-adrenergic antagonists and alpha 1-adrenergic agonists.

Hypothermia induced by either clozapine or clonidine in mice was blocked by the alpha 2-adrenergic antagonists yohimbine, idazoxan, CH-38083, SKF 86466, and L-657,743. These effects were dose related, and the ID50 values for inhibition of clozapine- or clonidine-induced hypothermia were fairly comparable. The order of potency for blocking clonidine-induced hypothermia was: L-657,743 greater than CH-38083 greater than yohimbine greater than idazoxan greater than SKF 86466. A very similar blockade hierarchy for clozapine-induced hypothermia was observed, with the order of the two most effective compounds being reversed. Hypothermia induced by either compound was not blocked by the peripherally-acting, selective alpha 2-adrenergic antagonist, L-659,066, indicating that blockade by the other compounds occurred centrally. The centrally-acting, alpha 1-adrenergic agonists St 587, cirazoline, and SKF 89748 were very effective in blocking the response to clozapine, but ineffective in antagonizing clonidine-induced hypothermia. The ED50 values for the blockade of this response to clozapine, however, did not correlate with their reported potencies in stimulating either peripheral or central alpha 1-adrenergic receptors. This indicates that clozapine-induced hypothermia in mice is not a suitable model for evaluating the properties of central alpha 1-adrenergic compounds. Moreover, since the clonidine-induced hypothermia is not influenced by alpha 1-adrenergic agonists, this paradigm is preferable to clozapine-induced hypothermia in the assessment of alpha 2-adrenergic antagonism The ability of alpha 2-adrenergic antagonists to block clozapine-induced hypothermia may result from the central overflow of norepinephrine, which is known to be brought about by this group of compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1990

Effect of BMY 21502 on acquisition of shape discrimination and memory retention in monkey.

BMY 21502 is a novel pyrrolidinone nootropic with demonstrated ability to reverse electroconvulsively induced amnesia in rodents. We administered BMY 21502 intramuscularly to four monkeys (Macaca radiata) during testing using two separate paradigms. The first test involved the acquisition of a visual shape discrimination task where each monkey learned to select the correct lighted panel. In the second task, memory retention was tested by having the monkeys select and press the correct lighted panel using a delayed matching-to-sample procedure. A dose-response relationship was established for the acquisition of shape discrimination for each monkey. Two performance-enhancing doses in the visual discrimination task were then employed to test for effects on memory retention at different delay intervals in the delayed-matching-to-sample task. Results indicate that BMY 21502, when administered over a wide dose range, enhanced acquisition of shape discrimination in three of four monkeys when combined drug scores were compared to vehicle-only scores (p less than 0.02). However, BMY 21502 produced no significant improvement in memory retention at any of seven different delay intervals when low-dose and high-dose scores for the three responding monkeys were compared to vehicle-only scores.

Animals↗
PubMed1989

Involvement of noradrenergic system in a remarkably rapid tongue clonus produced by acute hypnotic doses of ethanol in Fischer F344 rats.

Ethanol (2.95 g/kg, IP) eliminated the righting reflex and induced vigorous tongue clonus spontaneously or following tactile tongue stimulation in Fischer F344 rats. Responses normally lasted 30-60 min, and was reinstated by tactile stimulation in those cases where it subsided quickly. Sub-hypnotic (1.95 g/kg) or high (3.95 g/kg) doses failed to elicit clonus, even after tactile stimulation. A lipophilic alpha 1-adrenergic agonist (St 587) promptly initiated tongue clonus in rats treated with a 3.95 g/kg dose of ethanol. Prazosin, a selective alpha 1-adrenergic antagonist, blocked clonus, while the dopamine selective antagonist pimozide failed to modify this response. We infer an alpha 1-adrenergic effect in which norepinephrine is released by ethanol.

Animals↗
PubMed1988

Interaction between clozapine and a lipophilic alpha 1-adrenergic agonist.

Acute intraperitoneal injection of clozapine produced marked hypothermia and ataxia in Swiss-Webster mice. These two effects were almost completely blocked by the lipophilic alpha 1-adrenergic agonist, St 587, but not by the peripherally-acting alpha 1 agonist methoxamine. It was inferred that these effects of clozapine are central in origin and probably resulted from alpha 1 adrenergic blockade. However, since prazosin, a selective alpha 1-adrenergic antagonist did not elicit either hypothermia or ataxia in mice it became clear that the alpha 1 adrenergic blocking effect of clozapine is not entirely responsible for these effects, but has a major contributory role in their production. Both clozapine and prazosin inhibited the d-amphetamine-induced locomotor stimulation in mice. St 587 did not significantly reduce this amphetamine-blocking effect of clozapine. It was inferred that this response to d-amphetamine involving the release of mesolimbic dopamine is distinct from the other two St 587-sensitive responses. The hypothermic and ataxic effects of clozapine developed complete tolerance after just four days of treatment, but ten days of such treatment was required for the development of tolerance to the amphetamine-blocking effect of clozapine. The possible relationships between St 587-sensitive and insensitive effects of clozapine and its antipsychotic property are discussed.

Adrenergic alpha-Agonists↗
PubMed1988

Influence of D-1 receptor system on the D-2 receptor-mediated hypothermic response in mice.

The hypothermia induced by apomorphine, a mixed dopamine (DA) agonist in male Swiss-Webster mice, was not blocked by the selective D-1 antagonist SCH 23390 but was completely blocked by the selective D-2 antagonists haloperidol, sulpiride and YM-09151-2. The selective D-1 agonist SKF 38393 did not elicit hypothermic response but the selective D-2 agonist quinpirole caused a marked lowering of rectal temperature. D-2 antagonists blocked this response to quinpirole. SCH 23390 enhanced and SKF 38393 attenuated the hypothermia induced by quinpirole. Ineffective doses of haloperidol and SKF 38393, when given together, completely blocked the effect of quinpirole. It was concluded that hypothermia is a D-2 receptor mediated response but modulated by the D-1 receptor system. In another series of experiments the influence of neuroleptics and antidepressants on the hypothermic effect of apomorphine and quinpirole was investigated. The hypothermic effect of a low dose (1 mg/kg) of apomorphine was blocked by the D-2 receptor antagonists, but not by classical antidepressants. However, the response to a high dose (10 mg/kg) of apomorphine was blocked by both classical antidepressants and D-2 antagonists (except haloperidol). These drugs did not show similar effect on quinpirole-induced hypothermia. It is clear that the hypothermic response, especially that of quinpirole, is not a suitable model for testing either neuroleptics or antidepressants.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Modification of certain pharmacological effects of ethanol by lipophilic alpha-1 adrenergic agonists.

The influence of four centrally-acting alpha-1 adrenoceptor agonists, namely, 2(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587), cirazoline, (-) 1,2,3,4-tetrahydro-8-methoxy-5-methylthio-2-naphthalenamine ((-)SKF 89748A) and 2-(2-methylindazol-4-imino)imidazolidine (Sgd 101/75) on the pharmacological effects of ethanol was investigated. All four drugs reduced the duration of ethanol-induced hypnosis in C57B1/6 mice, this effect being proportional to their relative potencies to exert central alpha-1 agonism. In prazosin-pretreated mice, St 587 failed to reduce the hypnotic effect of ethanol, which provided strong evidence for the role of alpha-1 agonism for the hypnosis reducing effect of St 587. Hyperactivity induced in C57B1/6 mice by a subhypnotic dose of ethanol and St 587 was reported earlier. In the present study, St 587, cirazoline and (-)SKF 89748A produced similar response, but no correlation between this effect and ethanol hypnosis blockade could be established. Interestingly, this hyperactivity response was not exhibited by Swiss-Webster, BALB/c or DBA-2 mice--strains in which St 587 exerted little or no antagonism to ethanol-induced hypnosis. Of the alpha-1 agonists, only St 587 reduced the ethanol-induced hypothermia in C57B1/6 mice. St 587 also blocked this effect of ethanol in BALB/c mice in which this drug failed to reduce the ethanol-induced hypnosis. It was concluded that ethanol-induced hypothermia and hypnosis are not interrelated. None of the alpha-1 agonists modified the pentobarbitone-induced hypnosis or the rate of elimination of ethanol in C57B1/6 mice. In this strain, the reduction of the duration of ethanol-induced hypnosis by the alpha-1 agonists is a selective and centrally-mediated response.

Adrenergic alpha-Agonists↗
PubMed1986

An in vivo pharmacological method for the quantitative evaluation of the central effects of alpha 1 adrenoceptor agonists and antagonists.

A new in vivo pharmacological method for the quantitative evaluation of alpha 1-adrenoceptor agonists and antagonists has been developed. It consists of recording the myoclonic twitch activity (MTA) of the suprahyoideal muscle of rats anesthetized with urethane. In these animals, the isomers of amphetamine elicited myoclonic twitch activity; their effects were dose-related and the d-isomer was approximately 3.5 times more effective than the l-isomer. While pimozide did not block this response, the postsynaptic alpha 1-antagonist prazosin fully blocked the myoclonic twitch activity induced by d-amphetamine. Other postsynaptic alpha 1-antagonists, such as haloperidol, phenoxybenzamine and clozapine, were also effective in blocking this response to d-amphetamine. Since d-amphetamine elicited myoclonic twitch activity in rats pretreated with reserpine and alpha-methyl-p-tyrosine, it was concluded that d-amphetamine exerted a direct alpha 1-adrenoceptor stimulation. In rats pretreated with nialamide and pimozide, l-DOPA elicited myoclonic twitch activity which was dose-related. This effect of l-DOPA was promptly and fully blocked by prazosin. It was concluded that this response to l-DOPA resulted from stimulation of alpha 1-adrenoceptors. The relative potencies of four alpha 1-adrenoceptor stimulants, namely, cirazoline, St-587, (-)SKF 89748A and Sgd 101/75 were determined using this method. The results correlated very well with their relative potencies to increase the diastolic blood pressure of pithed rats. Evidence that myoclonic twitch activity is a centrally-mediated response has also been presented. It appears that the method is a simple, sensitive, versatile and easily quantifiable procedure for the evaluation of the central effects of alpha 1-adrenoceptor agonists and antagonists.

Adrenergic alpha-Agonists↗
PubMed1985

Further studies on the ethanol antagonism exhibited by 2(2-chloro-5-trifluoromethyl phenylimino) imidazolidine (St 587).

A lipid soluble alpha 1-adrenoceptor agonist 2-(2-chloro-5-trifluoromethyl phenylimino) imidazolidine (St 587) dose-dependently antagonized the hypnotic, hypothermic and respiratory depressant effects of ethanol in C57B1/6 mice. This effect was present whether St 587 was given before or after ethanol. St 587 did not block the pentobarbitone-induced hypnosis. It also did not influence the elimination of ethanol. Combined treatment with a subhypnotic dose of ethanol and St 587 resulted in marked hyperactivity in mice. This effect was completely abolished by pimozide pretreatment. It was inferred that the dopamine released from brain areas by this dose of ethanol together with the norepinephrine receptor activation offered by St 587 resulted in this hyperactivity. Cirazoline, a more potent alpha 1-adrenoceptor agonist than St 587 was relatively more effective than the latter in blocking the ethanol-induced hypnosis in mice. It seems that alpha 1-adrenoceptor stimulation is a major contributing factor to the ethanol antagonism exerted by St 587. This drug might prove to be useful in the treatment of acute ethanol intoxication and in understanding the mode of action of ethanol.

Animals↗
PubMed1985

Antagonism of the hypnotic effect of ethanol in mice by an alpha-1 adrenoceptor agonist.

A lipid soluble alpha 1-adrenoceptor agonist 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587) antagonized the hypnotic effect of ethanol in C57Bl/6 and CD-1 mice. In Swiss-Webster mice the effect of St 587 was weak and in BALB/c mice this drug potentiated ethanol hypnosis. St 587 did not enhance the elimination of ethanol. Cirazoline, an alpha 1-adrenoceptor agonist which is more potent than St 587, was relatively more effective in antagonizing the ethanol-induced hypnosis. Though it appears that St 587 exerted its ethanol antagonism by virtue of its alpha 1-adrenoceptor agonistic effect, other contributing factors may also have to be considered. St 587 may prove to be of value in understanding the mechanism of action of ethanol and in the treatment of acute ethanol intoxication.

Adrenergic alpha-Agonists↗
PubMed1984

Evidence for presynaptic antagonism by amantadine of indirectly acting central stimulants.

In mice, amantadine pretreatment (150 mg/kg, but not 10 mg/kg, 2 h prior to testing) markedly inhibited the locomotor stimulation produced by submaximal doses of d-amphetamine, amfonelic acid, methylphenidate, caffeine, memantin, phencyclidine, and cocaine. A 50-mg/kg dose was ineffective in blocking the effects of caffeine and memantin, but blocked the responses to the other five stimulants. Amantadine did not modify the locomotor stimulant effect of apomorphine in reserpinized mice. These results indicate that amantadine acts as a presynaptic antagonist to the above seven stimulants. Even the highest dose of amantadine did not modify the hyperactivity induced in mice by morphine and levorphanol. This result is consistent with evidence showing opiate actions at postsynaptic striatal neurons, sites where presumably amantadine is unable to exert an antagonist effect. Amantadine did not modify the central depressant effects of ethyl alcohol and pentobarbital. Amantadine could be of value as a pharmacological tool in understanding the mode of action of central stimulants, and in the management of stimulant abuse. The present data do not support the currently held view that the antiparkinsonism effect of amantadine results from its ability to potentiate the central effects of dopamine.

Amantadine↗
PubMed1984

Suitability of amfonelic acid-induced locomotor stimulation in mice as a model for the evaluation of classical and atypical antipsychotics.

The potential usefulness of amfonelic acid ( AFA ), a selective dopamine (DA)-releasing agent, in quantitatively assessing the antidopaminergic and antipsychotic potencies of drugs, was evaluated. The procedure consisted of determining the ED50S of a number of neuroleptics in inhibiting the locomotor-stimulant effect of amfonelic acid in mice. These results were compared with the published data on the relative potencies of the neuroleptics to induce catalepsy in rats, to block drug-induced stereotypy and to alleviate psychotic symptoms clinically. It was observed that the amfonelic acid model was as good as, but not superior to, the other three procedures in identifying the potencies of classical antipsychotics. This model, however, was able to predict the clinical effectiveness of two atypical antipsychotics, thioridazine and clozapine, much more accurately than could be achieved by the other methods. Certain other atypical antipsychotics such as, mezilamine , RMI 81, 582, sulpiride and sultopride also produced a dose-related blockade of the amfonelic acid induced locomotor stimulation in mice. The antagonism to amfonelic acid exhibited by mezilamine was weaker, and that of RMI 81,582 was stronger than that of chlorpromazine. Only large doses of the two benzamides were effective in blocking the effect of amfonelic acid, sultopride being about 3 times more effective than sulpiride in this regard. Another analogue of benzamide, YM-09151-2, known to have the profile of a classical antipsychotic, was more effective than haloperidol in blocking the stimulant effect of amfonelic acid. Trebenzomine , which is considered to have the properties of an atypical antipsychotic, although this was proved otherwise when tested clinically, actually potentiated the response of mice to amfonelic acid. Apomorphine antagonized the stimulant effect of amfonelic acid, which could be attributed to its agonist activity at presynaptic DA receptors. Apomorphine has been reported to have clinical antipsychotic effects. Certain non-antipsychotic drugs such as prazosin (but not phenoxybenzamine), promethazine, methysergide, diazepam, as well as the gamm -aminobutyric acid agonists, muscimol and THIP, also inhibited the amfonelic acid-induced locomotor stimulation. In spite of this drawback, the present procedure should prove to be a useful animal model for the evaluation of the antipsychotic potencies of drugs. Its ability to identify the potential usefulness of atypical antipsychotics is noteworthy.

Animals↗
PubMed1984

Pharmacological studies on the antagonism by antidepressants of the hypothermia induced by apomorphine.

In male Swiss mice, the hypothermia induced by apomorphine (10 mg/kg) was completely blocked by administration of haloperidol and d-butaclamol, but not by l-butaclamol, phenoxybenzamine, clozapine or propranolol. This substantiated the dopaminergic nature of the hypothermia induced by apomorphine. Desipramine, imipramine, chlorimipramine, fluoxetine and mazindol produced a dose-dependent blockade of apomorphine-induced hypothermia, their ED50S being 0.313, 0.733, 1.88, 6.04 and 0.0033 mg/kg, respectively. Iprindole failed to block the hypothermia induced by apomorphine. Because chlorimipramine and fluoxetine, which are relatively more selective and more potent blockers of the uptake of serotonin (5-HT) than is desipramine, were considerably less effective than the latter in antagonizing hypothermia induced by apomorphine, it was concluded that the property of blocking uptake of 5-HT alone does not contribute to the antagonism to apomorphine exhibited by the classical antidepressants. Quipazine, a 5-HT agonist, blocked the hypothermia induced by apomorphine, this effect developed tolerance on repeated administration. However, no cross-tolerance between quipazine and the antidepressants could be demonstrated. This finding provided further support for the non-involvement of 5-HT in the antagonism to apomorphine. No correlation existed between the potencies of these antidepressants to block the reuptake of norepinephrine (NE) in brain and their relative potencies to block the hypothermia induced by apomorphine. Moreover, selective depletion of high affinity binding sites for [3H]desipramine and [3H]-NE, achieved by treatment with DSP-4, failed to reduce the effectiveness of desipramine in blocking the hypothermia induced by apomorphine. Hence, inhibition of uptake of NE does not account for the antagonism by the antidepressants of apomorphine-induced hypothermia. A possibility was considered that certain antidepressants selectively blocked the hypothalamic DA receptors, thereby antagonizing the hypothermic effects of apomorphine, leaving the extra-hypothalamic dopaminergic responses of this DA agonist unaffected.

Animals↗
PubMed1982

Gamma-hydroxybutyrate in experimental myoclonus.

In Swiss mice, muscimol (3 mg per kilogram, intraperitoneally) caused myoclonic jerks of the hindquarters. These jerks were strong, repetitive, more or less regular, and of high frequency (peak response, 76 per minute). Pretreatment with sodium gamma-hydroxybutyrate (50 to 200 mg per kilogram) caused a dose-dependent blockade of these jerks. This drug also nullified an already developed muscimol response. All of the drugs currently being used in the management of postanoxic action myoclonus (Lance-Adams syndrome) block this response of muscimol. Gamma-hydroxybutyrate may be of value in the management of Lance-Adams syndrome and other forms of myoclonus.

Animals↗