Asunto(s)

RESUMEN

Of the world's five billion people, 75% of whom live in developing countries, 25-50% have little or no access to basic pharmaceuticals. To ensure an adequate supply of safe and effective drugs of good quality, a national drug policy (NDP) should be incorporated into the national health policy. Elements of a NDP include: identification of therapeutic needs; objective selection of essential drugs; drug supply and distribution system; effective legislation and regulation; quality assurance; manpower development; and dissemination of drug-related information. Drug availability does not ensure their rational prescribing or dispensing or appropriate patient use. It is proposed that a flexible multi-disciplinary curriculum be established for healthcare professionals and students and public policy formulators to provide instruction in NDP elements and the principles of rational drug use. Such courses may stimulate multi-disciplinary drug-related scholarly activities.

Asunto(s)

Asunto(s)

RESUMEN

Experiments were designed to gain information on the mechanisms leading to diabetic urinary bladder dysfunction. Bladders from control rats, animals subjected to 4-5 wk streptozocin-induced diabetes, and rats subjected to equivalent diuresis produced by 5% sucrose feeding were studied with an in vitro whole-bladder preparation and neurochemical measurements. The diuretic group was used to distinguish alterations produced by metabolic effects on nerve and muscle from those induced by prolonged periods of excessive diuresis. Diuresis alone explains many of the diabetes-induced effects, including decreased norepinephrine levels, postsynaptic supersensitivity for sympathetic regulation of bladder storage, decreased responsiveness to parasympathetic regulation of emptying, and enhanced prostaglandin F2 alpha-induced contraction. Other diabetes-induced effects were not observed in the diuretic controls and are presumed to result from metabolic alterations associated with diabetes. These effects were decreases in norepinephrine uptake and in choline acetyltransferase activity, both markers of nerve terminal function. Thus, diuretic and metabolic factors appear to contribute to the early signs of parasympathetic and sympathetic neuropathy. In contrast, we found no evidence for loss of sensory nerve function in the diabetic bladder, at least at the organ level, because no diabetes- or diuresis-induced changes were observed in responsiveness to substance P or capsaicin.

Asunto(s)

RESUMEN

In a previous study we investigated the effects of age on the micturition characteristics and bladder function of male Fischer rats ages five to seven, 16 to 18 and 22 to 24 months. The 24 hr. water intake and urine output increases significantly with age; 22 to 24 month rats showed a 39% increase in water intake and a 93% increase in urine output compared to five to seven month rats. The intravesical pressure at micturition is 100% greater in 22 to 24 month and 16 to 18 month rats compared to five to seven month old rats with no age-related change in bladder volume at micturition. In the present study, in vitro bladder capacity did not differ between the three age groups although the average plateau pressure significantly decreased with advancing age. Using the isolated whole bladder model, the contractile response to the autonomic agonists bethanechol, phenylephrine, and isoproterenol did not change significantly with age. Similarly, there were no age-related changes in the response of the bladder to non-autonomic drugs (histamine, oxytocin, serotonin, substance P, and PGF2 alpha) except for PGF2 alpha which produced an age-related increase in the maximum bladder contraction. In summary, while in vivo micturition clearly changes with age, the in vitro contractility of the bladders to autonomic agents did not. Therefore, age related differences in micturition would be related primarily to the changes in neuronal innervation and central control of micturition rather than alterations in the contractility of the bladder. In addition, these studies show the importance of correlating in vivo bladder function (micturition frequency and volume, cystometry and urodynamics) with in vitro contractile and functional studies.

Asunto(s)

RESUMEN

1. A comparison was made of the proposed neurotoxic effects of acrylamide, capsaicin, and diabetes on rat urinary bladder pressure responses elicited by infusion of buffer into the organ (distension). 2. Treatment with capsaicin or acrylamide completely abolished the bladder pressure responses. 3. After 4 weeks of diuresis equivalent to that of the diabetic model, the pressure response was markedly diminished compared to control. This response was greatly increased following L-DOPA, which augments the micturition reflex. 4. After 4 weeks of streptozoticin-induced diabetes, the pressure response was slightly diminished compared to control and most closely resembled the response from the diuretic group treated with L-DOPA.

Asunto(s)

RESUMEN

Studies were done to characterize the bladder dysfunction associated with diabetes mellitus and to distinguish between changes occurring from increased diuresis and autonomic neuropathy. Four experimental conditions were compared: control, 4-wk-streptozocin-induced diabetes, sucrose feeding (diuretic), and galactose feeding (diuretic and sugar alcohol). A 10-fold increase in urine output and 25-50% increases in bladder weight, protein content, and DNA content were observed in all noncontrol treatment groups. Compliance properties were studied by measuring the intravesicular pressure as the bladder was infused with buffer in vitro. All treated bladders exhibited a reduction in plateau pressure and an increase in fluid capacity. Thus, diuresis results in an increased bladder size, which correlates with an alteration of compliance properties. Nervous system control in anesthetized rats was examined by monitoring contractions as the bladder was infused with buffer. Three distinct patterns of response were observed: normal, diabetic, and diuretic (galactose and sucrose treatments). The difference between responses in diuretic and diabetic animals suggests the presence of a diabetes-induced alteration in nerve regulation of the bladder. Reserpine pretreatment of control or diuretic models produced marked changes in the pattern of contractions, whereas pretreatment of diabetic rats had only modest effects. This suggests that diabetic bladders were lacking sympathetic control before the drug treatment. When rats treated for 4 wk with galactose were removed from this diet for 4 wk before testing, the bladders responded similarly to controls. This observation, coupled with the fact that galactose did not produce the same response as diabetes in the in vivo experiment, suggests that the galactose model does not produce irreversible functional neuropathies.

Asunto(s)

RESUMEN

Neurochemistry of the base and body of the rat urinary bladder was compared for both adrenergic and cholinergic parameters using Fischer 344 rats. In bladder base and body, respectively, the concentration (pmol./mg. wet weight) of norepinephrine was 23.4 and 2.16, of acetylcholine was 26.7 and 18.3, and of choline was 96.7 and 199. The activity (nmol./mg. protein/hour) of tyrosine hydroxylase was 422 and less than 50, of monoamine oxidase was 80.6 and 126, of choline acetyltransferase was 17.4 and 11.5, and of acetylcholinesterase (nmol./mg. wet weight/hour) was 485 and 165. Treatment with alpha-methyl-p-tyrosine did not alter norepinephrine concentration in bladder base but decreased it by 27% in bladder body. Studies were also done to determine whether age-related changes exist in the adrenergic and cholinergic neurochemistry of the rat urinary bladder. Bladders from rats of 6-7, 15-17, and 22-24 mo. of age were examined. The only age-related differences noted were a progressive decrease in level of monoamine oxidase activity in both bladder regions and an increase in bladder base norepinephrine concentration from 6-7 to 15-17 mo. followed by a decrease at 22-24 mo. Overall, the results show marked regional variations in bladder neurochemistry which remain remarkably stable as the animals grow old.

Asunto(s)

RESUMEN

The effects of age on micturition in male Fischer 344 rats, ages five to seven, 16 to 18 and 22 to 24 months, were studied. The 24 hr. water intake, 24 hr. urine output, frequency and volume of each micturition were obtained from rats housed individually in metabolic cages. Intravesical pressure and volume at which the micturition contraction occurred were evaluated using natural-fill cystometry. The 24 hr. water intake and urine output increased significantly with advancing age; 22 to 24 months rats showed a 39% increase in water intake and a 93% increase in urine output compared to five to seven month rats. The increase in urine output observed in the 22 to 24 month old rats was manifested by a 95% increase in volume per micturition and a 52% increase in frequency of micturition compared to five to seven month old rats. The pressure at micturition (PAM) was 100% greater in 22 to 24 and 16 to 18 month old rats compared to five to seven month old rats with no age-related difference in bladder volume at micturition (BVM). These studies demonstrate that in vivo micturition changes with age in the male F344 rat. Although there were no overt urological dysfunctions observed in the aging rats, the alterations in function would indicate that there were changes in either the mechanisms controlling micturition, or changes in the musculature itself. These possibilities will be the subject of further investigations.

Asunto(s)

RESUMEN

The effects of age on the responsiveness of the body of the urinary bladder and base of the bladder to alpha-adrenergic agonists were studied. Regions of the bladder were isolated from Fischer 344 rats, ages 7, 16, and 27 months. Maximum isotonic contractions elicited by potassium chloride (KCl) in both regions of the bladder were unaffected by age. In the bladder body there was an age-related increase in the maximum contraction elicited by phenylephrine, norepinephrine and clonidine. No such alteration in responsiveness was observed in the base of the bladder with age. The ED50 values of all three agonists were unchanged with age in both regions of the bladder. The pA2 values of prazosin and yohimbine were approximately 8.5 and 6.0, respectively, in the body of the bladder, and these values were not altered by age. Thus, it is concluded that an age-related increase occurs in the responsiveness of the body of the bladder to alpha-adrenergic activation and that these changes are mediated by alpha 1-adrenoceptors.

Asunto(s)

RESUMEN

The effects of age on urinary bladder responsiveness to muscarinic agonists and on the Bmax and Kd of the binding of [3H]quinuclidinyl benzilate (QNB) to muscarinic receptors of the bladder were studied. Bladder bodies and bases were isolated from Fischer 344 rats, ages seven, 16 and 27 months. No age-dependent change in maximum KCl-elicited isotonic contractions was observed in either bladder region. The bladder base showed an age-dependent increase in the maximum contractions (Emax) elicited by muscarinic agonists. The Emax values for bladder bases from rats 27 months of age were 44 per cent, 58 per cent and 76 per cent greater than those from rats seven months of age for acetylcholine, bethanechol and oxotremorine, respectively. No such alteration in responsiveness was observed in the bladder body with age. There were no age-related changes in ED50 values for the three agonists in either bladder region. Analysis of [3H]QNB binding in the bladder base demonstrated a modest 18 per cent increase in the Bmax (fmol./mg. tissue) from seven to 16 months and a significant 39 per cent decrease from 16 to 27 months. In the bladder body, the Bmax progressively increased by 25 per cent from seven to 27 months. The Kd values of [3H]QNB did not change with age in either region. The data demonstrate that the age-related increase in the responsiveness of the bladder is regionally specific and cannot be explained by a change in the number or affinity of muscarinic receptors.

Asunto(s)

RESUMEN

We have reported previously that after nialamide pretreatment there is an age-related difference in the stimulation of locomotor activity produced by the injection of dopamine bilaterally into the nucleus accumbens. Thus, the stimulation of locomotor activity produced by dopamine in old rats was significantly less than that of young and mature rats. The purpose of the present study was to determine whether nialamide was an effective inhibitor of the metabolism of dopamine after dopamine was injected into the nucleus accumbens of old rats. When we measured the concentration of injected dopamine in the limbic forebrain (nucleus accumbens and olfactory tubercle) of young (6 months), mature (15 months) and old (26 months) rats pretreated with nialamide, the amount of dopamine that was present was significantly less in old rats than in young or mature rats. Consistent with this observation, the concentrations of the dopamine metabolites, homovanillic acid and dihydroxyphenylacetic acid were higher in nialamide-pretreated old rats than in young and mature rats, suggesting that there was a smaller inhibition of the metabolism of dopamine in the limbic forebrain of old rats after nialamide pretreatment. In support of this hypothesis, nialamide (25-100 mg/kg i.p.), which inhibited monoamine oxidase activity in limbic forebrain homogenates of old, mature and young rats, was a less effective inhibitor of this enzyme in the old rats. These results suggest that the reduced locomotor activity response of old rats to the intra-accumbens injections of dopamine after nialamide pretreatment may be due to the reduced ability of nialamide to inhibit monoamine oxidase (and dopamine metabolism) in these animals.

Asunto(s)

RESUMEN

The response of the urinary bladder body and base to autonomic agents was studied in streptozocin (STZ)-diabetic rats. The bladder body region from 6-wk diabetic rats showed no changes in response to acetylcholine, phenylephrine, or isoproterenol. In contrast, the bladder base region showed a 39% increase in contractile response to acetylcholine and a 37% increased response to phenylephrine. In tissues from 47-wk diabetic animals, the bladder body showed a 51% increased contractile response to acetylcholine and a 37% increased relaxation response to isoproterenol. The bladder base showed a 66% increased contraction to acetylcholine. Thus, in the bladder base, enhanced responses to acetylcholine are detected soon after induction of diabetes and continue to increase as the diabetic state progresses. Moreover, in the same bladder region, an increase in responsiveness to alpha-adrenergic stimuli occurs. In the bladder body, enhanced responses to cholinergic and to beta-adrenergic stimuli occur, but are only observed in a more chronic diabetic state. The data suggest that an effect associated with autonomic diabetic neuropathy of the urinary bladder is an increased postsynaptic responsiveness to cholinergic stimuli in both regions.

Asunto(s)

RESUMEN

Age-related increases occur in the response of isolated urinary bladders to the parasympathetic neurotransmitter acetylcholine (ACh). Experiments were carried out to determine whether long-term elevation or diminution in the amount of ingested choline can also affect the response of the urinary bladder to ACh. Female C57BL/6J mice were maintained on a choline-deficient chow and on drinking water supplemented with either 0, 1.5, or 4.0 mg/ml choline chloride from 8 to 20 months of age. Isolated bladders from choline deficient animals showed a 46% increase in the maximum response to ACh as compared to those from normal choline animals, while bladders from animals on choline enriched diets showed a 15% decrease in maximum contractile response. Radioligand binding experiments suggested that the functional changes result from alterations in the density of muscarinic receptors in the bladder. The results are consistent with the hypothesis that muscarinic receptors are down-regulated to compensate for increased parasympathetic activity associated with choline-enriched diets and up-regulated to compensate for decreased parasympathetic activity associated with choline-deficient diets.

Asunto(s)

RESUMEN

The objective of this study was to determine the locomotor activity response of young (6 month), mature (15 month), and old (26 month) rats to bilateral intraaccumbens injections of dopamine after pretreatment with nialamide. Young and mature rats responded to dopamine with high rates of activity, while old rats either did not respond at all or responded with a lower intensity of activity. In contrast, the response of old rats to dopamine or ergometrine alone or to dopamine after pargyline pretreatment was not less than that of mature and young rats. These results suggest that the attenuated response of old rats to dopamine after nialamide pretreatment is not due to a decrease in dopamine receptor activity, but appears to be due to some unique property of nialamide in these animals. However, the reduced response of old rats to dopamine was not due to the inability of nialamide to inhibit monoamine oxidase, since nialamide completely inhibited the activity of this enzyme in the nucleus accumbens of old rats.

Asunto(s)

RESUMEN

Experiments were done to determine if age-related changes occur in autonomic regulation of rat urinary bladder. The maximum contractile responses to acetylcholine were 63% and 15% greater in isolated bladders from 29-month and 17-month animals, respectively, as compared to 7-month animals. The amounts of [3H]quinuclidinyl benzilate bound to membrane preparations were 46% and 7% greater. In contrast, no age-related changes were observed in phenylephrine-induced contraction or in isoproterenol-induced relaxation of bladder. Thus, the urinary bladder of aged rats appears to develop increased sensitivity to cholinergic stimuli because of an increase in the number of muscarinic cholinergic receptors.

Asunto(s)

RESUMEN

The studies were designed to evaluate the effects of methylphenidate on endurance performance in vivo and on neuromuscular transmission in the isolated rat phrenic nerve-diaphragm preparation. Methylphenidate produced a biphasic effect on treadmill endurance performance, increasing running times by 41-61% at 2.5-5 mg/kg, while reducing running times by 35% at 20 mg/kg. A biphasic effect on nerve-stimulated muscle concentrations was also observed, with twitch tension increased by up to 49-106% at low concentrations (0.1-0.3 mM) and blocked at high concentrations (0.6-1.0 mM). Tissues obtained from rats pretreated with alpha-methyl-p-tyrosine or reserpine exhibited no change in twitch height. Methylphenidate failed to protect against irreversible blocking of the twitch by alpha-bungarotoxin and did not modify the resting membrane potential, miniature endplate potential (MEPP) frequency or nerve-stimulated acetylcholine release. High concentrations reduced the amplitudes of the MEPP and endplate potential. Whereas methylphenidate and amphetamine both produced biphasic effects on skeletal muscle contractions in vitro, they act by different neuropharmacological mechanisms. Unlike amphetamine, the biphasic effects of methylphenidate are produced by mechanisms that are independent of cholinergic or adrenergic interactions and may involve direct effects on the muscle.

Asunto(s)

RESUMEN

This study, conducted in the rat phrenic nerve-diaphragm preparation, was designed to establish more direct evidence that norepinephrine enhances acetylcholine (ACh) release from motor neurons and characterize the alpha-adrenoceptor type mediating this action. Norepinephrine (50 microM, alpha 1 + alpha 2 agonist) increased nerve-stimulated release by 183%, as determined by radioenzymatic assay. This effect was completely abolished by pretreatment with the alpha-adrenoceptor antagonists phentolamine (alpha 1 + alpha 2) and by WB 4101 (alpha 1) but only modestly reduced by yohimbine (alpha 2). Clonidine (alpha 2 agonist) did not enhance ACh release or nerve-stimulated muscle contractions, while phenylephrine (alpha 1 agonist) and norepinephrine increased muscle contractions up to 19.5-22.4%. These results support the hypothesis that norepinephrine increases ACh release from somatic motor nerves via a presynaptic alpha 1 interaction.

Asunto(s)

RESUMEN

Studies were designed to investigated the cholinergic-independent mechanism(s) by which (+)-amphetamine produces a biphasic modification of directly stimulated contractions of skeletal muscle in the rat phrenic nerve-diaphragm preparation. In tissues pretreated with alpha-bungarotoxin, low concentrations of (+)-amphetamine (2.7-1.08 x 10(-4) M) enhanced muscle blockade. In other studies (Gerald, Meldrum and Skau, Res. Commun, chem. Path. Pharmac., 1982), high K+ concentrations or low Na+ concentrations antagonized amphetamine-enhancement of the twitch, while potentiating the blockade; in contrast K+-free media augmented amphetamine-induced enhancement of contractions. Low concentrations of amantadine, tetracaine, and tetrodotoxin increased the facilitatory response to (+)-amphetamine while the inhibitory effects of (+)-amphetamine were potentiated by higher concentrations of these antagonists; similar biphasic effects were observed with (-)-amphetamine and tetracaine. (+)-Amphetamine reserved the marked enhancement of the twitch produced by veratridine while, conversely, this neurotoxin failed to alter muscle contractions after (+)-amphetamine pretreatment. These findings suggest that amphetamine-induced enhancement and blockade of directly-stimulated skeletal muscle resulted from alterations in Na+ fluxes, possibly through interactions with membrane ionic channels.

Asunto(s)

Asunto(s)