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Biomedical subjects

R M Levin

Publications and source records attributed to R M Levin.

At least 109 records · Page 6Linked to original sources
PubMed1995

Effects of diuresis on micturition.

Micturition can be characterized experimentally by monitoring both the frequency and volume of micturition. Previous studies demonstrated that the functional capacity of the rat and rabbit bladder, as determined by cystometry, is approximately equal to the maximal single micturition volume as recorded over a 24 hour period. Studies in many laboratories have demonstrated that chronic increases in diuresis induce increases in micturition frequency and capacity, and an increase in bladder mass. The current study compares the temporal relationship among these parameters in three models of diuresis: streptozotocin-induced diabetes in rats, sucrose-induced diuresis in rats, and furosemide-induced diuresis in rabbits. In both sucrose diuresis in rats and furosemide diuresis in rabbits there were immediate increases in both the frequency and volume of micturition. The magnitude of the increases in micturition frequency and micturition volume paralleled the increase in the total volume of urine excreted. Bladder mass increased progressively over the time course of the study. Streptozotocin-induced diabetes resulted in a more gradual (but parallel) increase in micturition frequency and volume, and again a more gradual increase in bladder mass. These studies demonstrate that functional bladder capacity is increased immediately upon the initiation of diuresis with sucrose or furosemide, as is the frequency of micturition. This indicates that functional bladder capacity is probably under neuronal regulation and the change in capacity is not a function of the increased bladder mass which occurs at a later time period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Use of injectable fat to obstruct the urethra in rabbits.

Bulking agents have been injected to correct urinary incontinence for at least 15 years. The injection seeks to increase bladder outlet resistance by partially obstructing the urethra and thereby reduce urinary leakage in patients with stress urinary incontinence. Although the implant is effective and requires a shorter in-hospital stay than more traditional procedures, no ideal implant substance has been discovered. To assess the effectiveness of injected fat as a bulking agent, we injected small volumes of perivesical fat into the bladder neck in New Zealand White (NZW) rabbits and tested the effect on the bladder. In eight rabbits, we harvested perivesical fat and partially closed the urethral lumen with an initial injection. A second injection 1 month later completely closed the urethral lumen. We injected six other rabbits with similar volumes of saline as controls. Two weeks after the second injection, we measured micturition frequency, bladder weight, response to electrical field stimulation, and response to bethanecol in each group. Fat implants were present at the injection site in each case 4 weeks after the first injection. Rabbits receiving fat implants had increased micturition frequency, increased bladder weight, and increased response to bethanecol and field stimulation. Previous studies have demonstrated that these changes are characteristic of mild outlet obstruction in rabbits. Injected fat can be made to close the urethra and create bladder outlet obstruction in rabbits. The short-term success of fat as a bulking agent in this experiment is encouraging and suggests the need for longer term studies.

Adipose Tissue↗
PubMed1995

Antiproliferative effects of tyrosine kinase inhibitors (tyrphostins) on human bladder and renal carcinoma cells.

Growth factor receptors with tyrosine kinase activity mediate paracrine and autocrine growth regulation of normal and malignant cells. The epidermal growth factor receptor (EGF-R) is a tyrosine kinase transmembrane protein that is overexpressed by many epithelial malignancies, including transitional cell and renal cell carcinoma. Ligand-induced stimulation of cell growth depends on activation of the tyrosine kinase activity of the EGF-R. Tyrphostins are small molecular weight compounds that have been shown to preferentially inhibit the EGF-R tyrosine kinase and thus may inhibit EGF-R-dependent cell growth. We examined the effect of two tyrphostins, RG14620 and AG555, on the proliferation of three transitional cell carcinoma lines (RT4, J82, and T24) and three renal cell carcinoma lines (A-198, Caki-1, and Caki-2). Both tyrphostins inhibited proliferation of all six cell lines in a dose-dependent fashion. They were equally effective with IC50s ranging between 3 and 16 microM. Complete inhibition of growth was achieved at tyrphostin concentrations between 10 and 30 microM. Although both tyrphostins inhibited proliferation of T24 transitional carcinoma cells in growth assays, only RG14620 but not AG555 was found to specifically inhibit EGF-R autophosphorylation in this cell line. These results suggest that other intracellular targets in addition to the EGF-R are affected by these agents. In summary, tyrphostins are potent growth inhibitors for urological malignancies.

Adult↗
PubMed1995

Bladder function in experimental outlet obstruction: pharmacologic responses to alterations in innervation, energetics, calcium mobilization, and genetics.

The two functions of the urinary bladder is to store urine at low intravesical pressures, and to periodically expel the urine through a coordinated contraction of the bladder and relaxation of the urethra. To a large extent, urinary bladder function depends upon the underlying structure of the organ as a whole, particularly on the inter-relationships among the smooth muscle, connective tissue, and neuronal elements. An alteration in the ratio of connective tissue to smooth muscle, for example, can significantly alter compliance and functional capacity, structurally impairing the bladder's ability to empty efficiently and fully. Thus, a change in structural compartmentation can affect bladder function independent of autonomic receptor density, response to receptor stimulation, and the contractile capabilities of the smooth muscle elements. Similarly, a selective alteration in either the afferent or efferent innervation of the bladder or urethra can induce significant alterations in the structural interrelationships between smooth muscle and connective elements. In addition, the bladder responds rapidly to alterations in urine volume and urethral resistance with marked changes in bladder and urethral structure and function, and these changes are under the controls of specific genes that are known to control cellular growth, hypertrophy, and hyperplasia. A knowledge of the mechanisms that control the response to specific forms of stress may lead to novel therapies for specific disease states.

Animals↗
PubMed1995

The effect of cholinergic stimulation on cultured smooth muscle cells.

OBJECTIVE: To assess the role of cholinergic angonists and antagonists on the growth control of cultured rabbit detrusor smooth muscle cells. DESIGN: Dosage dependent growth curve analysis of smooth muscle cells in standard media to bethanechol and atropine at concentrations from 1 x 10(-5) to 1 x 10(-9) mMol. RESULTS: Exogenous exposure to bethanechol results in a significant dose dependent increase in total cell number over a 10 day period. At a concentration of 1 x 10-6 and 1 x 10-5 mMol a 20% to 50% growth increase is noted. Exogenous atropine at all concentrations decreased growth by approximately five fold. CONCLUSIONS: The exogenous application of muscarinic cholinergic agonists and antagonists can significantly effect bladder muscle cell growth in vitro. The mechanism of growth control through these pharmacological receptors remains to be elucidated.

Animals↗
PubMed1995

Peptide growth factors in normal and hypertrophied bladder.

The bladder is a dynamic organ that responds to the stress of outlet obstruction by rapidly increasing in mass and cellular content to compensate for increased urethral resistance. If the outlet obstruction is released prior to decompensation, the hypertrophied bladder will shrink, returning to normal size and cellularity. However, with chronic obstruction the bladder will continue to increase in mass, developing drastic alterations in the amount and composition of the extracellular matrix and, ultimately, losing the ability to function. The extensive tissue remodeling associated with each of these changes requires different bladder components to undergo cellular proliferation, cellular hypertrophy, and even programmed cell death (apoptosis). Each of these cellular processes is known to be regulated by various peptides that are referred to as growth factors. Herein we provide an overview of the growth factors that are known to influence the bladder in addition to a variety of experimental animal studies that putatively identify a role of four particular growth factors [basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), nerve growth factor (NGF), and epidermal growth factor (EGF)] in the obstructive bladder response.

Animals↗
PubMed1995

Comparison of the pharmacological response of human corpus cavernosal tissue with the response of rabbit cavernosal tissue.

1. This study directly compares the response of cavernosal tissue obtained from sexually mature rabbits with the response of human corpus cavernosal tissue obtained during implant surgery for psychogenic impotence (five individual samples) to field stimulation and specific autonomic agonists. 2. At 2 g basal tension, field stimulation of the rabbit corpus cavernosal tissue produced a frequency dependent biphasic response consisting of an initial relaxation followed by contraction. Low frequency stimulation induced primarily relaxations whereas high frequency stimulation induced primarily contractions. FS of human corpus cavernosal tissue induced a frequency dependent contraction. 3. In general, the rabbit corpus cavernosal strips showed a significantly greater degree of spontaneous activity than the strips of human cavernosal tissue. 4. Phenylephrine stimulated a rapid and sustained increase in basal tension in both tissues. Although the isolated strips weighed the same, the magnitude of the response of the rabbit tissue was significantly greater than the response of the human tissue. 5. For both tissues, FS relaxations were completely inhibited by L-NAME showing that the relaxations were mediated by nitric oxide. Similarly, for both tissues, nitroprusside, ATP, and bethanechol induced similar dose-response relaxations of pre-stimulated tissue. 6. In conclusion, the major difference between the response of human and rabbit tissue to various forms of stimulation was that isolated strips of human corporal tissue responded to FS with contractions at all frequencies whereas the rabbit tissue responded to the relaxations at low frequencies of stimulation; a clear bi-phasic response at intermediate frequencies; and contraction at high frequencies.

Animals↗
PubMed1995

Contractility and phenotype transitions in serosal thickening of obstructed rabbit bladder.

Partial outlet obstruction of rabbit bladder induces serosal thickening and smooth muscle (SM) cell hypertrophy that are accompanied by phenotypic changes in the expression of cytoskeletal and cytocontractile proteins. In the present study, we compare the observed progressive phenotypic changes with the contractile responses of strips of the thickened serosa. At 15 days after partial outlet obstruction, although cells in thickened serosa demonstrate the presence of nonmuscle (NM) myosin of A-like type, vimentin, and SM alpha-actin, no contractile responses of this tissue were noted. At later times (30 days), this tissue expressed in addition SM myosin, and this pattern was paralleled by the development of KCl-stimulated contractility. It is only after 60 days that the serosa demonstrated the expression of desmin, phosphoglucomutase (PGM)-related protein, and was locally negative for NM myosin, indicating a maturation toward adult SM cells. Concomitant to this phenotypic change, the response to KCl increased, and a bethanechol-stimulated contractile response developed. At no time period did the serosal layer react with anti-synaptophysin or anti-neurofilament proteins nor did the strips respond to field stimulation (via release of neurotransmitters), showing that SM cell differentiation and development of contractile responses during serosal thickening are independent of innervation.

Animals↗
PubMed1995

The role of the mucosa in the in vitro changes in guinea pig bladder function which occur after sensitization with ovalbumin.

Bladder strips from sensitized guinea pigs respond to ovalbumin challenge with a contraction accompanied by release of histamine, prostaglandin, and leukotriene. Histamine and prostaglandin release occurs preferentially from the bladder mucosa, while leukotrienes are released by the smooth muscle. This study investigated the effects of removal of the bladder mucosa on contractile responses of strips from control and sensitized guinea pigs to electrical stimulation and to contractile agonists. Removal of the mucosa potentiated the contractile response to electrical stimulation at low voltages and pulse durations. The presence of ovalbumin had no effects on the response to electrical stimulation. Removal of the mucosa had no effect on the contractile responses of bladder strips to bethanechol, histamine, KCl, or ovalbumin, although after correction for the decreased strip mass after mucosa removal there was a tendency for the responses to increase. We conclude that the responsiveness of bladder strips from sensitized guinea pigs to ovalbumin challenge results primarily from effects which occur within the smooth muscle.

Animals↗
PubMed1995

Effect of magnesium ions on rabbit detrusor contractility and intracellular free calcium.

Magnesium (Mg2+) is one of the most abundant ions in the body. In the human body, Mg2+ plays important roles including cofactors in many crucial enzyme systems, especially those involving energy transfer, storage and utilization. Alteration of the concentration of Mg2+ may cause neuromuscular hyperactivity, psychiatric disturbances, calcium/potassium abnormalities, and overactivity of cardiac muscle. Most information on the effect of Mg2+ on muscle contraction has been obtained from studies on cardiac, skeletal, and vascular muscle; much less is known about the effect of Mg2+ in other smooth muscle systems. In the current study, we investigated the effect of Mg2+ on the contraction and intracellular free calcium of rabbit urinary bladder detrusor muscle in response to carbachol and transmural field stimulation (FS). The results can be summarized as follows: (1) Reduction of the concentration of magnesium [Mg2+] from normal Tyrode's solution enhanced the spontaneous basal activity, whereas addition of Mg2+ gradually abolished this spontaneous activity. (2) Muscle contraction induced by FS or carbachol was enhanced in Mg(2+)-free Tyrode's solution. Addition of Mg2+ inhibited the response to both forms of stimulation in a dose-dependent manner. (3) Inhibitory effects of Mg2+ were potentiated when the Ca2+ concentration in the Tyrode's solution was reduced to 0.6 mM, whereas increasing the extracellular concentration of Ca2+ (5.4 mM) reduced the inhibitory effects of Mg2+. (4) Using FURA-2 to monitor intracellular free calcium simultaneous with contractile tension, we demonstrated that the alterations in the contractile responses observed at different concentrations of extracellular Mg2+ correlated with similar changes in intracellular free calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Developmental factors in the contractile response of rabbit urinary bladder: effect of anoxia and extracellular acidosis.

Previous studies have demonstrated that the mechanism of excitation contraction coupling changes with normal development in rabbit urinary bladder smooth muscle. The present study was designed to determine whether there were any differences in the effects of anoxia and extracellular acidosis in response to field stimulation, bethanechol and KCl between mature (8 weeks) and neonatal (3 days) rabbit bladder smooth muscle. Bladder smooth muscle strips from mature and neonatal New Zealand White rabbits were mounted in organ baths and bathed in oxygenated Tyrode's solution. Anoxia was produced by changing the gas mixture to 95% nitrogen/5% CO2 and the effects on contractility were determined at different times after initiation of anoxia. The extracellular acidosis was produced by decreasing the buffer's NaHCO3 concentration. We conclude that bladder smooth muscle does not exhibit an age-specific ability to counteract the effects of anoxia or acidosis as is seen in the developing rabbit myocardium. Instead it appears that the purinergic mechanisms of contraction are much more sensitive to the effects of anoxia or acidosis. Neonatal bladder smooth muscle exhibits a greater drop in contractility with anoxia or acidosis at low frequency (2 Hz) field stimulation; we attribute this to the fact that neonatal bladder smooth muscle has a greater purinergic component in its response to field stimulation. These differences in the responses to anoxia and pH reflect alternate mechanisms of pharmacologic activation, and not inherent differences in the biochemistry of the maturing smooth muscle.

Acidosis↗
PubMed1995

Effects of the peptide leukotriene receptor antagonist ICI 198,615 on the in vivo and in vitro changes in guinea pig bladder function which occur after sensitization with ovalbumin.

PURPOSE: The present studies were designed to determine the effects of in vivo and in vitro administration of ICI 198,615 (ICI), a leukotriene receptor antagonist, on the inflammatory changes that occur in the bladder after sensitization with ovalbumin. MATERIALS AND METHODS: The effect of intravenous administration of ICI on urodynamic changes after instillation of ovalbumin to sensitized guinea pigs was evaluated by in vivo cystometry. Responses of in vitro bladder muscle strips to contractile stimuli and ovalbumin were also evaluated in the presence of ICI. RESULTS: In sensitized guinea pigs, in vivo cystometry with ovalbumin induced a marked decrease in bladder capacity and increase in intravesical pressure. Pretreatment with ICI prior to cystometry prevented the ovalbumin-induced changes in capacity and intravesical pressure. There were no significant differences between control and sensitized animals in the responses of in vitro bladder muscle strips to field stimulation or bethanechol. However, maximal contractile responses to ovalbumin were significantly greater in the strips from sensitized animals than in controls. Preincubation with ICI, indomethacin, or pyrilamine alone was unable to inhibit the contractile responses to ovalbumin. However, combined administration of ICI, indomethacin and pyrilamine completely blocked the responses. CONCLUSIONS: In vivo administration of the leukotriene receptor antagonist ICI 198,615 reversed the urodynamic changes induced by ovalbumin challenge in sensitized guinea pigs. These results indicate that leukotrienes are primarily responsible for the changes in in vivo bladder function associated with sensitization.

Animals↗
PubMed1995

Expression of smooth muscle myosin isoforms in urinary bladder smooth muscle during hypertrophy and regression.

BACKGROUND: Partial ligation of the urinary out-flow tract of rabbit bladder induces hypertrophy of the smooth muscle layer in the bladder wall, and it is reversible by the removal of the ligature. The expression of smooth muscle myosin heavy chain isoforms SM1 and SM2 after hypertrophy and the regression of hypertrophy (reversal) was investigated at the translational and transcriptional levels using this experimental model. DESIGN: The contractile activity of smooth muscle strips derived from normal, hypertrophied, and reversal bladders was measured using electrical stimulation. Expression of SM1 and SM2 in normal, hypertrophied, and reversal muscle tissue was characterized using SDS-PAGE, reverse transcriptase-PCR (RT-PCR), and RNase protection assay. RESULTS: Smooth muscle strips from hypertrophied urinary bladder revealed a decrease in both force and rate of force generation in response to field stimulation. These alterations in contractility were reversed by removal of the obstruction. The altered function in bladder hypertrophy was also associated with changes in translation and transcription of the smooth muscle heavy chain isoforms SM1 and SM2. Upon regression of the hypertrophy by removal of the obstruction, the relative ratio of myosin heavy chain SM2:SM1 returned to nearly normal values. Analyses by RT-PCR showed a decrease in the mRNA transcript for SM2 in hypertrophied bladder muscle; and, on reversal of the hypertrophy, the SM2 mRNA level returned to that of normal bladder. These data suggest that the obstruction-induced hypertrophy activates a down-regulating mechanism for the expression of myosin SM2 heavy chain. CONCLUSIONS: Obstruction-induced alteration in the contractile characteristics of the urinary bladder smooth muscle is associated with changes in the expression of smooth muscle myosin heavy chains at both the protein and mRNA levels. The contractile function and the myosin heavy chain expression return to normal after regression of the smooth muscle hypertrophy on removal of the obstruction.

Amino Acid Sequence↗
PubMed1995

Effect of anoxia on the urethral response to phenylephrine.

PURPOSE: Smooth muscle requires oxygen for proper contractile function. In addition, anoxia has been shown to inhibit the contractile response to various forms of stimulation. Continence, at least in part, depends upon active alpha-adrenergic tone, which provides intraurethral tension during bladder filling. The current study was designed to determine the effect of anoxia on the ability of the urethra to sustain tension. MATERIALS AND METHODS: Standard isolated urethral strip preparations were used to determine the effect of anoxia on the contractile response to phenylephrine; isolated whole urethra preparations were used to determine the effect of anoxia on the intraurethral pressure--flow characteristics. RESULTS: The peak tension responses of the female and male urethra to phenylephrine were significantly greater than the plateau tension. Anoxia induced an immediate decrease in phenylephrine-stimulated tonic tension to baseline tension. In the whole urethra preparation, phenylephrine increased opening pressure to a greater extent in the male urethra than in the female urethra. In both sexes, anoxia reduced the opening pressure and completely prevented phenylephrine stimulated increases in opening pressure. CONCLUSION: The tonic response to phenylephrine is lost virtually immediately upon the initiation of hypoxia. This suggests that hypoxia decreases the ability of the urethra to maintain a tonic response to alpha-adrenergic stimulation during bladder filling and may be a factor in incontinence, especially in females.

Adenosine Triphosphate↗
PubMed1995

Temporal changes in micturition and bladder contractility after sucrose diuresis and streptozotocin-induced diabetes mellitus in rats.

Studies were done to compare the acute effects of streptozotocin-induced diabetes and sucrose consumption on micturition, bladder mass and contractile responses of bladder strips to field stimulation and contractile agonists. Micturition changes occurred gradually in diabetic rats, reached maximal values within 7 to 14 days, and were accompanied by significant increases in bladder mass after 7 days. Bladder strips from diabetics responded to field stimulation, carbachol and KCl with significantly greater contractions than did those from controls within 7 days. Sucrose-drinking rats had maximal increases in fluid consumption and micturition frequency on the first night after starting treatment. Increases in micturition volumes were slower to develop than in diabetics. Bladder mass was significantly increased 30 and 60 days after starting sucrose treatment. Bladder strips from sucrose-drinking rats responded to field stimulation and carbachol with significantly greater contractions than did those from controls only after 60 days. Monitoring of drinking and micturition patterns established that diabetic rats drink and urinate during both the dark and light cycles. In contrast, control and sucrose-drinking rats drink and urinate principally at night. The results demonstrate that differences in bladder function between diabetic and sucrose drinking rats are apparent during the first month after treatment begins. The data suggest that the effects of diabetes and sucrose consumption on contractile bladder function are related to the diuresis-induced increases in bladder mass.

Animals↗
PubMed1995

Genetic and cellular characteristics of bladder outlet obstruction.

Urinary bladder outlet obstruction is a common medical problem. In order to understand the effects of outlet obstruction on bladder morphology, physiology, and pharmacology, several animal models of obstruction have been developed using a variety of species. Although there are marked differences in bladder size, capacity, compliance, physiology, and pharmacology among these species, responses to outlet obstruction have many common characteristics. This article will be separated into six areas: introduction, genetic factors mediating the response during the initial period of partial outlet obstruction and overdistension, cytostructural alterations that accompany compensated bladder function, alterations in innervation accompanying bladder hypertrophy secondary to partial outlet obstruction, alterations in calcium translocation during bladder hypertrophy, and metabolic factors involved in the response to partial outlet obstruction.

Animals↗