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PubMed1981

Distribution of muscarinic receptors in the digestive tract organs.

We have studied the binding of the potent muscarinic antagonist, (3H)-quinuclidinyl benzilate [(3H)-QNB], in order to characterize muscarinic receptors of the digestive tract organs and evaluate their population. In each tissue examined, the binding sites were saturable and stereoselective; (3H)-QNB could also be displaced by known muscarinic agonists and antagonists. Along the digestive tract, the stomach (for stomach, fundus, antrum) and the colon possess the highest number of binding sites while the secretory (parotid, mandibular and pancreas), with a comparable amount of sites, are among those with less receptors. This study presents for the first time a complete distribution of the muscarinic receptors in organs of the digestive system evaluated under identical experimental conditions.

Animals↗
PubMed1982

Induction of wet dog shakes by intracerebroventricular bethanechol in rats. Antagonism by neurotransmitter receptor blockers.

Bethanechol chloride, administered intracerebroventricularly, induces a characteristic wet dog shake (WDS) response in rats in a dose-related manner. WDS induced by bethanechol at the dose of 100 micrograms was antagonized by atropine, scopolamine and spiperone (muscarinic cholinergic and dopaminergic antagonists, respectively), whilst metergoline, methysergide, phentolamine, propranolol and bicuculline (serotonergic, alpha-adrenergic, beta-adrenergic and GABA-ergic antagonists) fail to inhibit this effect. The present experiments show that the shaking response may be produced by bethanechol, a potent muscarinic agent administered by the intracerebral route, and suggest that bethanechol-induced shaking behavior in rats may be a useful animal model for delineating agents with antimuscarinic activity.

Animals↗
PubMed1984

Comparative study of pA2 values of pirenzepine and atropine for guinea-pig gastric fundus and gastric smooth muscle.

Concentration-response curves of bethanechol were obtained from isolated guinea pig gastric fundus and gastric circular smooth muscle strips before and after exposure to pirenzepine or atropine. In the presence of pirenzepine and atropine these curves were shifted parallel to the right with no change in maximum response. Against bethanechol, mean pA2 values were 7.06 for pirenzepine and 8.16 for atropine on gastric fundus, with slopes of Schild plots close to unity for both antagonists, whereas in the case of gastric smooth muscle pA2 values were 6.52 for pirenzepine and 8.52 for atropine, with the slope of the Schild plot significantly less than -1 in the case of pirenzepine. The values of the Schild slope seem to indicate that pirenzepine interacts with a single, apparently homogeneous population of muscarinic receptors on gastric mucosa, at variance with the behaviour of pirenzepine on receptors of gastric smooth muscle.

Animals↗
PubMed1985

Effect of diltiazem on in vitro rabbit bladder function.

The relationship between extracellular calcium and urinary bladder function was investigated by studying the effect of the specific calcium antagonist diltiazem on the functional ability of the in vitro whole rabbit urinary bladder to empty in response to pharmacological stimulation. The bladder was found to require an extracellular calcium concentration of 4.5 X 10(-4) M to elicit near complete cholinergic-mediated emptying. Diltiazem (1 X 10(-6) - 1 X 10(-4) M) inhibition of bladder function was competitively antagonized by increasing the extracellular calcium concentration (0.45 X 10(-4) - 3.6 X 10(-4) M). In the absence of diltiazem, alterations in the extracellular calcium concentration between 0.45 X 10(-4) and 3.6 X 10(-4) M had no significant effects on bladder response to bethanechol. KCl-mediated bladder emptying was significantly more sensitive to diltiazem inhibition than was bethanechol-stimulated emptying. Even at the intermediate diltiazem concentration of 1 X 10(-5) M, increasing the extracellular calcium concentration did not completely reverse the inhibitory effect of diltiazem on bladder response to KC1. These findings are consistent with the hypothesis that diltiazem at low concentrations may inhibit extracellular calcium influx while at higher concentrations translocation of intracellular stores of calcium may be inhibited as well. The study also suggests that diltiazem is capable of inhibiting urinary bladder function and deserves further consideration as a possible therapeutic agent in certain forms of urinary bladder dysfunction.

Animals↗
PubMed1989

Effects of muscarinic stimulation on intracellular calcium in the rabbit bladder: comparison with metabolic response.

Urinary bladder emptying is mediated primarily by a co-ordinated contraction of the bladder body in response to parasympathetic stimulation and muscarinic receptor activation. In a previous study using surface spectrophotometry to monitor the nicotinamide adenine dinucleotide (oxidized form)/nicotinamide adenine dinucleotide (reduced form) (NADH/NAD) ratio, we demonstrated that muscarinic stimulation results in a rapid decrease in this ratio which precedes the contractile response, and that the ED50 for the NADH response is significantly lower than the ED50 for contraction. The current study was designed to correlate changes in intracellular free calcium using FURA-2 fluorescence with both the contractile and metabolic response to muscarinic stimulation. Isolated strips of urinary bladder body were monitored in vitro for changes in intracellular free calcium, NADH/NAD ratio, and contraction. Intracellular free calcium was monitored by preincubation with FURA-2 AM and continuously measuring the fluorescence with an MB2 surface spectrofluorometer using excitation wavelengths of 340 and 380 nm, and an emission wavelength of 510 nm. The NADH/NAD ratio was monitored with the MB2 surface spectrophotometer using an excitation wavelength of 366 nm and an emission wavelength of 450 nm. Contraction was monitored using an isometric force transducer connected to a Grass model D polygraph. The results can be summarized as follows: (1) Bethanechol stimulates a sharp decrease in the NADH/NAD ratio, a rapid increase in intracellular free calcium, and a slower increase in contractile force. (2) The ED50 for NADH fluorescence was significantly less than the ED50 for either contraction or calcium fluorescence which were equal to each other.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Length-tension relationship of urinary bladder strips from streptozotocin-diabetic rats.

Streptozotocin-induced diabetes mellitus or the consumption of 5% sucrose in place of drinking water cause an increase in rat urinary bladder capacity and mass. Length-tension curves were generated using bladder body strips isolated from control, diabetic, or sucrose-drinking rats to determine whether the length-tension relationship was altered by the bladder hypertrophy associated with diabetic and nondiabetic diuresis. In addition, we compared the data using three different methods of expression: (1) absolute grams tension developed; (2) grams tension/100 mg tissue, and (3) grams tension/mm2. The cross-sectional area of strips from diabetic rats was increased compared to the other two groups. The length-passive tension curves for all three groups increased with increasing tissue length to a plateau. No optimal resting length for generation of active tension was found. Strips from diabetic and sucrose-drinking rats reached the plateau at a slightly larger passive tension than did strips from control rats. In addition, strips from diabetic and sucrose-drinking rats generally developed a greater active tension than did strips from control rats depending on the method of data presentation used. The data suggest that the complex nonlinear arrangement of smooth muscle fibers in the bladder wall results in the unusual length-tension curves generated by urinary bladder strips (as compared to skeletal or vascular smooth muscle). This relationship would be of benefit in the urinary bladders of early-stage diabetic patients before neuropathy development, where the stretching of the bladder wall would allow accommodation without any compromise of bladder function. The data indicate that comparisons of bladder strip function from control and diabetic rats should be done at passive tensions of greater than or equal to 2 g to ensure that maximal active tension is generated.

Animals↗
PubMed1990

Differential affinities of AF-DX 116, atropine and pirenzepine for muscarinic receptors of guinea pig gastric fundus, atria and urinary bladder: might atropine distinguish among muscarinic receptor subtypes?

The pA2 values and the Schild plots of the antimuscarinic drugs AF-DX 116, atropine and pirenzepine for muscarinic receptors of isolated guinea pig gastric fundus (acid secretion) and atrial and urinary bladder preparations (contractile force) obtained from the same animals were calculated against bethanechol as the agonist. The antimuscarinic drugs concentration-dependently shifted the concentration-response curves to bethanechol to the right without any change in the maximum response. The analysis of data based on Schild plots was consistent with a simple competitive antagonism, since regression slopes did not differ significantly from unity. The pA2 values indicated a significantly higher affinity of AF-DX 116 and atropine for atrial muscarinic receptors with respect to those of the gastric mucosa or urinary bladder. By contrast, in the case of pirenzepine the pA2 values for the three tissues did not differ significantly. These results suggest that each examined tissue apparently contains homogeneous population of acetylcholine muscarinic (M2) receptors. The pA2 values found for AF-DX 116 and atropine suggest, however, that the putative M2 subtype of atrial muscarinic receptor differs from both those of the gastric fundus and those of the urinary bladder.

Animals↗
PubMed1990

Development factors in the contractile response of the rabbit bladder to both autonomic and non-autonomic agents.

Previous work in this laboratory has demonstrated that the bladders of 1-day-old and 1-week-old rabbits generate higher pressures in whole-bladder preparations than bladders from mature 8-week-old rabbits. In addition, the density of cholinergic receptors does not change during this maturation period. The present study was designed to determine if the increased responsiveness of the neonatal bladder was specific for cholinergic stimulation. Using bladder strips, we have demonstrated that the newborn bladders generated much greater tension in response to ATP, serotonin, histamine, and substance P. The response of the 1-day-old bladder smooth muscle to these contractile agents was at least double the response of the 8-week-old bladders. However, the response of all age groups to bethanechol was approximately the same, and the response to KCl was only 40% greater in the 1-day-old bladders as compared to the adult. These current studies indicate that the newborn bladder responds to a variety of nonadrenergic, noncholinergic agonists to a significantly higher degree than the adult bladder, and that maturation is accompanied by substantial changes in the pharmacology of the bladder.

Adenosine Triphosphate↗
PubMed1990

Examination of the potential antiulcer activity of the calcium antagonist propyl-methylenedioxyindene. III. Lack of effect on cysteamine-induced duodenal ulcers in rats.

Since propyl-methylenedioxyindene (pr-MDI) exhibits significant protective effects against stress-induced ulcers in rats at subcardiovascular doses (10-30 mg/kg, i.p.), the aim of the present study was to explore the effect of this intracellular calcium antagonist on cysteamine-induced duodenal ulcers at the same low doses. Duodenal ulcers were induced in rats with a single dose of cysteamine (425 mg/kg, s.c.), which produced an 80% ulcer incidence within 24 h without affecting gastric acid concentration. Administration of pr-MDI (10 and 30 mg/kg, i.p.) at 0, 6 and 12 h post-cysteamine did not afford protection against ulceration. On the other hand, atropine (10 mg/kg, s.c., administered at 0, 6 and 12 h post-cysteamine) resulted in a 69% inhibition of ulceration, and the antacid Maalox (2 ml, administered p.o. at 0, 2, 4, 6 and 12 h post-cysteamine) completely prevented ulceration. The failure of pr-MDI to protect against duodenal ulceration is discussed in relation to its pharmacological mechanism of action and the pathogenetic mechanism of action of cysteamine.

Aluminum Hydroxide↗
PubMed1991

Comparison of the contractile and metabolic effects of muscarinic stimulation with those of KCl.

Urinary bladder emptying is mediated primarily by a coordinated contraction of the bladder body in response to parasympathetic stimulation and muscarinic receptor activation. In previous studies we presented evidence that the contractile response to bethanechol stimulation could be dissociated from the metabolic response through the use of diltiazem (calcium channel blockade). The conclusion from these studies was that muscarinic stimulation resulted in a significant increase in metabolic activity which was not directly associated with contraction. KCl stimulates contraction in isolated strips by directly depolarizing the membrane rather than from binding to specific membrane receptors. The current study directly compares the metabolic and contractile activity of bethanechol (muscarinic stimulation) with KCl (direct membrane depolarization). Isolated strips of rabbit urinary bladder body were monitored in vitro for changes in intracellular-free calcium, NADH/NAD ratio, and contraction. Intracellular-free calcium was monitored by preincubation of isolated bladder smooth muscle strips with FURA-2 AM and continuously measuring the fluorescence with an MB2 surface spectrofluorometer using excitation wavelengths of 340 and 380 nm, and an emission wavelength of 510 nm. The NADH/NAD ratio was monitored with the MB2 surface spectrophotometer using an excitation wavelength of 366 nm and an emission wavelength of 450 nm. Contraction was monitored using a isometric force transducer connected to a Grass model D polygraph. The results can be summarized as follows. (1) Both bethanechol and KCl stimulate a sharp decrease in the NADH/NAD ratio, a rapid increase in intracellular-free calcium, and a slower increase in contractile force.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1991

Effect of the steroidal alkaloid buxaminol-E on blood pressure, acetylcholinesterase activity and (3H)quinuclidinyl benzilate binding in cerebral cortex.

Pharmacological properties of the steroidal alkaloid buxaminol-E isolated from Buxus sempervirens varietas bullata were studied in relation to the cholinergic nervous system. In anaesthetised cats buxaminol-E (1.25 mumol/kg) initially induced a small short-lasting increase in blood pressure followed by marked hypotension. Atropine (1.47 mumol/kg) inhibited the hypotensive effect almost completely and methylatropine (1.47 mumol/kg) partially. Buxaminol-E and the muscarinic agonists McN-A-343 and bethanechol inhibited the binding of the muscarinic antagonist (3H)quinuclidinyl benzilate in cat and rabbit cerebral cortex membranes in decreasing order of potency. In about 10-fold higher concentrations they also inhibited acetylcholinesterase activity in cat cerebral cortex in the same order of potency. The results suggest that the hypotensive effect of buxaminol-E could be due to both central and peripheral activation of muscarinic receptors, and to a lesser degree to inhibition of acetylcholinesterase activity.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1991

Developmental aspects of bladder contractile function: sensitivity to extracellular calcium.

The urinary bladders of 1-day and 1-week-old rabbits generate higher intravesical pressures in response to bethanechol and field stimulation than bladders isolated from mature 8-week-old rabbits. Yet the density of cholinergic receptors in the rabbit bladder does not change with maturation (1 day to 8 weeks). In an effort to better understand the molecular mechanisms by which newborn rabbit bladders generate greater pressures than the bladders of adult rabbits, we studied the effect of maturation on the relationship between extracellular calcium and contraction. Our results showed quite clearly that (1) at physiologic concentrations of calcium (2.5 mumol/l), isolated bladder strips of 1-day- and 1-week-old rabbits contracted in response to bethanechol to 98% of their maximal tension as opposed to 68% for their 8-week-old counterparts, (2) the ED50 (for calcium) for the 1-day and 1-week bladders was 0.4 mmol/l whereas the ED50 for the adult bladder strips was 2.2 mmol/l, and (3) the neonatal bladders demonstrated a much greater sensitivity to diltiazem than the adult bladders. The contractile response to calcium of the neonatal bladders was significantly inhibited by 1 mumol/l diltiazem whereas the 8-week-old bladders showed no inhibition at this concentration. In a second series of experiments, the effect of extracellular calcium on concentration was correlated with the intracellular concentration of free calcium using the calcium fluoride FURA-2 and surface spectrofluorometry. These studies confirmed that the increased contractile response of the neonatal bladder strips to calcium or cholinergic agonists was associated with an increase in the maximal intracellular free calcium concentration.

Animals↗
PubMed1991

Effect of anoxia on in vitro bladder function.

Previous studies have demonstrated that the ability of the in vitro whole bladder to empty in response to bethanechol administration was inhibited by anoxia while its ability to generate pressure decreased only slightly. One question was not addressed by these early studies: Is the anoxic effect selective for receptor-mediated contractile stimulation (as opposed to non-receptor-mediated contractile stimulation)? The present study was designed to compare the effect of anoxia on the ability of the in vitro bladder to generate pressure, sustain pressure, and empty in response to field stimulation (FS), bethanechol and KC1 administration. Each New Zealand white rabbit was anesthetized with pentobarbital and the bladder removed. The bladder was mounted as a whole-bladder preparation in a 300-ml isolated bath containing Tyrode's solution at 37 degrees C and equilibrated with 95% O2, 5% CO2. Anoxia was produced by changing the gas mixture to 95% nitrogen, 5% CO2. The effect of anoxia on the response to FS, bethanechol, and KCl was determined at different times after the initiation of anoxia. The results of these studies can be summarized as follows. (1) Anoxia induced a time-dependent decrease in the rate of pressure generation, the magnitude of pressure generation, and the percent volume emptied in response to FS and bethanechol. (2) At all time periods of anoxia, the ability of the bladder to empty was inhibited to a significantly greater degree than either the rate of magnitude of pressure generation (for both FS and bethanechol administration).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Chronic nicotine intake increases the responses to muscarinic receptor stimulation.

Chronic nicotine administration depresses the autonomic ganglia, but its effects on the muscarinic receptors at the neuroeffector sites remain unclear. The present study, using rats, examines the influence of chronic treatment with nicotine (25 micrograms/ml drinking water) for 10 or 15 days on muscarinic receptor responses, as reflected by bethanechol-evoked gastric secretion or by acetylcholine-induced decreases in mean blood pressure. Bethanechol, 0.4, 0.8, 1.6 or 3.2 mg/kg injected subcutaneously, dose-dependently increased the basal gastric secretory volume and acid output in pylorus-ligated control animals which normally drank tap water. Rats given nicotine in their drinking water for 10 or 15 days showed a further marked increase in both the volume of gastric secretion and acid output in response to bethanechol injections. Although bethanechol dose-dependently increased acid secretion, the ulcer index was very small and there was no significant difference between the control and nicotine-treated groups. The basal mean blood pressure remained normal after the 10-day nicotine treatment. Acetylcholine, 0.1, 0.3, 1 or 3 micrograms/kg given intravenously, decreased the mean blood pressure; this acetylcholine-evoked blood pressure fall was intensified by nicotine pretreatment. The findings suggest that the responses to muscarinic receptor stimulation are increased by chronic nicotine treatment for 10 or 15 days. These exaggerated effects are possibly the consequence of persistent autonomic ganglion blockade by chronic nicotine treatment.

Acetylcholine↗
PubMed1992

Effects of anoxia on the biphasic response of isolated strips of rabbit bladder to field stimulation, bethanechol, methoxamine and KCl.

The contractile response of the bladder can be divided into two phases: an initial rapid increase in tension and a prolonged period of sustained tension (plateau phase). The bladder empties primarily during the plateau phase of the contractile response. These two phases can be differentiated using both pharmacologic and metabolic agents, indicating that the two phases have independent energy requirements. The present study compares the phasic (peak) and tonic (plateau) components of the responses of isolated strips of bladder body and base to field stimulation, bethanechol, methoxamine and KCl administration. New Zealand White rabbits were anesthetized with pentobarbital, and the bladder was removed. The bladder was divided between body and base at the level of the ureteral orifices. Three strips of bladder body and three strips of bladder base were mounted in separate baths containing Tyrode's solution at 37 degrees C and equilibrated with 95% O2, 5% CO2. Anoxia was produced by changing the gas mixture to 95% nitrogen, 5% CO2. The effects of anoxia on the responses to field stimulation, bethanechol, methoxamine and KCl were determined at different times after the initiation of anoxia. The results of these studies can be summarized as follows: (1) Anoxia induced time-dependent plateau phases of the response to field stimulation (2 and 32 Hz). (2) The rate of inhibition of the plateau phase was significantly and substantially greater than that of the peak phase in both the bladder body and base. (3) Similarly, anoxia inhibited the plateau phase of the bladder body's response to bethanechol to a significantly and substantially greater degree than anoxia inhibited the peak contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Influence of the bathing medium on the contractile responses of the rabbit urinary bladder.

This study examined contractile responses of the in vitro rabbit whole-bladder preparation to field stimulation, bethanechol and KCl in Tyrode's solution and minimum essential medium (MEM). We found frequency-dependent increases in intravesical pressure in bladders incubated in Tyrode's solution and MEM. However, bladders incubated in MEM consistently responded with greater increases in intravesical pressure compared to those incubated in Tyrode's solution. Similarly, there were frequency-dependent increases in the rate of pressure generation in bladders incubated in Tyrode's solution and MEM, and bladders incubated in MEM responded with greater rates of pressure generation than those incubated in Tyrode's solution at frequencies of 1, 2 and 4 Hz. In addition, there were significant increases in intravesical pressure generated in response to administration of 500 mmol/l bethanechol and 186.4 mmol/l KCl in bladders incubated in MEM compared to Tyrode's solution but no changes in the rate of pressure generation. The influence of L-methionine, one of the constituents of MEM, on the responses of whole bladders to nerve stimulation was also investigated. L-methionine at concentrations of 0.1 and 1.0 mmol/l had no effects on the increase in intravesical pressure or rate of pressure generation following nerve stimulation. It is speculated that the increases in contractile responsiveness of bladders incubated in MEM are related to the combination of amino acids, vitamins and other constituents of the cell culture medium.

Animals↗
PubMed1993

The effect of terodiline on hyperreflexia (in vivo) and the in vitro response of isolated strips of rabbit bladder to field stimulation, bethanechol and KCL.

Hyperreflexia, a condition characterized by contractions of the urinary bladder, is not mediated by a micturition reflex. The contractions can be of neurogenic origin through spinal or supraspinal reflexes or of myogenic origin, independent of neuronal mediation. There is a clear relationship between hyperreflexia and symptoms such as urgency, frequency, nocturia and urinary incontinence. Therapies to reduce the presence of uninhibited bladder contractions include oral drug therapy, instillation drug therapy and parasympathetic nerve ablation. The current study characterizes the ability of terodiline to inhibit an experimental form of hyperreflexia and compares the efficacy and potency of terodiline and other agents on hyperreflexia and evoked contractions. The results can be summarized as follows: (1) terodiline inhibits the amplitude of the hyperreflexia at lower concentrations than it inhibits the frequency of hyperreflexia; (2) terodiline had no statistically significant effect on mean blood pressure at any concentration utilized; (3) terodiline had approximately the same potency for inhibition of 2 and 32 Hz stimulation for both the bladder body and base; (4) terodiline inhibited the maximum contractile response to bethanechol and also shifted the curve to the right, demonstrating that terodiline is a mixed inhibitor, and (5) terodiline was a noncompetitive inhibitor of KCl.

Animals↗
PubMed1993

Correlation of contractile function of the rabbit corpus cavernosum with NADH fluorescence.

The NADH/NAD ratio is a measure of potential metabolic energy in smooth muscle tissue. Previous studies on bladder smooth muscle demonstrated that during active contraction when energy utilization is high, NADH is rapidly oxidized to NAD resulting in a decrease in the ratio of NADH/NAD. Intracellular systems utilizing ATP as an energy source are characterized by changes in the NADH/NAD ratio. This ratio can be monitored simultaneously with changes in smooth muscle tissue tone using an optical fiber probe which continually monitors NADH fluorescence and contractile activity of the same smooth muscle preparation. The present study correlates alterations in the ratio of NADH/NAD with both spontaneous and induced contractions and relaxations in the rabbit corpora cavernosa. The results show a high degree of correlation between a decrease in spontaneous fluorescence (decrease in the NADH/NAD ratio) and spontaneous contraction. An increase in tension was followed in time by a decrease in the NADH/NAD ratio. This was consistent for all strips showing significant spontaneous activity. ATP caused a rapid decrease in tension which was correlated with a decrease in fluorescence. The relative decrease in NADH fluorescence was proportional to the relative decrease in tension. Under basal conditions (0.8 g passive tension) ATP and nitroprusside stimulated a marked reduction in tension, but only ATP stimulated a substantial decrease in NADH fluorescence. Bethanechol and isoproterenol relaxed the corporal tissue to a relatively small degree which correlated with relatively small decreases in fluorescence. Methoxamine stimulated a substantial contraction of corporal smooth muscle which correlated with a rapid and significant decrease in NADH fluorescence.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗