- Email: [email protected]
Uropharmacology: IV. Parasympathomimetic drugs
UROPHARMACOLOGY
UROPHARMACOLOGY: IV. PARASYMPATHOMIMETIC ALEX E. FINKBEINER, NABIL K. BISSADA, LARRY WELCH,
DRUGS
M.D.
M.D.
PH.D.
From the Departments of Urology and Pharmacology, University of Arkansas College of Medicine, Little Rock, Arkansas
ABSTRACT - Parasympathomimetic drugs include (1) acetylcholine and esters and related derivatives, and (2) naturally occurring cholinomimetic lated synthetic compounds. Pharmacology of acetylcholine, the prototype presented, as well as ,an introduction to other parasympathomimetic drugs
Drugs which mimic the effects of stimulating the parasympathetic nerves to various organs are called parasympathomimetics. The term cholinergic is applied to nerve fibers which liberate acetylcholine (ACh) when a nerve impulse passes. The term cholinergic also describes drugs whose actions mimic those of ACh. Although the terms parasympathomimetic and cholinergic are frequently used interchangeably, they are not synonymous terms. The confusion in terms is due to the varied actions of ACh. When appropriate nerves are stimulated, ACh is released at the following sites: (1) ends of all autonomic preganglionic fibers (both sympathetic and parasympathetic); (2) ends of somatic motor nerves to skeletal muscles; (3) ends of postganglionic fibers of all parasympathetic nerves; (4) ends of postganglionic sympathetic nerves to sweat glands and certain blood vessels in the skin; (5) ends of sympathetic fibers to the adrenal medulla. When ACh is administered in appropriate doses, it will stimulate all parasympathetically innervated effector organs, all peripheral autonomic ganglia in both parasympathetic and sympathetic systems, the adrenal glands to release cathecholamines, the sweat glands, and skeletal muscles. Parasympathomimetic agents mimic only the actions of ACh which are blocked by atropine (that is, muscarinic effects). The actions of cholinergic drugs are commonly classified as either “muscarinic” or 474
several synthetic choline alkaloids and certain reparasympathomimetic, is and choline esters.
“nicotinic. ” “Muscarinic” actions are those seen after stimulation of organs innervated by postganglionic fibers of parasympathetic nerves and those associated with stimulation of sympathetic cholinergic nerves to sweat glands and cutaneous blood vessels. This action is called “muscarinic” because muscarine produces similar effects. Recent evidence indicates that autonomic ganglia also possess some “muscarinic” receptors. The “nicotinic” actions of these drugs refers to their initial stimulation, and in high doses, to subsequent blockade of autonomic (sympathetic and parasympathetic) ganglion cells and the neuromuscular junction (somatic muscles); actions comparable to that of nicotine. Most “muscarinic” effects can be prevented by a small dose of atropine while the “nicotinic” actions are not completely blocked by atropine. The nicotinic actions at the ganglia, however, are blocked by hexamethonium and those on skeletal muscle by d-tubocurarine chloride. After the administration of atropine the “muscarinic” effects of ACh will be blocked, and ACh will evoke only such effects as are mediated by stimulation of autonomic ganglion cells or neuromuscular junction in skeletal muscles. Groups of Parasympathomimetics Parasympathomimetic drugs can be divided into two groups:’ (1) acetylcholine and several synthetic choline esters and related derivatives;
UROLOGY
/ APRIL 1977 / VOLUME
IX, NUMBER 4
and (2) naturally occurring cholinomimetic alkaloids (pilcarpine, muscarine, and arecholine) and certain related synthetic compounds. We outline the general pharmacology of choline esters and the detailed pharmacology of acetylcholine, the prototype of parasympathomimetic drugs. In the following article we will discuss the detailed basic and clinical pharmacology of the other choline esters as well as the cholinomimetic alkaloids. Choline
esters
Acetylcholine is the General considerations. prototype of parasympathomimetic choline esters. Its clinical application is severely limited because of its diffuse action and its rapid hydrolysis by acetylcholinesterase. Consequently, synthetic choline derivatives (methacholine, carbachol, and bethanechol) have been introduced which are resistant to hydrolysis by acetylcholinesterase and have a prolonged action and more specific “muscarinic” actions. In general, the direct cardiovascular effects of choline esters are vasodilation, a decrease in heart rate and a decreased force of cardiac contraction. The cardiovascular effects are most pronounced with acetylcholine and methacholine while carbachol and bethanechol exert minimal cardiovascular effects following recommended therapeutic doses, The choline esters affect the gastrointestinal system by increasing peristaltic activity of the stomach and intestines as well as stimulating secretory activity of these organs. These gastrointestinal effects are most pronounced with carbachol and bethanechol and less so with acetylcholine and methacholine. The choline esters also activate secretion of all glands innervated by the parasympathetic system (lacrimal, tracheobronchial, salivary, and exocrine sweat glands). They also cause bronchoconstriction and stimulation of the carotid body and aortic arch chemoreceptors.’ Atropine counteracts the “muscarinic” action of these drugs by competitively occupying cholinergic receptor sites at the neuroeffector junction (that is, smooth muscle, heart, and glands). The nicotinic actions of these drugs can be competitively blocked by hexamethonium at the ganglia and by d-tubocurarine at the neuromuscular junction (skeletal muscles). Major contraindications to the clinical use of choline esters are asthma, hyperthyroidism, coronary insufficiency, and peptic ulcer disease.’ Choline esters should be administered only by the oral or subcutaneous routes.
UROLOGY
/ APRIL 1977
/ VOLUME
IX, NUMBER
4
Acetylcholine
(ACh)
Acetylcholine is the General considerations. endogenous chemical mediator at cholinergic synapses, and its liberation is stimulated by electrical impulses transmitted to the synapse. After liberation it is rapidly hydrolyzed locally by acetylcholinesterase. ACh exhibits both “muscarinic” and “nicotinic” activity. Its action on autonomic ganglion cells is dose-related. Small doses of ACh initiate ganglionic impulses while larger doses block transmission of impulses by keeping the ganglion cells depolarized. Experimental
Pharmacology
.Detrusor
Acetylcholine (O.OOOl- 10.0 Muscle strips. pg./ml.) causes a dose-related contraction of the detrusor, manifested by increased isometric tension and increased frequency and magnitude of contractile activity, followed by either a gradual return to baseline or a vigorous sustained contraction.3‘8 These effects are potentiated by physostigmine, an anticholinesterase.5~8,g Atropine appears to antagonize the effect of acetylcholine competitively.5 Most workers have found that atropine (1.0-10.0 pg./ml.) completely blocks acetylcholine-induced contractions with equimolar doses.3*‘-10 Others have shown that atropine (0.1-1.0 pg./ml.) does not block all activity of acetylcholine (0.1-10 pg./ ml.), particularly the sustained contraction. “J Sympathetic agonists and blockers can modify acetylcholine’s activity on detrusor strips. Adrenergic neuronal blockers (especially guanethidine 10e4 Gm./ml.) reduce the response of the detrusor to ACh even more than they reduce the response to nerve stimulation.13 Imipramine decreases but does not abolish ACh-induced contractile activity. 11,i4 Bladder in uivo. Acetylcholine (0.001-0.02 mg./Kg. intravenous) causes a rapid and immediate dose-related contraction. 15-‘0 This response may not be purely muscarinic.” The response to ACh is either unchanged or potentiated by electrical stimulation,” and there is increased sensitivity to ACh after parasympathetic denervation and decentralization. lg Atropine (0.01-l mg./Kg.) blocks the response to ACh (0.001-0.02 mg./Kg.) if the ACh dose is small “muscarinic” effect). 21 If the concentration of ( ACh is increased, it overcomes the effect of atropine (1 mg./Kg.) and causes a contraction which is thought to be a nicotinic effect.16,18,20,22,23This effect of ACh is similar to
475
that produced by nicotine (fast and of short duration) and is produced by a much larger dose of ACh in the presence of atropine.” The mechanism is presumably one of ganglionic stimulation because the effect is abolished by hexamethonium or pentolinium (ganglionic blockers) at a concentration that does not affect the muscarinic response to ACh.23-26 Anticholinesterases potentiate acetylcholine-induced contractions.22 Neostigmine (0.1 mg./Kg.) increases the potency of ACh by 13 times.23 Adrenergic drugs can affect the ACh-induced Epinephrine or norepinephrine response. (0.1-2 pg./ml.) produced small contractions. When the bladder was contracted in the presence of ACh, epinephrine and norepinephrine produced relaxation. 22 Phenoxybenzamine (alpha blocker) blocks acetylcholine-induced contractions.‘5 Bladder outlet (bladder neck and urethra) Muscle strips. Rohner, et a1.6 state that consistent contractile responses to ACh are not seen in strips taken from the trigone or posterolateral bladder neck areas. It does, however, cause a dose-related contraction of the musculature of the anterior neck, but this response is not as strong as in the detrusor. However, other investigators note that ACh causes contraction of both the trigone and anterior base. Nergirdh and Boreu’s2’ state that ACh causes contraction of muscle strips of the outflow region regardless of whether the strips are taken from regions parallel to or perpendicular to the longitudinal axis of the outlet. However, the ACh-induced contractions of the perpendicular strips (circular musculature would play no part in the opening mechanism of the outlet. Nergardh and Boreui2* used a preparation of the bladder outlet region which was perfused in a tissue bath. This allowed the monitoring of longitudinal tension and resistance to flow. Acetylcholine, at a threshold concentration of 0.5 pg./ml., caused a dose-related contraction of the bladder neck and urethra. The strength of the contraction increased if the preparation was first stretched. However, overstretching decreased the contractile response. At a low concentration of ACh, contraction of the longitudinal musculature was noted without change in resistance to flow. At higher concentrations of ACh, however, the resistance to flow increased in about half of the preparations, decreased in about 25 per cent, and revealed diphasic or nil changes in another 25 per cent. All of these re-
476
sponses were dose-dependent. Slight stretching of the preparation decreased the resistance response to ACh while decreasing the length increased the resistance to flow in response to ACh. One tenth pg./ml. of atropine resulted in complete blockade of the isometric response of the longitudinal muscle to ACh; it did not block ACh-induced effects of resistance to flow. Adrenergic drugs can modify the cholinergic effects on outflow resistance. If the alpha receptors of the outlet are stimulated with an alpha agonist (phenylephrine), there is an increased resistance to flow. Subsequent administration of ACh decreased this resistance to flo~.~~ Alpha blockade by phentolamine (0.5 pg./ml.) had no effect on ACh-induced contraction of the longitudinal muscle. It does, however, reverse the ACh-induced increase in resistance to flow, and this reversal (decrease) can then be blocked by a beta blocker. The response (that is, r.:versal of increased resistance to flow) to alpha blockade is dose-dependent and reversible.28 Stimulation of beta receptors with isoprenaline causes relaxation of the circular muscle of the outlet region which can be reversed by ACh.29 Propranolol (beta blocker) augments ACh’s effects on the outlet to increase resistance to flow. Likewise, if the initial response to ACh is a decrease in resistance, this is changed to an increase in resistance following ACh if a beta blocker is present.28 The initial effect of ACh on resistance to flow, irrespective of whether it was an increase or decrease, is abolished if phentolamine and propranolol are present simultaneously.28 In summary, it thus appears that acetylcholine can influence the smooth muscle of the vesical outlet by at least two mechanisms: 1. Contraction of the longitudinal musculature of the outflow tract is an effect mediated by atropine-sensitive (cholinergic) receptors and is not affected by alpha or beta blockade.28 2. Resistance to flow is apparently mediated by tension in the circular muscle of the bladder outlet. Resistance may either increase or decrease after stimulation by ACh and either response is unaffected by atropine. Both alpha and beta blockade alter the ACh-induced resistance to flow: alpha receptors mediate an increase and beta receptors a decrease. When both alpha and beta blockers are present, ACh does not influence resistance to flow. It is postulated that this effect of ACh on the circular muscle is mediated through short, intramural, postganglionic, adrenergic neurons. ACh stimulates their ganglion cells causing a release of
UROLOGY
I
APRIL 1977 I
VOLUME
IX, NUMBER 4
norepinephrine on to adrenergic receptors in the circular muscle. The concentration of norepinephrine at the muscle receptor sites will determine whether the resistance to flow decreases or increases. Small amounts of norepinephrine elicit a beta-mediated response while larger amounts produce an alphamediated effect. 28-30 Urethra - in viva Acetylcholine (0.3- 1 pg./Kg.) results in a slow and irregular increase in resistance a few seconds after the onset of bladder contractions. Larger doses of acetylcholine result in a relaxation preceding this urethral contraction.31 The functional effects of acetylcholine on the outlet region are inconsistent (that is, contraction at times and relaxation at other times).2g After atropine the effects of small doses of ACh (0.3-30 pg./Kg.) disappear but large doses of ACh (0.1-0.3 mg./Kg.) cause rapid urethral relaxation and forceful bladder contractions.31 Ganglionic blockade with hexamethonium blocks the ACh response on the vesical outlet but increasing doses of ACh overcomes this ganglionic blockade.31 Little Rock, Arkansas 72201 (DR. FINKBEINER) References 1. KOELLE, G. B.: Parasympathomimetic Agents, chap. 23, in Goodman, L. S. and Gilman, A.: The Pharmacological Basis of Therapeutics, 5th ed., New York, Macmillan Publishing Co., Inc., 1975, p. 467. 2. Ibid: pp. 468-470. 3. DESY, W.: The reactivity of isolated urinary bladder strips of the guinea-pig towards electric stimulation, Arch. Int. Physiol. Biochem. 79: 459 (1971). 4. MALIN, J. M., JR., and BOYARSKY, S.: The effects of cholinergic and adrenergic drug stimulation of detrusor muscle, Invest. Urol. 8: 286 (1970). 5. PATON, D. M.: Pharmacology of isolated rabbit detrusor muscle, Clin. Res. 16: 393 (1968). 6. ROHNER, T. J., RAEZER, D. M., WEIN, A. J., and SCHOENBERG, H. W.: Contractile responses of dog bladder neck muscle to adrenergic drugs, J. Urol. 105: 657 (1971). 7. CAINE, M., BAZ, S., and ZIEGLER, M.: Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck, Br. J. Urol. 47: 193 (1975). 8. TODD, J. K., and MACK, A. J.: A study of human bladder detruser muscle, ibid. 41: 448 (1969). 9. RAEZER, D. M., WEIN, A. J., JACOBOWITZ, D., and CORRIERE, J. N., JR.: Autonomic innervation of canine urinary bladder, Urology 2: 211 (1973). 10. URSILLO, R. C., and CLARK, R. B.: The action of atropine on the urinary bladder of the dog and on the isolated nerve-bladder strip preparation of the rabbit, J. Pharmacol. Exp. Therap. 118:338 (1956). 11. LABAY, P., and BOYARSKY, S.: The action of imi-
UROLOGY
/
APRIL 1977 !
VOLUME IX, NUMBER4
pramine on the bladder musculature, J. Ural. 109:387 (1973). 12. NERG~RDH, A. : Autonomic receptor functions in the lower urinary tract, ibid. 113: 180 (1975). 13. BOYD, H., et al. : The cholinergic blocking action of adrenergic blocking agents in the pharmacological analysis of autonomic innervation, Br. J. Pharmacol. 20: 418 (1963). 14. LABAY, P., and BOYARSKY, S.: Urinary bladder contractility: action of imipramine, Arch. Phys. Med. Rehabil. 55: 166 (1974). 15. DESY, W. A.: Pharmacological interference with the autonomic innervation of the urinary bladder of the cat, Arch. Int. Pharmacodyn. Ther. 196 (Suppl.): 99 (1972). 16. EDGE, N. D.: A contribution of the innervation of the urinary bladder of the cat, J. Physiol. 127: 54 (1955). 17. MATSUMURA, S., TAIRA, N., and HASHIMOTO, K.: The pharmacological behavior of the urinary bladder and its vasculature of the dog, Tohoku J. Exptl. Med. 96: 247 (1968). 18. VANOY, S.: Responses of the rat urinary bladder in situ to drugs and to nerve stimulation, Br. J. Pharmacol. 24: 591 (1966). 19. ELMER, J.: Action of drugs on the innervated and denervated urinary bladder of the rat, Acta Physiol. Scand. 91: 289 (1974). 20. CHESHER, G. B., and THORP, R. H.: The atropineresistance of the response to intrinsic nerve stimulation of the guinea-pig bladder, Br. J. Pharmacol. 25: 288 (1965). 21. SAUM, W. R., and DEGROAT, W. C.: The actions of 5-hydroxytryptamine on the urinary bladder and on vesical autonomic ganglia in the cat, J. Pharmacol. Exp. Ther. 185: 70 (1973). 22. HUKOVIC, S., RAND, M. J., and VANOY, S.: Observation on an isolated innervated preparation of rat urinary bladder, Br. J. Pharmacol. 24: 178 (1965). 23. GYERMEK, L. : Cholinergic stimulation and blockade on urinary bladder, Am. J. Physiol. 201: 325 (1961). 24. AMBACHE, N.: The use and limitations of atropine for pharmacological studies on autonomic effecters, Pharmacol. Rev. 7: 467 (1955). 25. DUMSAY, B.: Atropine-resistance of the urinary bladder innervation, J. Pharm. Pharmacol. 23: 222 (1971). 26. KHANNA, 0. P., and GONICK, P.: Effects of phenoxybenzamine hydrochloride on canine lower urinary tract, Urology 6: 323 (1975). 27. NERG~RDH, A., and BoR~uS, L. 0.: Autonomic receptor function in the lower urinary tract of man and cat, Stand. J. Urol. Nephrol. 6: 32 (1972). 28. IDEM: The functional role of cholinergic receptors in the outlet region of the urinary bladder, Acta Pharmacol. Toxicol. 32: 467 (1973). 29. NERGARDH, A. : The interaction between cholinergic and adrenergic receptor functions in the outlet region ofthe urinary bladder, Stand. J. Urol. Nephrol. 8: 108 (1974). 30. OWMAN, C., OWMAN, T., and SJOBERG, N.: Short adrenergic neurons innervating the female urethra of the cat, Experientia 27: 313 (1971). 31 GIRADO, J. M., and CAMPBELL, J. B.: The innervation of the urethra of the female cat, Exp. Neurol. 1: 44 (1959).
477
UROPHARMACOLOGY: IV. PARASYMPATHOMIMETIC ALEX E. FINKBEINER, NABIL K. BISSADA, LARRY WELCH,
DRUGS
M.D.
M.D.
PH.D.
From the Departments of Urology and Pharmacology, University of Arkansas College of Medicine, Little Rock, Arkansas
ABSTRACT - Parasympathomimetic drugs include (1) acetylcholine and esters and related derivatives, and (2) naturally occurring cholinomimetic lated synthetic compounds. Pharmacology of acetylcholine, the prototype presented, as well as ,an introduction to other parasympathomimetic drugs
Drugs which mimic the effects of stimulating the parasympathetic nerves to various organs are called parasympathomimetics. The term cholinergic is applied to nerve fibers which liberate acetylcholine (ACh) when a nerve impulse passes. The term cholinergic also describes drugs whose actions mimic those of ACh. Although the terms parasympathomimetic and cholinergic are frequently used interchangeably, they are not synonymous terms. The confusion in terms is due to the varied actions of ACh. When appropriate nerves are stimulated, ACh is released at the following sites: (1) ends of all autonomic preganglionic fibers (both sympathetic and parasympathetic); (2) ends of somatic motor nerves to skeletal muscles; (3) ends of postganglionic fibers of all parasympathetic nerves; (4) ends of postganglionic sympathetic nerves to sweat glands and certain blood vessels in the skin; (5) ends of sympathetic fibers to the adrenal medulla. When ACh is administered in appropriate doses, it will stimulate all parasympathetically innervated effector organs, all peripheral autonomic ganglia in both parasympathetic and sympathetic systems, the adrenal glands to release cathecholamines, the sweat glands, and skeletal muscles. Parasympathomimetic agents mimic only the actions of ACh which are blocked by atropine (that is, muscarinic effects). The actions of cholinergic drugs are commonly classified as either “muscarinic” or 474
several synthetic choline alkaloids and certain reparasympathomimetic, is and choline esters.
“nicotinic. ” “Muscarinic” actions are those seen after stimulation of organs innervated by postganglionic fibers of parasympathetic nerves and those associated with stimulation of sympathetic cholinergic nerves to sweat glands and cutaneous blood vessels. This action is called “muscarinic” because muscarine produces similar effects. Recent evidence indicates that autonomic ganglia also possess some “muscarinic” receptors. The “nicotinic” actions of these drugs refers to their initial stimulation, and in high doses, to subsequent blockade of autonomic (sympathetic and parasympathetic) ganglion cells and the neuromuscular junction (somatic muscles); actions comparable to that of nicotine. Most “muscarinic” effects can be prevented by a small dose of atropine while the “nicotinic” actions are not completely blocked by atropine. The nicotinic actions at the ganglia, however, are blocked by hexamethonium and those on skeletal muscle by d-tubocurarine chloride. After the administration of atropine the “muscarinic” effects of ACh will be blocked, and ACh will evoke only such effects as are mediated by stimulation of autonomic ganglion cells or neuromuscular junction in skeletal muscles. Groups of Parasympathomimetics Parasympathomimetic drugs can be divided into two groups:’ (1) acetylcholine and several synthetic choline esters and related derivatives;
UROLOGY
/ APRIL 1977 / VOLUME
IX, NUMBER 4
and (2) naturally occurring cholinomimetic alkaloids (pilcarpine, muscarine, and arecholine) and certain related synthetic compounds. We outline the general pharmacology of choline esters and the detailed pharmacology of acetylcholine, the prototype of parasympathomimetic drugs. In the following article we will discuss the detailed basic and clinical pharmacology of the other choline esters as well as the cholinomimetic alkaloids. Choline
esters
Acetylcholine is the General considerations. prototype of parasympathomimetic choline esters. Its clinical application is severely limited because of its diffuse action and its rapid hydrolysis by acetylcholinesterase. Consequently, synthetic choline derivatives (methacholine, carbachol, and bethanechol) have been introduced which are resistant to hydrolysis by acetylcholinesterase and have a prolonged action and more specific “muscarinic” actions. In general, the direct cardiovascular effects of choline esters are vasodilation, a decrease in heart rate and a decreased force of cardiac contraction. The cardiovascular effects are most pronounced with acetylcholine and methacholine while carbachol and bethanechol exert minimal cardiovascular effects following recommended therapeutic doses, The choline esters affect the gastrointestinal system by increasing peristaltic activity of the stomach and intestines as well as stimulating secretory activity of these organs. These gastrointestinal effects are most pronounced with carbachol and bethanechol and less so with acetylcholine and methacholine. The choline esters also activate secretion of all glands innervated by the parasympathetic system (lacrimal, tracheobronchial, salivary, and exocrine sweat glands). They also cause bronchoconstriction and stimulation of the carotid body and aortic arch chemoreceptors.’ Atropine counteracts the “muscarinic” action of these drugs by competitively occupying cholinergic receptor sites at the neuroeffector junction (that is, smooth muscle, heart, and glands). The nicotinic actions of these drugs can be competitively blocked by hexamethonium at the ganglia and by d-tubocurarine at the neuromuscular junction (skeletal muscles). Major contraindications to the clinical use of choline esters are asthma, hyperthyroidism, coronary insufficiency, and peptic ulcer disease.’ Choline esters should be administered only by the oral or subcutaneous routes.
UROLOGY
/ APRIL 1977
/ VOLUME
IX, NUMBER
4
Acetylcholine
(ACh)
Acetylcholine is the General considerations. endogenous chemical mediator at cholinergic synapses, and its liberation is stimulated by electrical impulses transmitted to the synapse. After liberation it is rapidly hydrolyzed locally by acetylcholinesterase. ACh exhibits both “muscarinic” and “nicotinic” activity. Its action on autonomic ganglion cells is dose-related. Small doses of ACh initiate ganglionic impulses while larger doses block transmission of impulses by keeping the ganglion cells depolarized. Experimental
Pharmacology
.Detrusor
Acetylcholine (O.OOOl- 10.0 Muscle strips. pg./ml.) causes a dose-related contraction of the detrusor, manifested by increased isometric tension and increased frequency and magnitude of contractile activity, followed by either a gradual return to baseline or a vigorous sustained contraction.3‘8 These effects are potentiated by physostigmine, an anticholinesterase.5~8,g Atropine appears to antagonize the effect of acetylcholine competitively.5 Most workers have found that atropine (1.0-10.0 pg./ml.) completely blocks acetylcholine-induced contractions with equimolar doses.3*‘-10 Others have shown that atropine (0.1-1.0 pg./ml.) does not block all activity of acetylcholine (0.1-10 pg./ ml.), particularly the sustained contraction. “J Sympathetic agonists and blockers can modify acetylcholine’s activity on detrusor strips. Adrenergic neuronal blockers (especially guanethidine 10e4 Gm./ml.) reduce the response of the detrusor to ACh even more than they reduce the response to nerve stimulation.13 Imipramine decreases but does not abolish ACh-induced contractile activity. 11,i4 Bladder in uivo. Acetylcholine (0.001-0.02 mg./Kg. intravenous) causes a rapid and immediate dose-related contraction. 15-‘0 This response may not be purely muscarinic.” The response to ACh is either unchanged or potentiated by electrical stimulation,” and there is increased sensitivity to ACh after parasympathetic denervation and decentralization. lg Atropine (0.01-l mg./Kg.) blocks the response to ACh (0.001-0.02 mg./Kg.) if the ACh dose is small “muscarinic” effect). 21 If the concentration of ( ACh is increased, it overcomes the effect of atropine (1 mg./Kg.) and causes a contraction which is thought to be a nicotinic effect.16,18,20,22,23This effect of ACh is similar to
475
that produced by nicotine (fast and of short duration) and is produced by a much larger dose of ACh in the presence of atropine.” The mechanism is presumably one of ganglionic stimulation because the effect is abolished by hexamethonium or pentolinium (ganglionic blockers) at a concentration that does not affect the muscarinic response to ACh.23-26 Anticholinesterases potentiate acetylcholine-induced contractions.22 Neostigmine (0.1 mg./Kg.) increases the potency of ACh by 13 times.23 Adrenergic drugs can affect the ACh-induced Epinephrine or norepinephrine response. (0.1-2 pg./ml.) produced small contractions. When the bladder was contracted in the presence of ACh, epinephrine and norepinephrine produced relaxation. 22 Phenoxybenzamine (alpha blocker) blocks acetylcholine-induced contractions.‘5 Bladder outlet (bladder neck and urethra) Muscle strips. Rohner, et a1.6 state that consistent contractile responses to ACh are not seen in strips taken from the trigone or posterolateral bladder neck areas. It does, however, cause a dose-related contraction of the musculature of the anterior neck, but this response is not as strong as in the detrusor. However, other investigators note that ACh causes contraction of both the trigone and anterior base. Nergirdh and Boreu’s2’ state that ACh causes contraction of muscle strips of the outflow region regardless of whether the strips are taken from regions parallel to or perpendicular to the longitudinal axis of the outlet. However, the ACh-induced contractions of the perpendicular strips (circular musculature would play no part in the opening mechanism of the outlet. Nergardh and Boreui2* used a preparation of the bladder outlet region which was perfused in a tissue bath. This allowed the monitoring of longitudinal tension and resistance to flow. Acetylcholine, at a threshold concentration of 0.5 pg./ml., caused a dose-related contraction of the bladder neck and urethra. The strength of the contraction increased if the preparation was first stretched. However, overstretching decreased the contractile response. At a low concentration of ACh, contraction of the longitudinal musculature was noted without change in resistance to flow. At higher concentrations of ACh, however, the resistance to flow increased in about half of the preparations, decreased in about 25 per cent, and revealed diphasic or nil changes in another 25 per cent. All of these re-
476
sponses were dose-dependent. Slight stretching of the preparation decreased the resistance response to ACh while decreasing the length increased the resistance to flow in response to ACh. One tenth pg./ml. of atropine resulted in complete blockade of the isometric response of the longitudinal muscle to ACh; it did not block ACh-induced effects of resistance to flow. Adrenergic drugs can modify the cholinergic effects on outflow resistance. If the alpha receptors of the outlet are stimulated with an alpha agonist (phenylephrine), there is an increased resistance to flow. Subsequent administration of ACh decreased this resistance to flo~.~~ Alpha blockade by phentolamine (0.5 pg./ml.) had no effect on ACh-induced contraction of the longitudinal muscle. It does, however, reverse the ACh-induced increase in resistance to flow, and this reversal (decrease) can then be blocked by a beta blocker. The response (that is, r.:versal of increased resistance to flow) to alpha blockade is dose-dependent and reversible.28 Stimulation of beta receptors with isoprenaline causes relaxation of the circular muscle of the outlet region which can be reversed by ACh.29 Propranolol (beta blocker) augments ACh’s effects on the outlet to increase resistance to flow. Likewise, if the initial response to ACh is a decrease in resistance, this is changed to an increase in resistance following ACh if a beta blocker is present.28 The initial effect of ACh on resistance to flow, irrespective of whether it was an increase or decrease, is abolished if phentolamine and propranolol are present simultaneously.28 In summary, it thus appears that acetylcholine can influence the smooth muscle of the vesical outlet by at least two mechanisms: 1. Contraction of the longitudinal musculature of the outflow tract is an effect mediated by atropine-sensitive (cholinergic) receptors and is not affected by alpha or beta blockade.28 2. Resistance to flow is apparently mediated by tension in the circular muscle of the bladder outlet. Resistance may either increase or decrease after stimulation by ACh and either response is unaffected by atropine. Both alpha and beta blockade alter the ACh-induced resistance to flow: alpha receptors mediate an increase and beta receptors a decrease. When both alpha and beta blockers are present, ACh does not influence resistance to flow. It is postulated that this effect of ACh on the circular muscle is mediated through short, intramural, postganglionic, adrenergic neurons. ACh stimulates their ganglion cells causing a release of
UROLOGY
I
APRIL 1977 I
VOLUME
IX, NUMBER 4
norepinephrine on to adrenergic receptors in the circular muscle. The concentration of norepinephrine at the muscle receptor sites will determine whether the resistance to flow decreases or increases. Small amounts of norepinephrine elicit a beta-mediated response while larger amounts produce an alphamediated effect. 28-30 Urethra - in viva Acetylcholine (0.3- 1 pg./Kg.) results in a slow and irregular increase in resistance a few seconds after the onset of bladder contractions. Larger doses of acetylcholine result in a relaxation preceding this urethral contraction.31 The functional effects of acetylcholine on the outlet region are inconsistent (that is, contraction at times and relaxation at other times).2g After atropine the effects of small doses of ACh (0.3-30 pg./Kg.) disappear but large doses of ACh (0.1-0.3 mg./Kg.) cause rapid urethral relaxation and forceful bladder contractions.31 Ganglionic blockade with hexamethonium blocks the ACh response on the vesical outlet but increasing doses of ACh overcomes this ganglionic blockade.31 Little Rock, Arkansas 72201 (DR. FINKBEINER) References 1. KOELLE, G. B.: Parasympathomimetic Agents, chap. 23, in Goodman, L. S. and Gilman, A.: The Pharmacological Basis of Therapeutics, 5th ed., New York, Macmillan Publishing Co., Inc., 1975, p. 467. 2. Ibid: pp. 468-470. 3. DESY, W.: The reactivity of isolated urinary bladder strips of the guinea-pig towards electric stimulation, Arch. Int. Physiol. Biochem. 79: 459 (1971). 4. MALIN, J. M., JR., and BOYARSKY, S.: The effects of cholinergic and adrenergic drug stimulation of detrusor muscle, Invest. Urol. 8: 286 (1970). 5. PATON, D. M.: Pharmacology of isolated rabbit detrusor muscle, Clin. Res. 16: 393 (1968). 6. ROHNER, T. J., RAEZER, D. M., WEIN, A. J., and SCHOENBERG, H. W.: Contractile responses of dog bladder neck muscle to adrenergic drugs, J. Urol. 105: 657 (1971). 7. CAINE, M., BAZ, S., and ZIEGLER, M.: Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck, Br. J. Urol. 47: 193 (1975). 8. TODD, J. K., and MACK, A. J.: A study of human bladder detruser muscle, ibid. 41: 448 (1969). 9. RAEZER, D. M., WEIN, A. J., JACOBOWITZ, D., and CORRIERE, J. N., JR.: Autonomic innervation of canine urinary bladder, Urology 2: 211 (1973). 10. URSILLO, R. C., and CLARK, R. B.: The action of atropine on the urinary bladder of the dog and on the isolated nerve-bladder strip preparation of the rabbit, J. Pharmacol. Exp. Therap. 118:338 (1956). 11. LABAY, P., and BOYARSKY, S.: The action of imi-
UROLOGY
/
APRIL 1977 !
VOLUME IX, NUMBER4
pramine on the bladder musculature, J. Ural. 109:387 (1973). 12. NERG~RDH, A. : Autonomic receptor functions in the lower urinary tract, ibid. 113: 180 (1975). 13. BOYD, H., et al. : The cholinergic blocking action of adrenergic blocking agents in the pharmacological analysis of autonomic innervation, Br. J. Pharmacol. 20: 418 (1963). 14. LABAY, P., and BOYARSKY, S.: Urinary bladder contractility: action of imipramine, Arch. Phys. Med. Rehabil. 55: 166 (1974). 15. DESY, W. A.: Pharmacological interference with the autonomic innervation of the urinary bladder of the cat, Arch. Int. Pharmacodyn. Ther. 196 (Suppl.): 99 (1972). 16. EDGE, N. D.: A contribution of the innervation of the urinary bladder of the cat, J. Physiol. 127: 54 (1955). 17. MATSUMURA, S., TAIRA, N., and HASHIMOTO, K.: The pharmacological behavior of the urinary bladder and its vasculature of the dog, Tohoku J. Exptl. Med. 96: 247 (1968). 18. VANOY, S.: Responses of the rat urinary bladder in situ to drugs and to nerve stimulation, Br. J. Pharmacol. 24: 591 (1966). 19. ELMER, J.: Action of drugs on the innervated and denervated urinary bladder of the rat, Acta Physiol. Scand. 91: 289 (1974). 20. CHESHER, G. B., and THORP, R. H.: The atropineresistance of the response to intrinsic nerve stimulation of the guinea-pig bladder, Br. J. Pharmacol. 25: 288 (1965). 21. SAUM, W. R., and DEGROAT, W. C.: The actions of 5-hydroxytryptamine on the urinary bladder and on vesical autonomic ganglia in the cat, J. Pharmacol. Exp. Ther. 185: 70 (1973). 22. HUKOVIC, S., RAND, M. J., and VANOY, S.: Observation on an isolated innervated preparation of rat urinary bladder, Br. J. Pharmacol. 24: 178 (1965). 23. GYERMEK, L. : Cholinergic stimulation and blockade on urinary bladder, Am. J. Physiol. 201: 325 (1961). 24. AMBACHE, N.: The use and limitations of atropine for pharmacological studies on autonomic effecters, Pharmacol. Rev. 7: 467 (1955). 25. DUMSAY, B.: Atropine-resistance of the urinary bladder innervation, J. Pharm. Pharmacol. 23: 222 (1971). 26. KHANNA, 0. P., and GONICK, P.: Effects of phenoxybenzamine hydrochloride on canine lower urinary tract, Urology 6: 323 (1975). 27. NERG~RDH, A., and BoR~uS, L. 0.: Autonomic receptor function in the lower urinary tract of man and cat, Stand. J. Urol. Nephrol. 6: 32 (1972). 28. IDEM: The functional role of cholinergic receptors in the outlet region of the urinary bladder, Acta Pharmacol. Toxicol. 32: 467 (1973). 29. NERGARDH, A. : The interaction between cholinergic and adrenergic receptor functions in the outlet region ofthe urinary bladder, Stand. J. Urol. Nephrol. 8: 108 (1974). 30. OWMAN, C., OWMAN, T., and SJOBERG, N.: Short adrenergic neurons innervating the female urethra of the cat, Experientia 27: 313 (1971). 31 GIRADO, J. M., and CAMPBELL, J. B.: The innervation of the urethra of the female cat, Exp. Neurol. 1: 44 (1959).
477