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Uropharmacology: IX. direct-acting smooth muscle stimulants and depressants
UROPHARMACOLOGY:
IX. DIRECT-ACTING
MUSCLE
AND DEPRESSANTS
ALEX
STIMULANTS
E. FINKBEINER,
M.D.
LARRY
T. WELCH,
Pl3.D.
NABIL
K. BISSADA,
1I.D.
From the Departments University of Arkansas Little Rock, Arkansas
SMOOTH
of Urology and Pharmacoloa, for Medical Sciences,
ABSTRACT -Agents which exert their effect on the louvr urinary tract by stilnuluting or dqmssing the activity of smooth muscle directly are discu.s.sed. Many of these drugs also rwrf other actimv on th
Some pharmacologic stimulants and depressants of smooth muscle exert their effect directly on smooth muscle. However, most of the drugs included in this section also exert other actions. Some exert secondary effects on smooth muscle by acting on the autonomic innervation to the muscle. Some of these agents possess both stimulating and depressant effects on smooth muscle depending on the target organ and/or the dosage administered. The terms stimulant and depressant will refer to the primaq. effect of the drug on the lower urinary tract. Direct-acting
Barium
Smooth
Muscle
Stimlllants
chloride
Barium chloride is a potent smooth muscle stimulant which is not used clinically because of its side effects. In pelvic nerve-urinary bladder preparations barium chloride causes bladder contractions which are not blocked b!r ganglionic blockers or atropinc. ’
Histamiw Histamine possesses both stimulant jcontractile) and depressant (relaxant) properties on smooth muscle. Its primary effect on vascular beds in man is relaxation, while it is a mild stimulant on many other smooth musclecontaining organs. On strips of detrusor muscle,
histamine (0.1 pg./ml.) elicits a contraction which is antagonized by mep!mmine (0.01 pg./ml.)2 and by atropine3 hut the agonist action is not potentiated by eserine. 3 In r;ihi histaininc induces contraction of the (0.3-30 pg.) detrusor . . 4-6 The response of the Idetrusor to histamine is not altered by atropille. ’ ganglionic blockade. ’ or tetrodotoxin.’
5-Hydroxytryptamine possessc~s both direct stimulatory and inhibitory activity on a variety of smooth muscles. It also acts indirectly at autonomic ganglia by producing both excitator!. and inhibitory effects. In detrllsor mllscle strips 5-HT (0.15 pg./ml.) causes contraction but tachyphylaxis develops rapidly. “J This .5-HTinduced contraction is potentiated b!. eserine,‘i antagonized by methylsergide,’ and partially antagonized 1)~. atropine. 3 In the isolated inllervated bladder 5-HT (0.2-10 /~g.!ml.) causes a slowly developing contraction which can bcl blocked by methylsergide (0.25 pg./ml.).’ In situ 5-HT (0. l- 10 pg.) enhance’s spontaneous activity of the bladder and causes a contraction, 1*4.5.HSuccessive increases in dosage rc’suit in an increased magnitude of contraction.’ It is more potent than ACh or histamine in eliciting contractions of the I)laddt~r.5 Its agonist action on the Hadder is inlril~itetl tj\. cocainr~”
and is reduced by methylserand morphine9 8 The response is not affected gide’ and atropine. by hexamethonium.’ Saum and de GroatlO found that in the resting bladder in situ 5-HT (0.01-50 pg. intraarterially) causes a bimodal contraction, that is, an initial transient contraction and then a more prolonged contraction. Only the initial contraction was accompanied by neural firing of the pelvic postganglionic nerve. Methylsergide, which blocks the direct actions of 5-HT, blocked the late but not the early contraction. Picrotoxin, a known blocker of the excitatory action of 5-HT on the sympathetic ganglia, reversibly antagonized the early contraction but had no effect on the late contraction. Saum and de Groat concluded that the early contraction was induced by 5-HT through activation of neural input to the bladder while the late contraction was due to a direct myotropic action of 5-HT. Furthermore, although 5-HT elicits a contraction of the resting bladder, it depresses the contractile response of the bladder to stimulation of the parasympathetic innervation. They concluded that 5-HT influences bladder activity by acting on excitatory receptors in the vesical smooth muscle and on both excitatory and inhibitory receptors in parasympathetic ganglia.
Ergotamine
urethral muscle strips angiotensin (10 pg./ml.) elicits a marked increase in tension. The increase in tension is reduced by 50 per cent after the addition of phentolamine (100 pg./ml.). This finding suggests that the effect is mediated directly and through alpha-adrenergic receptors. l1 In situ angiotensin (0.5 mg./Kg.) caused an inconsistent12 but sometimes marked rise13 in urethral pressure which was partially reduced by phenoxybenzamine. l3 At a dose of 0.5 pg./Kg., angiotensin causes a delayed but longer lasting increase in resistance to flow through the urethra than does epinephrine (2.5 pg.IKg.).14 These observations suggest that angiotensin also acts on the urethra both directly and via alphaadrenergic receptors. Brudykinin. This is an endogenous plasma kinin which is characterized by very brief action. This compound is a potent vasodilator at low doses. Its effects on nonvascular smooth muscle may cause either contraction or relaxation. In isolated, innervated strips of detrusor muscle bradykinin (0.1 pg./ml.) causes a very slow contraction which is potentiated by physostigmine (0.02 pg./ml.). Atropine or hyoscine decreases this response by about one-half.’ In situ bradykinin (0.01-3 pg.) dilates the vascular bed in the bladder and elicits a contraction of the detrusor. 5 Elcdoisin and kullikreinin. Both of these drugs dilate blood vessels in the urinary bladder and cause contraction of the detrusor in situ. 5
The ergot alkaloids are stimulants of smooth muscle, probably as a result of their direct action. They cause potent vasoconstriction and uterine stimulation. In situ ergotamine (5-50 pg.) causes a slowly developing and sustained contraction of the bladder and augmentation of spontaneous detrusor activity. 5
In situ vasopressin (0.01-3 pg.) causes vesical vasoconstriction and at much larger doses contraction of the detrusor.’
Actitie polypeptides
Oxytocin
These endogenous compounds exert many effects, one of which is stimulation of smooth muscle. Several of these have been evaluated for their effects on the lower urinary tract. Angiotensin and angioten.Gn Il. Angiotensin and angiotensin II cause vasoconstriction b, direct action on vascular smooth muscle. Angiotensin is a stimulant of the central nervous system and sympathetic ganglion cells. The decapeptide facilitates ganglionic transmission. Angiotensin3 and angiotensin II” (0. l-l /.~g.Icc.) both cause contraction of detrusor muscle strips. The angiotensin-induced contraction is neither potentiated by eserine nor antagonized by mepyramine, phentolamine, or atropine.3 On
This posterior pituitary hormone causes contraction of detrusor muscle strips. This contraction is potentiated by magnesium but is not affected by eserine, mepyramine, or atropine.3 In situ, at doses of 0.01-l pg., oxytocin causes vesical vasoconstriction and contraction of the detrusor. 5
Vasopressin
(antidiuretic
hormone)
These “local tissue hormones” are ubiquitous in body tissues and appear to be modulators of intracellular metabolism. In a sequence of complex enzymatic actions, thev are released in response to nervous, chemical, or mechanical stimuli resulting in an alteration of fimction of
various organ systems. Prostaglandins act by direct effects on smooth muscle and indirectly b? modulation of the autonomic nervous system. There are indications that prostaglandins can specifically influence the adrenergic nerve terminal and ultimately alter the amount of transmitter released. They also can potentiate various qmpathomimetic substances. Distention of dog bladders in vivo resulted in release of epinephrine into the circulation in 14 of 17 dogs.‘” The rate of release depended on the pressure within the bladder. In several experiments prostaglandin-like substances were released after emptying the distended bladders. The reaction of other organ systems to this substance was the same as their reaction to prostaglandins particularly PGF2a. The release of this substance may be due, in part, to the autonomic response to urinary bladder distention and suggests that prostaglandin release may be a response to stretch. that is, a local mechanism to resist the distorting force or to accommodate to it.
In strips of rabbit bladder PGEl causes a contraction \vhich is not potentiated by eserine or antagonized by atropine, phentolamine, or mepyramine. 3 In the guinea pig and rat PGEI increased tone and motility in situ but failed to do so in vitro; it also increased the response to stimulation of the hypogastric nerve in vivo and potentiated the action of ACh both in vivo and in vitro. 16. PGEz and PGFzu were evaluated in strips of guinea pig detrusor. PGEz and F2a did not imitate the rapid twitch evoked by electrical stimulation. PGE2, even at doses of 500 ng./ml., caused only sluggish and greatly delayed contractions beginning twenty to thirty seconds after their administration. The effect was long lasting and persisted for ten minutes after PGEz was washed from the system. The effect of PGF2a was even \veaker than that of PGE2.’ The competitive antagonist SC-19220 is known to abolish the action of PGEl and PGE2 on other preparations of smooth muscle. In a concentration of l-.5 pg./ml., the drug failed to block the response to PGEz or to reduce the twitches elicited by a single pulse. Ten pg. of SC-19220 reduced the response of detrusor strips to PGE2 (50 ng./ml.) by 76 per cent. At the same time the responses to 1-5 electrical pulses only diminished by 7 to 23 per cent.2 Another prostaglandin antagonist, polypholoretin phosphate (20 ng./ml.), failed to block the effect of PGE2. In higher concentrations it cle-
pressed the detrusor muscle and abolished the contractile response to histamine, thus losing its specificity. 2 The effect of PGF2.a was e\~aluated on the bladder of dogs in vivo in which the pelvic and hypogastric nerves were seve~red. ” PGF2a (lo-100 pg.) intra-arterially caused a slight increase in intravesical pressure (,increased tone) which lasted about ten minutes. (Inlike ACh, increasing doses of PGF2cr scarcely caused an increase in response. PGFza (lo-100 pg.) also caused a transient but definite fall in perfusion pressure. Although the bladder’s vascular response to PGFza was smaller than those to ACh in corresponding doses, the response increased in a dose-dependent manner. With higher doses (30- 100 pg.) of PGFza, the initial decrease in perfusion pressure was followed 1,~. a slight but sustained increase. Tetrodotoxin (which abolishes contractions of the bladder in response to pelvic nerve stimulation) did not affect the vascular or muscular responses to PGFza (100 pg.). Physostigmine, which usually augments bladder contractions in response to submaximal pelvic nerve stimulation and to ACh, had no effect on vascular or muscular responses to PGF2a. Since the response to PGF2a is not neural excitation is abolished by tetrodotoxin, apparently not involved in producing the response. Also the response is not altered by physostigmine, suggesting the absence of a cholinergic component. It is highly probable that PGFza elicits the bladder contraction and vesical vasodilation by a direct action. Ii Direct-acting
Smooth
Muscle
Depressants
Vasodilators (dipyridamolr, hydraltrzine, nitroglycerine, papaceriw i These drugs are classified together because of their common action on vascular smooth muscle. Each dilated the vesical bed without influencing the musculature of the bladder in situ.5 Mebeverine (100 mg. intramuscularly) had no effect on normal human bladders as monitored clinically by cystometry. lx
This xanthine is a central ner\‘ous system stimulant, a cardiac stimulant, and ..I diuretic. It acts directl!. on smooth muscle (notably bronchial smooth muscle) to cause relaxation. On detrusor muscle strips theophylline (_jOO /+/ml.) causes a decrease in spontaneous rhythmic activity and a decrease in baseline tension. ‘!’ At a
dose of 500 pg./ml. it affects bethanecholinduced contractile response by increasing the threshold concentration of bethanechol necessary to elicit a response, decreasing the force of contraction and delaying its onset of action. l9 Conflicting reports were published regarding the in situ effect of theophylline on the detrusor. Theophylline (5-10 mg./Kg.) was reported to cause a decrease in intravesical baseline pressure in one report’” buy no effect was reported in another.”
Flavoxate
hydrochloride
(Urispus)
Flavoxate hydrochloride is a tertiary amine chromone which selectively acts directly on the bladder producing relaxation.*’ Experimental studies on nonbladder smooth muscle reveal that flavoxate has no atropine-like action and does not interfere with the autonomic nervous system. It does, however, possess marked analgesic and local anesthetic action. *’ recepBenson et al. ** assessed the cholinergic tor blocking ability and direct muscle inhibitory effects of atropine, propantheline, flavoxate, and imipramine on dog detrusor strips. They concluded that flavoxate produced very minimal decreases in both the bethanechol (cholinergic) and barium chloride (direct smooth muscle)induced contractions. In fact, flavoxate exhibited slightly greater anticholinergic than musculotropic relaxant properties. They further stated that the reportedly marked clinical benefits derived from flavoxate could be secondary to a musculotropic relaxant action not related to its known analgesic and local anesthetic properties. Clinical studies evaluating the effectiveness of flavoxate on the urinary tract include adult patients with frequency, urgency, dysuria, nocturia, and suprapubic discomfort. Symptoms improved in about two thirds of the patients treated with 200 mg. flavoxate hydrochloride four times a day for seven days.*” Flavoxate (200 mg. four times a day) was significantly better than phenazopyridine (Pyridium, 200 mg. three times a day) in providing symptomatic relief in patients with prostatitis, cystitis, urethritis, and trigonitis. 24 In 25 patients with neurogenic bladder disease flavoxate (200 mg.) produced an increase in bladder c’apacity with little or no change in resting bladder pressure. The side effects were minimal compared with propantheline.” treated 38 patients who had Stanton’” symptoms of urinary frequency, urgency, and incontinence secondary to various etiologies
234
with flavoxate hydrochloride 200 mg. orally three times a day. Stress incontinence and urgency improved in 75 to 85 per cent of the patients with detrusor instability and in 50 per cent with sphincter dysfunction. Flavoxate reduced diurnal frequency in all patients. Three of the 38 patients had side effects of drowsiness, bloating, and depression. Urethral pressure profiles were unaltered by flavoxate therapy. Cystometrograms before and after therapy revealed no changes in residual urine volume. Flavoxate therapy resulted in a decrease in intravesical pressure, increased capacity, and a delay in the sensations of first and strong desires to void.
Oxybubynin
chloride (Ditropan)
This newly available tertiary amine with smooth muscle depressant properties has been discussed previously in this series. 26
Dicyclomine
(Bentyl)
Dicyclomine has been shown to have a direct smooth muscle relaxant effect as well as antimuscarinic action on guinea pig ileum.27 In a clinical study’” 27 patients with symptoms of increased urinary frequency, urgency, nocturia, suprapubic discomfort, and urge incontinence were treated with dicyclomine. Cystometrograms were performed before and after the administration of dicyclomine. Dicyclomine administered intramuscularly (20 mg.) significantly increased bladder capacity and, when given orally (20 mg. three times a day for four to eight weeks) increased bladder capacity and the patient’s symptoms improved. When dicyclomine was given orally, improvement was not observed for seven to ten days, and an eightweek course was necessary to achieve a maximum subjective response. None of the patients had significant side effects. Little Rock, Arkansas 72201 (DR. FINKBEINER)
UROLOCX i AUC:VST 1978 / \‘OLU\4E X11. Nt_‘\lBEH 2
ical hth;r\ ior of tl (CAurinay bladder and its \ascrllatllrc~ of the dog. Tohoku J, Exp. Med. 96: 247 ,1968!. 6. \Vwtmatr DF: The guinea-pig isolated, innen atrd lhtldr~ preparation: the rffrcts of some autonomic drug\. Arch. Int. Pharmacody Ther. 1%: 383 (19721. 7 Hukovic S. Rand SlJ. and Vanm S: Olarrvation on an iwIatrd, innewatcd preparation of rat urinal? hladdc~r. RI-. J. Phart~~acol. 24: 1% (1965). 8. Van~n S: Rrspon~~*s of the rat urinary, bladder in situ to drugs and to nene stimulation, ibid. 24: 581 ~1965). 9. Tairu N: Thch autonomic pharmacolog) of the hlxldcr. 4nnu. Rrv. Pharmawl. 12: 197 [1972) 10. Saum \VR. and de Groat \t’(:: Thr actions of ,j-h~drox?-t~l,talnin~ on thr urinary bladder and on vesical autonomic ganglia in the, cat. J. Pharmacol. Exp Thor 185: 70 (1973i. 11. Ral S, Zeiglrr X1, and Cainr SI: Isometric studicls on canine urrthral muwrllatnw, Invest. 1lrol. 9: 443 / 1972). 12. Tanagho E4, and 542levrrs FH: The “internal sphincter”: 1s it Ilndrr \ympathrtic control’? ibid. 7: 79 (1969). 13. Raz S. ;u~d Caine hl: Adrenrrgic rweptors in thr femal(~ hid. 9: 319 j 1972). caCnr ur(&x. 1-L. Tanagho E.4. &Icyers FH, and Smith DR: I’rethral reistancc: its wmponents and implications. ibid 7: 136 (1969~. IS, Crimson KS, Orgain ES, and Rowr CR, Jr: Caution with regard to USC of I,~zamt,thollirlln and “.4presolinr.” J. A. IL1.A. 149: 215 (1952‘. 16. I\‘amzada blK: .4cticm of prostaglandin El 011 the hladdrr, Boll. Sot. Ital. Biol. Sper. 43: S18 (1967). Ii’. Taira \ : Mode of actions of prostaglandin Fz, on the rlrinary IMdrr and its artrrial lwd in thr dog, Europ J. Pharmxol. 29: 30 (1974).
\‘ROLOC:Y
4I’GUST
197X
/
VOLUVE
91.
YI’\IBER
2
the> smooth m~~wle of thr I&ddrr. RI-. J. I’IoI 44: .31 (lS72). 19. Ixoni J. \f’cin .4J. and Schocmlwrg II\\‘: Thr, r+Twts of iv)protcrenol and aminophyllinc on tlvtruol- tnr~v~lr c,(mtractilit> in an organ hath apparatus. In\cst. L i-01. 10: 458 , 1973l. 20. Stanton SL: A comparison of emepron~rlm hronridv and H;nwatc hydl-ochloridr in the twatnwnt of Iuiwl-\ incotltinrwcc~. J. L’1.01. 110: 529 (1973).
22. Benaon (ZS. Sar\hik SA. Raescr DCl. .tnd \V(,in .4J Bl;<~~ muscle contractilit> : cw~~parative rfFects and mrxhanisrns of action of atropine, propanthelinr, Havoxatta. and inlilx.uninc*. L’rolo~ 9: :31 (1977). 23. Bradley D\.. and Cavort RJ Relic~f of hladtlc~r spasm I)! Havosate. A comparative study, J. (:lill. Pharn~u)l. 10: 6.5 (19701. 24. Gould S. L’rinary tract disordrrs: clinic,al c~onrp;wison of’ Havoxate and I)l1ella~np).ridille, Urology 5: 612 197Fil. of’ fl;n 25. Kohler FP, and Morales PA. Cystonretric r\aluation oxate hydrochloride in normal and ncwrtrgrrlic~ Ibluddr~rs. J. Ural. 100: 729 (1968). 26. Finkhrincr 4E, Bissada h K. nnd \l’elch 1,T: (‘ropharmacology, Part VI. Parasympathrtic dtyrwsu~ts. Ilrolog! 10: 503 f19771. 27. lic(l;rath \VR, Lrwis HE, and Kuhn i\.L,: Thr, dud modem of thr antisp”.s”lodi~ &ct of dicycllnniw h~tlrr)~~l1l,)ritlr, J Phw macol. Exp. Ther. 146: 354 (1964). 28. Awxl S.4, Bryniak S, Do\vnic J1V. ;md Brwc .-\\I~. Tht~ treatment of the uninhihitcd hladtl~~r \\ith rlic~\cl~mrint~. J. L’r~ll. 117: 161 (19771. 29. \Vtain AJ. (Gregory JC;, Sansorw T(:. ,md Schormlxq Ii\\‘: The effects of arninophylline on uwthral md hlarldc~r contractilit) Invest. LTrol 9: 290 (1972).
IX. DIRECT-ACTING
MUSCLE
AND DEPRESSANTS
ALEX
STIMULANTS
E. FINKBEINER,
M.D.
LARRY
T. WELCH,
Pl3.D.
NABIL
K. BISSADA,
1I.D.
From the Departments University of Arkansas Little Rock, Arkansas
SMOOTH
of Urology and Pharmacoloa, for Medical Sciences,
ABSTRACT -Agents which exert their effect on the louvr urinary tract by stilnuluting or dqmssing the activity of smooth muscle directly are discu.s.sed. Many of these drugs also rwrf other actimv on th
Some pharmacologic stimulants and depressants of smooth muscle exert their effect directly on smooth muscle. However, most of the drugs included in this section also exert other actions. Some exert secondary effects on smooth muscle by acting on the autonomic innervation to the muscle. Some of these agents possess both stimulating and depressant effects on smooth muscle depending on the target organ and/or the dosage administered. The terms stimulant and depressant will refer to the primaq. effect of the drug on the lower urinary tract. Direct-acting
Barium
Smooth
Muscle
Stimlllants
chloride
Barium chloride is a potent smooth muscle stimulant which is not used clinically because of its side effects. In pelvic nerve-urinary bladder preparations barium chloride causes bladder contractions which are not blocked b!r ganglionic blockers or atropinc. ’
Histamiw Histamine possesses both stimulant jcontractile) and depressant (relaxant) properties on smooth muscle. Its primary effect on vascular beds in man is relaxation, while it is a mild stimulant on many other smooth musclecontaining organs. On strips of detrusor muscle,
histamine (0.1 pg./ml.) elicits a contraction which is antagonized by mep!mmine (0.01 pg./ml.)2 and by atropine3 hut the agonist action is not potentiated by eserine. 3 In r;ihi histaininc induces contraction of the (0.3-30 pg.) detrusor . . 4-6 The response of the Idetrusor to histamine is not altered by atropille. ’ ganglionic blockade. ’ or tetrodotoxin.’
5-Hydroxytryptamine possessc~s both direct stimulatory and inhibitory activity on a variety of smooth muscles. It also acts indirectly at autonomic ganglia by producing both excitator!. and inhibitory effects. In detrllsor mllscle strips 5-HT (0.15 pg./ml.) causes contraction but tachyphylaxis develops rapidly. “J This .5-HTinduced contraction is potentiated b!. eserine,‘i antagonized by methylsergide,’ and partially antagonized 1)~. atropine. 3 In the isolated inllervated bladder 5-HT (0.2-10 /~g.!ml.) causes a slowly developing contraction which can bcl blocked by methylsergide (0.25 pg./ml.).’ In situ 5-HT (0. l- 10 pg.) enhance’s spontaneous activity of the bladder and causes a contraction, 1*4.5.HSuccessive increases in dosage rc’suit in an increased magnitude of contraction.’ It is more potent than ACh or histamine in eliciting contractions of the I)laddt~r.5 Its agonist action on the Hadder is inlril~itetl tj\. cocainr~”
and is reduced by methylserand morphine9 8 The response is not affected gide’ and atropine. by hexamethonium.’ Saum and de GroatlO found that in the resting bladder in situ 5-HT (0.01-50 pg. intraarterially) causes a bimodal contraction, that is, an initial transient contraction and then a more prolonged contraction. Only the initial contraction was accompanied by neural firing of the pelvic postganglionic nerve. Methylsergide, which blocks the direct actions of 5-HT, blocked the late but not the early contraction. Picrotoxin, a known blocker of the excitatory action of 5-HT on the sympathetic ganglia, reversibly antagonized the early contraction but had no effect on the late contraction. Saum and de Groat concluded that the early contraction was induced by 5-HT through activation of neural input to the bladder while the late contraction was due to a direct myotropic action of 5-HT. Furthermore, although 5-HT elicits a contraction of the resting bladder, it depresses the contractile response of the bladder to stimulation of the parasympathetic innervation. They concluded that 5-HT influences bladder activity by acting on excitatory receptors in the vesical smooth muscle and on both excitatory and inhibitory receptors in parasympathetic ganglia.
Ergotamine
urethral muscle strips angiotensin (10 pg./ml.) elicits a marked increase in tension. The increase in tension is reduced by 50 per cent after the addition of phentolamine (100 pg./ml.). This finding suggests that the effect is mediated directly and through alpha-adrenergic receptors. l1 In situ angiotensin (0.5 mg./Kg.) caused an inconsistent12 but sometimes marked rise13 in urethral pressure which was partially reduced by phenoxybenzamine. l3 At a dose of 0.5 pg./Kg., angiotensin causes a delayed but longer lasting increase in resistance to flow through the urethra than does epinephrine (2.5 pg.IKg.).14 These observations suggest that angiotensin also acts on the urethra both directly and via alphaadrenergic receptors. Brudykinin. This is an endogenous plasma kinin which is characterized by very brief action. This compound is a potent vasodilator at low doses. Its effects on nonvascular smooth muscle may cause either contraction or relaxation. In isolated, innervated strips of detrusor muscle bradykinin (0.1 pg./ml.) causes a very slow contraction which is potentiated by physostigmine (0.02 pg./ml.). Atropine or hyoscine decreases this response by about one-half.’ In situ bradykinin (0.01-3 pg.) dilates the vascular bed in the bladder and elicits a contraction of the detrusor. 5 Elcdoisin and kullikreinin. Both of these drugs dilate blood vessels in the urinary bladder and cause contraction of the detrusor in situ. 5
The ergot alkaloids are stimulants of smooth muscle, probably as a result of their direct action. They cause potent vasoconstriction and uterine stimulation. In situ ergotamine (5-50 pg.) causes a slowly developing and sustained contraction of the bladder and augmentation of spontaneous detrusor activity. 5
In situ vasopressin (0.01-3 pg.) causes vesical vasoconstriction and at much larger doses contraction of the detrusor.’
Actitie polypeptides
Oxytocin
These endogenous compounds exert many effects, one of which is stimulation of smooth muscle. Several of these have been evaluated for their effects on the lower urinary tract. Angiotensin and angioten.Gn Il. Angiotensin and angiotensin II cause vasoconstriction b, direct action on vascular smooth muscle. Angiotensin is a stimulant of the central nervous system and sympathetic ganglion cells. The decapeptide facilitates ganglionic transmission. Angiotensin3 and angiotensin II” (0. l-l /.~g.Icc.) both cause contraction of detrusor muscle strips. The angiotensin-induced contraction is neither potentiated by eserine nor antagonized by mepyramine, phentolamine, or atropine.3 On
This posterior pituitary hormone causes contraction of detrusor muscle strips. This contraction is potentiated by magnesium but is not affected by eserine, mepyramine, or atropine.3 In situ, at doses of 0.01-l pg., oxytocin causes vesical vasoconstriction and contraction of the detrusor. 5
Vasopressin
(antidiuretic
hormone)
These “local tissue hormones” are ubiquitous in body tissues and appear to be modulators of intracellular metabolism. In a sequence of complex enzymatic actions, thev are released in response to nervous, chemical, or mechanical stimuli resulting in an alteration of fimction of
various organ systems. Prostaglandins act by direct effects on smooth muscle and indirectly b? modulation of the autonomic nervous system. There are indications that prostaglandins can specifically influence the adrenergic nerve terminal and ultimately alter the amount of transmitter released. They also can potentiate various qmpathomimetic substances. Distention of dog bladders in vivo resulted in release of epinephrine into the circulation in 14 of 17 dogs.‘” The rate of release depended on the pressure within the bladder. In several experiments prostaglandin-like substances were released after emptying the distended bladders. The reaction of other organ systems to this substance was the same as their reaction to prostaglandins particularly PGF2a. The release of this substance may be due, in part, to the autonomic response to urinary bladder distention and suggests that prostaglandin release may be a response to stretch. that is, a local mechanism to resist the distorting force or to accommodate to it.
In strips of rabbit bladder PGEl causes a contraction \vhich is not potentiated by eserine or antagonized by atropine, phentolamine, or mepyramine. 3 In the guinea pig and rat PGEI increased tone and motility in situ but failed to do so in vitro; it also increased the response to stimulation of the hypogastric nerve in vivo and potentiated the action of ACh both in vivo and in vitro. 16. PGEz and PGFzu were evaluated in strips of guinea pig detrusor. PGEz and F2a did not imitate the rapid twitch evoked by electrical stimulation. PGE2, even at doses of 500 ng./ml., caused only sluggish and greatly delayed contractions beginning twenty to thirty seconds after their administration. The effect was long lasting and persisted for ten minutes after PGEz was washed from the system. The effect of PGF2a was even \veaker than that of PGE2.’ The competitive antagonist SC-19220 is known to abolish the action of PGEl and PGE2 on other preparations of smooth muscle. In a concentration of l-.5 pg./ml., the drug failed to block the response to PGEz or to reduce the twitches elicited by a single pulse. Ten pg. of SC-19220 reduced the response of detrusor strips to PGE2 (50 ng./ml.) by 76 per cent. At the same time the responses to 1-5 electrical pulses only diminished by 7 to 23 per cent.2 Another prostaglandin antagonist, polypholoretin phosphate (20 ng./ml.), failed to block the effect of PGE2. In higher concentrations it cle-
pressed the detrusor muscle and abolished the contractile response to histamine, thus losing its specificity. 2 The effect of PGF2.a was e\~aluated on the bladder of dogs in vivo in which the pelvic and hypogastric nerves were seve~red. ” PGF2a (lo-100 pg.) intra-arterially caused a slight increase in intravesical pressure (,increased tone) which lasted about ten minutes. (Inlike ACh, increasing doses of PGF2cr scarcely caused an increase in response. PGFza (lo-100 pg.) also caused a transient but definite fall in perfusion pressure. Although the bladder’s vascular response to PGFza was smaller than those to ACh in corresponding doses, the response increased in a dose-dependent manner. With higher doses (30- 100 pg.) of PGFza, the initial decrease in perfusion pressure was followed 1,~. a slight but sustained increase. Tetrodotoxin (which abolishes contractions of the bladder in response to pelvic nerve stimulation) did not affect the vascular or muscular responses to PGFza (100 pg.). Physostigmine, which usually augments bladder contractions in response to submaximal pelvic nerve stimulation and to ACh, had no effect on vascular or muscular responses to PGF2a. Since the response to PGF2a is not neural excitation is abolished by tetrodotoxin, apparently not involved in producing the response. Also the response is not altered by physostigmine, suggesting the absence of a cholinergic component. It is highly probable that PGFza elicits the bladder contraction and vesical vasodilation by a direct action. Ii Direct-acting
Smooth
Muscle
Depressants
Vasodilators (dipyridamolr, hydraltrzine, nitroglycerine, papaceriw i These drugs are classified together because of their common action on vascular smooth muscle. Each dilated the vesical bed without influencing the musculature of the bladder in situ.5 Mebeverine (100 mg. intramuscularly) had no effect on normal human bladders as monitored clinically by cystometry. lx
This xanthine is a central ner\‘ous system stimulant, a cardiac stimulant, and ..I diuretic. It acts directl!. on smooth muscle (notably bronchial smooth muscle) to cause relaxation. On detrusor muscle strips theophylline (_jOO /+/ml.) causes a decrease in spontaneous rhythmic activity and a decrease in baseline tension. ‘!’ At a
dose of 500 pg./ml. it affects bethanecholinduced contractile response by increasing the threshold concentration of bethanechol necessary to elicit a response, decreasing the force of contraction and delaying its onset of action. l9 Conflicting reports were published regarding the in situ effect of theophylline on the detrusor. Theophylline (5-10 mg./Kg.) was reported to cause a decrease in intravesical baseline pressure in one report’” buy no effect was reported in another.”
Flavoxate
hydrochloride
(Urispus)
Flavoxate hydrochloride is a tertiary amine chromone which selectively acts directly on the bladder producing relaxation.*’ Experimental studies on nonbladder smooth muscle reveal that flavoxate has no atropine-like action and does not interfere with the autonomic nervous system. It does, however, possess marked analgesic and local anesthetic action. *’ recepBenson et al. ** assessed the cholinergic tor blocking ability and direct muscle inhibitory effects of atropine, propantheline, flavoxate, and imipramine on dog detrusor strips. They concluded that flavoxate produced very minimal decreases in both the bethanechol (cholinergic) and barium chloride (direct smooth muscle)induced contractions. In fact, flavoxate exhibited slightly greater anticholinergic than musculotropic relaxant properties. They further stated that the reportedly marked clinical benefits derived from flavoxate could be secondary to a musculotropic relaxant action not related to its known analgesic and local anesthetic properties. Clinical studies evaluating the effectiveness of flavoxate on the urinary tract include adult patients with frequency, urgency, dysuria, nocturia, and suprapubic discomfort. Symptoms improved in about two thirds of the patients treated with 200 mg. flavoxate hydrochloride four times a day for seven days.*” Flavoxate (200 mg. four times a day) was significantly better than phenazopyridine (Pyridium, 200 mg. three times a day) in providing symptomatic relief in patients with prostatitis, cystitis, urethritis, and trigonitis. 24 In 25 patients with neurogenic bladder disease flavoxate (200 mg.) produced an increase in bladder c’apacity with little or no change in resting bladder pressure. The side effects were minimal compared with propantheline.” treated 38 patients who had Stanton’” symptoms of urinary frequency, urgency, and incontinence secondary to various etiologies
234
with flavoxate hydrochloride 200 mg. orally three times a day. Stress incontinence and urgency improved in 75 to 85 per cent of the patients with detrusor instability and in 50 per cent with sphincter dysfunction. Flavoxate reduced diurnal frequency in all patients. Three of the 38 patients had side effects of drowsiness, bloating, and depression. Urethral pressure profiles were unaltered by flavoxate therapy. Cystometrograms before and after therapy revealed no changes in residual urine volume. Flavoxate therapy resulted in a decrease in intravesical pressure, increased capacity, and a delay in the sensations of first and strong desires to void.
Oxybubynin
chloride (Ditropan)
This newly available tertiary amine with smooth muscle depressant properties has been discussed previously in this series. 26
Dicyclomine
(Bentyl)
Dicyclomine has been shown to have a direct smooth muscle relaxant effect as well as antimuscarinic action on guinea pig ileum.27 In a clinical study’” 27 patients with symptoms of increased urinary frequency, urgency, nocturia, suprapubic discomfort, and urge incontinence were treated with dicyclomine. Cystometrograms were performed before and after the administration of dicyclomine. Dicyclomine administered intramuscularly (20 mg.) significantly increased bladder capacity and, when given orally (20 mg. three times a day for four to eight weeks) increased bladder capacity and the patient’s symptoms improved. When dicyclomine was given orally, improvement was not observed for seven to ten days, and an eightweek course was necessary to achieve a maximum subjective response. None of the patients had significant side effects. Little Rock, Arkansas 72201 (DR. FINKBEINER)
UROLOCX i AUC:VST 1978 / \‘OLU\4E X11. Nt_‘\lBEH 2
ical hth;r\ ior of tl (CAurinay bladder and its \ascrllatllrc~ of the dog. Tohoku J, Exp. Med. 96: 247 ,1968!. 6. \Vwtmatr DF: The guinea-pig isolated, innen atrd lhtldr~ preparation: the rffrcts of some autonomic drug\. Arch. Int. Pharmacody Ther. 1%: 383 (19721. 7 Hukovic S. Rand SlJ. and Vanm S: Olarrvation on an iwIatrd, innewatcd preparation of rat urinal? hladdc~r. RI-. J. Phart~~acol. 24: 1% (1965). 8. Van~n S: Rrspon~~*s of the rat urinary, bladder in situ to drugs and to nene stimulation, ibid. 24: 581 ~1965). 9. Tairu N: Thch autonomic pharmacolog) of the hlxldcr. 4nnu. Rrv. Pharmawl. 12: 197 [1972) 10. Saum \VR. and de Groat \t’(:: Thr actions of ,j-h~drox?-t~l,talnin~ on thr urinary bladder and on vesical autonomic ganglia in the, cat. J. Pharmacol. Exp Thor 185: 70 (1973i. 11. Ral S, Zeiglrr X1, and Cainr SI: Isometric studicls on canine urrthral muwrllatnw, Invest. 1lrol. 9: 443 / 1972). 12. Tanagho E4, and 542levrrs FH: The “internal sphincter”: 1s it Ilndrr \ympathrtic control’? ibid. 7: 79 (1969). 13. Raz S. ;u~d Caine hl: Adrenrrgic rweptors in thr femal(~ hid. 9: 319 j 1972). caCnr ur(&x. 1-L. Tanagho E.4. &Icyers FH, and Smith DR: I’rethral reistancc: its wmponents and implications. ibid 7: 136 (1969~. IS, Crimson KS, Orgain ES, and Rowr CR, Jr: Caution with regard to USC of I,~zamt,thollirlln and “.4presolinr.” J. A. IL1.A. 149: 215 (1952‘. 16. I\‘amzada blK: .4cticm of prostaglandin El 011 the hladdrr, Boll. Sot. Ital. Biol. Sper. 43: S18 (1967). Ii’. Taira \ : Mode of actions of prostaglandin Fz, on the rlrinary IMdrr and its artrrial lwd in thr dog, Europ J. Pharmxol. 29: 30 (1974).
\‘ROLOC:Y
4I’GUST
197X
/
VOLUVE
91.
YI’\IBER
2
the> smooth m~~wle of thr I&ddrr. RI-. J. I’IoI 44: .31 (lS72). 19. Ixoni J. \f’cin .4J. and Schocmlwrg II\\‘: Thr, r+Twts of iv)protcrenol and aminophyllinc on tlvtruol- tnr~v~lr c,(mtractilit> in an organ hath apparatus. In\cst. L i-01. 10: 458 , 1973l. 20. Stanton SL: A comparison of emepron~rlm hronridv and H;nwatc hydl-ochloridr in the twatnwnt of Iuiwl-\ incotltinrwcc~. J. L’1.01. 110: 529 (1973).
22. Benaon (ZS. Sar\hik SA. Raescr DCl. .tnd \V(,in .4J Bl;<~~ muscle contractilit> : cw~~parative rfFects and mrxhanisrns of action of atropine, propanthelinr, Havoxatta. and inlilx.uninc*. L’rolo~ 9: :31 (1977). 23. Bradley D\.. and Cavort RJ Relic~f of hladtlc~r spasm I)! Havosate. A comparative study, J. (:lill. Pharn~u)l. 10: 6.5 (19701. 24. Gould S. L’rinary tract disordrrs: clinic,al c~onrp;wison of’ Havoxate and I)l1ella~np).ridille, Urology 5: 612 197Fil. of’ fl;n 25. Kohler FP, and Morales PA. Cystonretric r\aluation oxate hydrochloride in normal and ncwrtrgrrlic~ Ibluddr~rs. J. Ural. 100: 729 (1968). 26. Finkhrincr 4E, Bissada h K. nnd \l’elch 1,T: (‘ropharmacology, Part VI. Parasympathrtic dtyrwsu~ts. Ilrolog! 10: 503 f19771. 27. lic(l;rath \VR, Lrwis HE, and Kuhn i\.L,: Thr, dud modem of thr antisp”.s”lodi~ &ct of dicycllnniw h~tlrr)~~l1l,)ritlr, J Phw macol. Exp. Ther. 146: 354 (1964). 28. Awxl S.4, Bryniak S, Do\vnic J1V. ;md Brwc .-\\I~. Tht~ treatment of the uninhihitcd hladtl~~r \\ith rlic~\cl~mrint~. J. L’r~ll. 117: 161 (19771. 29. \Vtain AJ. (Gregory JC;, Sansorw T(:. ,md Schormlxq Ii\\‘: The effects of arninophylline on uwthral md hlarldc~r contractilit) Invest. LTrol 9: 290 (1972).