Research in Veterinary Science 1991, 50, 259-263 c~- and/3-adrenoceptors in the sheep urinary bladder

L. RIVERA*, S. BENEDITO, D. PRIETO, M. HERNANDEZ, A. LABADIA, A. GARCIA-SACRISTAN, Departamento de Fisiolog&, Facultad de Veterinaria, Universidad Complutense, 28040-Madrid, Spain

A study was undertaken to determine the presence /3-adrenoceptor subtype varies according to the and distribution of c~- and ~3-adrenoceptors in the species; the ~-adrenoceptors present in the bladder of sheep bladder body and base. In the bladder body, the cat are of the/31-subtype (Nergardh et al 1977), noradrenaline and isoproterenoi induced relaxation whereas in pigs (Larsen 1979), rabbits (Anderson and which was significantly inhibited by propranolol, Marks 1984), cattle (Garcla-Sacristgm et al 1985) and pafenolol and butoxamine. In the presence of pro- horses (Labadla et al 1988) they are of the j32-subtype. pranolol (10 -s M), noradrenaline induced a small c~-adrenoceptors predominate in the bladder base contraction, as well as phenylephrine, but B-HT 920 (Edvardsen and Setekleiv 1968) and produce its con- failed to cause any effect on the bladder body. In the traction. This contractile effect is a result of the bladder base, noradrenaline caused a contraction that stimulation of either one or both of the c~-adreno- was significantly inhibited by prazosin but not by ceptor subtypes and also varies between species. yohimbine. Phenylephrine also induced a contractile Obviously there are important differences between response in this structure which was inhibited by species relating to the presence of adrenergic receptors prazosin, lsoproterenoi caused a relaxation that was in the urinary bladder. As no information has been significantly inhibited by propranolol and pafenolol provided for the sheep, the present study was under- but not by butoxamine. Relaxation was mediated by taken to investigate the distribution and the both ~t and/~2-adrenoceptors in the detrusor muscle functional control of the different adrenergic receptor and by /~l-adrenoceptors in the bladder base. r types and subtypes in the urinary bladder body and cq-adrenoceptors contributed to maintain the base of the sheep. detrusor tone and contract the bladder base.

THE autonomic nervous system plays an important Materials and methods role in regulating the activity of the smooth muscle of Twenty male lambs, three to four months old, with the urinary bladder in animals and man (Edvardsen no apparent lesions in their urinary tract, were and Setekleiv 1968, Gosling et al 1977, Larsen 1979) selected from the local slaughterhouse. Urinary and is of considerable importance during the storage bladders were removed immediately after death and phase of micturition (Edvardsen 1967), exerting an the adjacent connective and fatty tissues were inhibitory effect on the detrusor muscle and at the removed with care. same time producing contraction of the bladder base Strips of smooth muscle of the body and bladder smooth muscle (Edvardsen and Setekleiv 1968). base (8 to 10 mm long and 2 to 5 mm wide) were However, pharmacological studies have also obtained from each urinary bladder by means of demonstrated the existence of different adrenergic longitudinal incision. The strips were set up in a 30 ml receptor subtypes distributed throughout the urinary organ bath containing a modified Krebs solution bladder. These receptors belong to the c~- and (PSS) maintained at 37°C and bubbled with a mixture ~-adrenoceptor subtypes and their distribution of 95 per cent oxygen and 5 per cent carbon dioxide varies depending upon the portions of the bladder resulting in pH 7.4. The composition of the PSS was under study (Edvardsen and Setekleiv 1968, Levin et (in mM): sodium chloride 119; potassium chloride al 1980, Garcla-Sacrist~m et al 1985, Labadia et al 4-6; calcium chloride 1-5; magnesium chloride 1.2; 1988). sodium bicarbonate 24.9; glucose 11; ethylene- ~3-adrenoceptors predominate in the bladder body diamine tetraacetic acid (EDTA) 0"07. The proximal smooth muscle and produce relaxation. The portion of the strip was connected to an isotonic force transducer (Hugo Sachs Elektronik TVP B 368) when *Present address: Departarnento de Fisiologia, Facultad de recording contractile activity and to an isometric Veterinaria, Universidad Complutense, 28040-Madrid, Spain force transducer (Grass FT 03 C) when recording

259 260 L. Rivera, S. Benedito, D. Prieto, M. Herndndez, A. Labadfa, A~ Garc[a-Sacristdn

TABLE 1 : pD 2 values (expressed as - log EC50) for isoproterenol pafenolol, which was dissolved in 95 per cent ethanol, in the sheep bladder body, relating to the inhibition of propranolol and prazosin, which was dissolved in distilled water at (10 -6 M), pafenolol (10 -5 M} and butoxamine (10 -5 M). Values are expressed as mean 4- SEM (n = 4) 50°C, with a pH of 4-0 and under constant agitation for 20 minutes. Agonist Antagonist pD 2 ( - log EC50) Isoproterenol 8.68 4- 0' 10 Isoproterenol Propranolol 7" 03 4- 0" 28* * * Results Isoproterenol Pafenolol 5.99 4- O- 49* ** Isoproterenol Rutoxamine 8.33 4- 0.07* Spontaneous activity * Significantly different from isoproterenol at P< 0" 05 After 60 to 90 minutes' adaptation, all muscle strips * ** Significantly different from isoproterenol at P < 0. 001 from the body and base of the sheep urinary bladder exhibited a rhythmic spontaneous activity, charac- relaxant activity. The distal end of the preparation terised by the presence of phasi c contractions. The was fixed to the organ bath base. Isometric force amplitude of the contractions was smaller at the base transducers were used for recording relaxant activity, than in the bladder body, the frequency being 2.1 which could be observed in isometric recordings but contractions rain- 1in the detrusor muscle and 2.0 at not in isotonic ones (Karaki et al 1984). Preparations the bladder base. No significant difference between were allowed to equilibrate for at least 60 minutes the two structures was observed. under 2 g tension before the start of the experiment. Cumulative concentration response curves to Detrusor muscle agonists were obtained. The agonists were added Noradrenaline (10-8-10 -4 M) and isoproterenol directly to the bath and the concentration was ( I 0 - 9.10- 6 M) caused a dose-dependent relaxation of increased as soon as there was a stable response. detrusor smooth muscle strips. The relaxant response When studying relaxation, an increased concentra- to isoproterenol was greater in detrusor than in tion of the agonist was added to the bath at intervals bladder base, whereas the pD z values were similar in of 10 minutes. The apparent potency of an agonist both tissues (8.68 ± 0.10 and 8.12 ± 0 • 10, respec- was expressed by its pD 2 value, that is, pD 2 = log EC50 tively). Pretreatment with propranolol (10 -6 M) (- log of the molar concentration that had an effect resulted in a rightward shift of the isoproterenol dose- equal to 50 per cent of the maximal effect tested on the response curve (P<0"001) (pDz: 7.03 ± 0"28). same strip as reference). Adrenergic antagonists were Pafenolol (10 -5 M), a 31-adrenergic blocker, induced allowed to equilibrate with the preparations 20 an inhibition of the relaxant effect of isoproterenol minutes before a new concentration response curve of the agonist was repeated. The results are expressed as mean ± standard error H Isoproterenol of the mean of four experiments per dose and the Saibutamol statistical evaluation was calculated using Student's t 100- test. The following drugs were used: B-HT 920 (5-allyl- 2-amino-5,6,7,8-tetrahydro-4H-thiazolo = (4,5- d)azepin-dihydrochloride) (Dr Karl Thomae); butox- amine hydrochloride (Burroughs Wellcome) isopro- terenol hydrochloride (Boehringer Ingelheim); nor- adrenaline hydrochloride (Serva); pafenolol hydro- chloride (courtesy of Dr Nyborg, Aarhus, Denmark); 50- phenylephrine hydrochloride (Sigma); phentolamine hydrochloride (Sigma); prazosin hydrochloride (Pfizer); propranolol hydrochloride (If0; salbutamol sulphate (Glaxo); yohimbine hydrochloride (Sigma). All drugs were dissolved in PSS daily except

TABLE 2: pD 2 values (expressed as - log ECS0) for salbutamol in the sheep bladder body, relating to the inhibition of butoxamine (10 -5 M). Values are expressed as mean 4- SEM (n=4) I I I 8 7 s ; Agonist Antagonist pD 2 ( - log EC50) -Log (M) Salbutamol 6.48 4- 0- 08 Salbutamol Butoxamine 4.77 4- 0.14" FIG 1 : Dose-related relaxation of the sheep bladder body induced by 3-adrenoceptor agonists: Isoproterenol and salbutamol. Each * Significantly different from salbutamol at P < 0.05 point represents the mean ± SEM of four experiments per dose Adrenoceptors in the urinary bladder 261

TABLE 4: pD 2 values (expressed as - log EC60) for phenylephrine in the sheep bladder base, relating to prazosin (10- 7 M). Values Prop'aoo,o, ; ; ; ; " are expressed as mean ± SEM (n = 4) 10~M -log (M) Agonist Antagonist DD 2 ( - log EC50) Phenylephrine 5.83 + 0.18 Phenylephrine Prazosin 3.26 ± 0- 05* *

• * Significantly different from phenylephrine at P < 0-01

j~'~'-~ (b) fashion. Because of this, specific agonists of the cq p~ • • • Q • • and o/2 adrenergic receptors subtypes were used. Pro anolol 8 7 6 5 4 Phenylephrine (10-8-10 -4 M), a specific c~l-agonist, lOSM -log (M) also induced small but detectable concentration- 0.5g dependent contractions in this tissue. However, B-HT 1 920 (10-8-10 -4 M), a specific a2-agonist, failed to 4 rain cause any effect on the bladder body of the sheep (Fig 2a,b,c).

(c) Bladder base Prop~anolol ; ; ; ; ; • Noradrenaline (3 x 10-7-10 -4 M) induced a dose- 10"~M -log (M) dependent contraction of the bladder base smooth FIG 2: Dose-related contraction of the sheep bladder body muscle. This contractile effect was significantly induced by c~-adrenoceptor agonists: noradrenaline (a), phenyl- ephrine (b) and B-HT 920 (c), when/~-adrenoceptors are blocked inhibited by phentolamine (10 -7 M) (P < 0-01) (pD2: with propranolol ( 10- 5 M). The concentrations are expressed as 4.02 ± 0- 13) and prazosin (10 -7 M) (P <0.01) (pDz: ( - log M) and were added at the point marked ( • ) 3.66 ± 0-50). In contrast, yohimbine (10 -7 M), a specific c~2-antagonist, did not affect the contraction induced by noradrenaline (pDz: 4.97 ± 0.06) (P<0.001) (pD2:5-99 ± 0.49). Butoxamine (Table 3). Phenylephrine (10-7-3 × 10 -5 M) elicited a (10 -s M), a /32-adrenergic blocker, elicited an contractile effect in a dose-dependent manner, and inhibitory effect on the response of detrusor smooth this effect was inhibited (P<0-01) (PD2:3.26 ± muscle to isoproterenol (P<0-01) (pD2:8"33 ± 0"05) by previous administration of prazosin 0.07) (Table 1). Salbutamol (10-9-3× 10 -s M), a (10 -7 M) (Table 4). The potency (expressed as pD2) ~2-adrenergic agonist, induced relaxation of the of phenylephrine (5.83 ± 0-10) was similar to that of bladder body of the sheep in a dose-dependent noradrenaline (5-35 ± 0-13). manner. Butoxamine (10 -s M) induced a shift to the Isoproterenol (10-9-3× I0 -6 M) (PD2:8.12 ± right of the dose-response curve of salbutamol 0.16) caused a concentration-dependent relaxation of (P<0-05) (pD2:4.77 ± 0.14) (Table 2). Further- the bladder base strips. Pretreatment with pro- more, the potency (expressed as pD2) of isopro- pranolol (10 -6 M) and pafenolol (10 -5 M) inhibited terenol (8-68 ± 0.10) was higher with respect to that the relaxant response to isoproterenol with a statis- of salbutamol (6.48 ± 0.08) and the maximum effect tically significant reduction (P < 0.01) (pD2:6.81 ± (Emax) observed with isoproterenol was 22 per cent higher than that obtained with salbutamol (Fig 1). 0.18) and (P<0.001) (PD2; 6.01 ± 0" 14), respec- tively. Butoxamine did not exert any effect on the iso- In the presence of propranolol (10 -5 M), nor- adrenaline (10-s-10 -3 M) induced a slight contrac- proterenol-induced relaxation (PD2:7-83 ± 0-16) (Table 5). tion of the bladder body in a concentration-dependent

TABLE 5: pD 2 values (expressed as - log EC50) for isoproterenol TABLE 3: pD 2 values (expressed as - log ECS0| for noradrenaline in the sheep bladder base, relating to the inhibition of propranolol in the sheep bladder base, relating to the inhibition of phentol- (10 -6 M), pafenolol (10 -5 M) and butoxamine (10 -5 M). amine (10 -7 M), prazosin (10 -7 M) and yohimbine (10 -7 M). Values are expressed as mean + SEM (n = 4) Values are expressed as mean ± SEM (n = 4) Agonist Antagonist pD 2 (-log EC50) Agonist Antagonist pD 2 ( - log EC50) Isoproterenol 8. 12 ± 0.16 Noradrenaline 5- 35 ± 0" 13 Isoproterenol Propranolol 6.81 + 0.18* * Noradrenaline Phentolamine 4.02 ± O" 13* * Isoproterenol Pafenolol 6.01 ~ 0.14" * * Noradrenaline Prazosin 3" 66 + 0" 50"* Isoproterenol Butoxamine 7 • 83 =~ 0 • 16 NS Noradrenaline Yohimbine 4.97 ~- O. 06 NS NS Not significant NS Not significant * * Significantly different from isoproterenol at P < 0-01 * * Significantly different from noradrenaline at P < 0" 01 * * * Significantly different from isoproterenol at P

Discussion smooth muscle, this relaxation being blocked by butoxamine. These results are, therefore, consistent The detrusor and bladder base smooth muscle of the sheep showed spontaneous activity. The with those obtained in rats (Elmer 1974), pigs (Larsen 1979), cattle (Garcia-Sacrist~,n et al 1985), rabbits frequency of the contractions observed was similar in both structures and this is in agreement with Brading (Morita et al 1986) and horses (Labadia et al 1988). (1987), who did not find a significant difference in However, we cannot exclude /3~-adrenoceptor these tissues in either man or pig. activity in the sheep detrusor smooth muscle relaxa- The fact that noradrenaline caused a relaxation of tion because the relaxant response to isoproterenol the detrusor smooth muscle strips could indicate the was inhibited by pafenolol and the relative potency presence of ~-adrenoceptors in the sheep detrusor (expressed as maximum effect, Emax) of isopro- smooth muscle. Isoproterenol, a non-selective fl- terenol was greater than salbutamol. These results are adrenergic stimulant, caused a dose-dependent consistent with those obtained in rabbit urinary relaxation of the sheep detrusor muscle. This is bladder by Anderson and Marks (1984) who demon- consistent with observations by other authors in cats, strated the presence of both/3 Zand/32-adrenoceptors rabbits and guinea pigs (Edvardsen and Setekleiv by means of binding studies. 1968), man (Nergardh and Boreus 1972, Downie et al The relaxant response of the sheep bladder base to 1975), pigs (Larsen 1979), cattle (Puente et al 1981, isoproterenol could be considered to be mediated by Garcia-Sacrist~in et al 1985) and horses (Labadia et al /3t-adrenoceptors, because of the inhibition by 1988). Isoproterenol also induced relaxation of sheep pafenolol of the isoproterenol relaxing response, and bladder base in a concentration-dependent manner, in the lack of effect of butoxamine inhibiting the isopro- agreement with that obtained in man and cat by terenol action. Although relaxation of most smooth Nergardh and Boreus (1972) and rabbit by Levin et al muscles is mediated by /32-adrenoceptors (Garcia- (1980). The present authors' results show that the iso- Sacrist~in et al 1984, 1985, 1986, Labadia et al 1988), proterenol-induced relaxation was greater in detrusor relaxation of the cat urinary bladder (Nergardh et al than in bladder base smooth muscle at higher con- 1977), guinea pig ileum (Grassby and Broadley 1984), centrations. However, no significant differences in canine coronary left artery (O'Donell and Wanstall the pD 2 values for isoproterenol were observed 1985) and resistance coronary vessels (Nyborg and between the two structures. This is in agreement with Mikkelsen 1985) is mediated by /3~-adrenoceptors, results obtained by Levin et al (1980) and Downie et al whereas relaxation of rabbit bladder base (Morita et (1975) who did not find any difference in the pD 2 al 1986) is mediated by both/31 and ~2-adrenoceptors. values of this ~3-agonist in detrusor and bladder base The contractile effect of noradrenaline and phenyl- smooth muscle. ephrine with the lack of effect of B-HT 920 on sheep When /3-adrenoceptors were blocked by pro- detrusor muscle, suggests the presence of cq-adreno- pranolol, noradrenaline produced a lesser contractile ceptors and the absence of a2-adrenoceptors in this effect than in the bladder base, suggesting a sparse structure. This agrees with the results obtained by distribution of c~-adrenoceptors in the sheep detrusor Ueda et al (1984) in the rabbit urinary bladder, who muscle. observed a sparse distribution of cq-adrenoceptors Noradrenaline produced a dose-dependent con- and the absence of a2-adrenoceptors in the bladder traction of the sheep bladder base, and this showed dome. It is also in agreement with results obtained by that ct-adrenoceptors prevail over/3-adrenoceptors in Amark et al (1986) in man and cat, who considered this tissue. This is consistent with other reports: that these c¢-adrenoceptors were situated in short ct-adrenoceptors were found to predominate in intramural parasympathetic neurones. Shapiro and proximal urethra and bladder base in dog and man Lepor (1987) have also described the presence of (Rohner et al 1971, Benson et al 1976), cattle (Garcia- c~-adrenoceptors in dog urinary bladder. The Sacrist~in et al 1985) and in the horse bladder base presence of these aradrenoceptors could be related (Labadia et al 1988). to the maintenance of detrusor tone, since Khanna et The results obtained in the sheep urinary bladder al (1981) suggested that administration of c~- revealed a regional distribution of the adrenergic adrenergic agonists in conjunction with specific receptors. /3-adrenoceptors prevailed in the bladder ~2-blockers may help to restore detrusor tone in body and a-adrenoceptors in the bladder base. This patients with atonic bladder. agrees with results obtained in dogs (Khanna et al The contractile response of the sheep bladder base 1975), pigs (Larsen 1979), cattle (Garcia-Sacrist~in et could be considered to be mediated by c~l-adreno- al 1985) and horses (Labadia et al 1988). ceptors, since prazosin inhibited the contractile These results suggest that the relaxant response of effects exerted by noradrenaline and phenylephrine. the detrusor muscle could be considered to be Moreover, the contractile effects induced by nor- mediated by /32-adrenoceptors, since both isopro- adrenaline and phenylephrine are similar in terenol and salbutamol caused relaxation of this magnitude. The fact that yohimbine failed to cause Adrenoceptors in the urinary bladder 263 any effect on the noradrenaline-induced contraction GOSLING, J. A., DIXON, J. S. & LENDOND, R. G. (1977) The supports the fact that cq-adrenoceptors mediate con- autonomic innervation of the human male and female bladder neck and proximal urethra. Journal of Urology 118,302-305 traction in the sheep bladder base. This is consistent GRASSBY, P. J. & BROADLEY, K. J. (1984) Characterization of with results obtained in cattle (Garcia-Sacristfin et al beta-adrenoceptors mediating relaxation of the guinea-pig ileum. 1985), man (Kunisawa et al 1985), rabbits (Honda and Journal of Pharmacy and Pharmacology 36, 602-607 Nakagawa 1986) and dogs (Shapiro and Lepor 1987). HONDA, K. & NAKAGAWA, C. (1986) Alpha-1 adrenoceptor antagonist effects of the optical isomers of YM-12617 in rabbit However, Ueda et al (1984) demonstrated the lower urinary tract and prostate. Journal of Pharmacology and presence of both ~ and a2-adrenoceptor subtypes in Experimental Therapeutics 239, 512-516 rabbits and Labadla et al 0988) in horses. KARAKI, H., URAKAWA, N. & KUTSKY, P. (1984) Potassium- In summary, the relaxation of the sheep urinary induced contraction in smooth muscle. Japanese Journal of Smooth Muscle Research 20, 427-444 bladder is mediated by both ~ and/32-adrenoceptors KHANNA, O. P., HEBER, D. & GORNICK, P. (1975) Cholinergic in the detrusor muscle, and by/31-adrenoceptors in and adrenergic neuroreceptors in urinary tract of female dogs. the bladder base. Contraction is mediated by Urology 5, 616-623 c~j-adrenoceptors in the bladder base and detrusor KHANNA, O. P., BARBIERI, E. J. & McMICHAEL, R. F. (1981) The effects of adrenergic agonists and antagonists on vesico- muscle, and these a~-receptors contribute to main- urethral smooth muscle of rabbits. Journal of Pharmacology and taining the detrusor tone. These results, therefore, Experimental Therapeutics 216, 95-100 suggest that during sympathetic stimulation the KUNISAWA, Y., KAWABE, K., NHJIMA, T., HONDA, K. & bladder base contracts and the detrusor muscle TAKENAKA, T. (1985) A pharmacological study of alpha- adrenergic receptor subtypes in smooth muscle of human urinary relaxes, contributing to the filling of the sheep urinary bladder base and prostatic urethra. Journal of Urology 134, bladder during the storage phase of micturition. 396-398 LABAD[A, A., R1VERA, L., COSTA, G. & GARCIA- SACRISTAN, A. (1988) Influence of the autonomic nergous Acknowledgements system in the horse urinary bladder. Research in Veterinary Science 44, 282-285 We would like to thank to Dr M. Calzas (Boeh- LARSEN, J. J. (1979) Alpha and beta-adrenoceptors in the detrusor ringer Ingelheim SA, Spain) for generously supplying muscle and bladder base of the pig and beta-adrenoceptors in the detrusor muscle of man. British Journal of Pharmacology 65, ~-HT 920. Thanks are also given to Miss Julia M. 215-222 Barton for correcting the manuscript. LEVIN, R. M., SHOFER, F. S. & WE1N, A. 3. (1980) Cholinergic, adrenergic and purinergic response of sequential strips of rabbit urinary bladder. Journal of Pharmacology and Experimental References Therapeutics 212, 536-540 MORITA, T., KONDO, S., TSUCHIDA, S. &WEISS, R. M. (1986) AMARK, P., NERGARDH, A. & KINN, A. C. (1986) The effect of Characterization of functional beta-adrenoceptor subtypes in noradrenaline on the contractile response of the urinary bladder. rabbit urinary bladder smooth muscle. Tohoku Journal of Experi- Scandinavian Journal of Urology and Nephrology 20, 203-207 mental Medicine 149, 389-395 ANDERSON, G. F. & MARKS, B. H. (1984) Beta-adrenoceptors in NERGARDH, A. & BOREUS, L. O. (1972) Autonomic receptor the rabbit bladder detrusor muscle. Journal of Pharmacology and function in the lower urinary tract of man and eat. Scandinavian Experimental Therapeutics 228, 283-286 Journal of Urology and Nephrology 6, 32-36 BENSON, G. S., WEIN, A. J., RAEZER, D. M. & CORRIERE, NERGARDH, A., BOREUS, L. O. & NAGLO, A. S. 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Revista Espanola de Fisiologfa 42, 245-250 Accepted October 26, 1990