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ORIGINAL ARTICLE
Year : 2010 | Volume : 26 | Issue : 3 | Page : 364--368
Commonly used intravenous anesthetics decrease bladder contractility: An in vitro study of the effects of
propofol, ketamine, and midazolam on the rat bladder
Canan Ceran1, Arzu Pampal2, Ozgur Goktas3, H Kutluk Pampal4, Ercument Olmez3, 1 Department of Pediatric Surgery, Inonu University, Malatya, Turkey
2 Department of Pediatric Surgery, Ufuk University, Ankara, Turkey 3 Department of Pharmacology, Inonu University, Malatya, Turkey
4 Department of Anesthesiology and Reanimation, Mesa Hospital, Ankara, Turkey Correspondence Address:
Arzu Pampal
Ufuk Universitesi Tip Fakultesi, Cocuk Cerrahisi Bolumu, Konya Yolu No: 86-88 Balgat 06520 Ankara Turkey
Abstract
A m : Th s study was des gned to test the hypothes s that propofol, ketam ne, and m dazolam could alter the contract le act v ty of detrusor smooth muscle. Mater als and Methods : Four detrusor muscle str ps solated from each rat bladder (n = 12) were placed n 4 t ssue baths conta n ng Krebs-Hensele t solut on. The carbachol (10 -8 to 10 -4 mol/L)- nduced contract le responses as well as 5, 10, 20, 30, 40, 50 Hz electr cal f eld st mulat on (EFS)-evoked contract le responses of the detrusor muscles were recorded us ng sometr c contract on measurements. After obta n ng basal responses, the n v tro effects of propofol, ketam ne, m dazolam (10−5 to 10−3 mol/L), and sal ne on the contract le responses of the detrusor muscle str ps were recorded and evaluated. Results : All the 3 drugs reduced the carbachol- nduced and/or EFS-evoked contract le responses of rat detrusor smooth muscles n d fferent degrees. M dazolam (10−4 to 10−3 mol/L) caused a s gn f cant decrease n the contract le responses el c ted by e ther EFS or carbachol (P=0.000-0.013). Propofol (10−3 mol/L) caused a decrease only n EFS-evoked contract le responses (P=0.001-0.004) and ketam ne (10−3 mol/L) caused a decrease only n carbachol- nduced contract le responses (P=0.001-0.034). Conclus on : We evaluated the effects of the 3 d fferent ntravenous anesthet cs on detrusor contract le responses n v tro and found that there are poss ble nteract ons between anesthet c agents and detrusor contract le act v ty. The depressant effects of m dazolam on the contract le act v ty were found to be more s gn f cant than ketam ne and propofol. Desp te the necess ty of further stud es, t could be a p ece of w se adv ce to cl n c ans to keep the probable alterat ons due to ntravenous anesthet cs n m nd, wh le evaluat ng the results of urodynam c stud es n ch ldren under sedat on.
How to cite this article:
Ceran C, Pampal A, Goktas O, Pampal H K, Olmez E. Commonly used intravenous anesthetics decrease bladder contractility: An in vitro study of the effects of propofol, ketamine, and midazolam on the rat bladder.Indian J Urol 2010;26:364-368
How to cite this URL:
Ceran C, Pampal A, Goktas O, Pampal H K, Olmez E. Commonly used intravenous anesthetics decrease bladder contractility: An in vitro study of the effects of propofol, ketamine, and midazolam on the rat bladder. Indian J Urol [serial online] 2010 [cited 2018 Jul 31 ];26:364-368
Available from: http://www.indianjurol.com/text.asp?2010/26/3/364/70570
Full Text
Introduction
Urodynam c study s a matter of cho ce n the cl n cal pract ce to evaluate not only the funct onal d sorders of the lower ur nary tract but also the coord nat on between detrusor muscle and sph ncter. It s generally d ff cult to perform n ch ldren, and sedat on s somet mes needed dur ng th s evaluat on n ch ldren.
As most of the d agnost c and endoscop c procedures are performed under sedat on, the nteract ons between the anesthet c drugs and the r effects on the organs and systems have ga ned mportance. Many of the ntravenous anesthet cs are known to relax the smooth muscles and/or decrease the contract le responses of the smooth muscles of var ous organs. [1],[2],[3],[4], [5],[6],[7],[8],[9],[10],[11] However, there s l m ted data n the l terature about the effects of ntravenous anesthet cs on the contract le act v ty of the bladder smooth muscle. [12],[13],[14] Desp te the w despread usage of the anesthet cs dur ng urodynam c stud es n cl n cal pract ce, t s probable that ntravenous anesthet cs could affect the contract le act v ty of detrusor smooth muscle and could nterfere w th the results obta ned from the pat ents.
Th s study s undertaken to determ ne the probable effects of commonly used 3 ntravenous anesthet cs (propofol, ketam ne, and m dazolam) on rat detrusor smooth muscle contract le responses.
Materials and Methods
The study protocol was approved by the An mal Eth cs Comm ttee and performed accord ng to the gu del nes of the Research Comm ttee of Faculty of Med c ne at Inonu Un vers ty. All an mals rece ved human care n compl ance w th the "Pr nc ples of Laboratory An mal Care" formulated by Nat onal Soc ety for Med cal Research and the "Gu de for the Care and Use of Laboratory An mals" prepared by the Inst tute of Laboratory An mal Resources publ shed by the Nat onal Inst tutes of Health. Twelve young male W star alb no rats we gh ng 250-300 gr were k lled by a sharp blow to the head, wh ch was followed by exsangu nat ons. The whole bladder was exc sed and placed n a plate conta n ng oxygenated Krebs-Hensele t solut on (mmol/L: NaCl 118, KCl 4.7, CaCl 2 2.5, MgSO 4 1.2, KH 2 PO 4 1.2, NaHCO 3 25, glucose 10, pH 7.4). Four detrusor muscle str ps (2 × 8 mm) were obta ned from each an mal after cutt ng the bladder long tud nally. Each str p was only used to nvest gate the act on of one sedat ve on a s ngle type of external st mulus and then d scarded. S x an mals were used to test the effects of drugs on the EFS-evoked contract ons and 6 were used to test the effects on carbachol- nduced contract ons.
Bladder str ps were mounted n 4 vert cal chambers of 20 mL capac ty, conta n ng Krebs-Hensele t solut on and constantly oxygenated w th a m xture of 95% O 2 and 5% CO 2 . The lower end of the muscle str p was t ed to a glass hook attached to the muscle-holder and the upper end was attached to a Grass force transducer (FT03, Grass Instruments, Qu ncy, MA), wh ch was connected to an ampl f er (P-122, Grass). The analog s gnal obta ned from the force transducer was converted to a d g tal s gnal (Polyv ew, Grass) at a sampl ng rate of 5 Hz and stored on a computer n ASCII format.
Before start ng the exper ments, the str ps were allowed to equ l brate under a pass ve rest ng tens on of 1 gr for 60 m n, dur ng wh ch the bath solut on was changed every 10 m n. At the beg nn ng of each exper ment, 80 mmol/L KCl was added to the t ssue bath and the contract on was cons dered as the reference response (RR). At the end of each exper ment, the contract le response to 80 mmol/L KCl was remeasured to ver fy that the contract le mechan sms are ntact.
Evaluat ng the effects of ntravenous anesthet cs on electr cal f eld st mulat on-evoked detrusor contract ons
Follow ng the f rst KCl response, t ssues were washed tw ce and after a per od of 30 m n, electr cal f eld st mulat on (EFS), us ng Harward 50-8952 model st mulator, was accompl shed by means of 2 plat num plate electrodes, pos t oned on e ther s de of the t ssue to act vate the ntr ns c nerves (n = 6). Each st mulat on lasted 10 s at constant parameters: 50 V, 5 ms pulse
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durat on, and the frequency had been ncreased gradually (5, 10, 20, 30, 40, 50 Hz) every 2 m n. In separate ser es of exper ments, EFS was repeated n the presence of ketam ne, propofol, and m dazolam at concentrat ons of 10−5 to 10−3 mol/L n 3 of the baths and 1 bath served as control.
Evaluat ng the effects of ntravenous anesthet cs on carbachol- nduced detrusor contract ons
T ssues were washed tw ce n a per od of 30 m n follow ng the f rst KCl response, then the concentrat on-response curves to carbachol (10−8 to 10−4 mol/L) were obta ned cumulat vely (n = 6). Ketam ne, propofol, and m dazolam were appl ed (10−5 to 10−3 mol/L) n 3 of the baths and 1 bath served as control. Between each dose of the drugs, the t ssues were washed tw ce and after a per od of 30 m n, the concentrat on-response curves to carbachol (10−8 to 10−4 mol/L) were obta ned n the presence of each dose of ketam ne, propofol, and m dazolam aga n. Data analys s and stat st cs
Results are expressed as the percentages of the max mal contract ons nduced by f rst tra n of EFS n the EFS group and the max mal contract ons nduced by KCl (RR) n the carbachol group. The data were presented as the ar thmet c mean ± SEM of the number (n) of exper ments. Stat st cal analyses were performed us ng one-way analys s of var ance (ANOVA) followed by Tukey mult ple compar sons test w th commerc ally ava lable software (SPSS 10.0, Ch cago, Ill no s, USA). Values of P < 0.05 were cons dered to be stat st cally s gn f cant.
Results
KCl responsesNo stat st cally s gn f cant d fference was observed n KCl responses before and after each exper ment [Table 1].{Table 1} Effect of ntravenous anesthet cs on electr cal f eld st mulat on-evoked detrusor contract ons
H gh concentrat on of propofol (10−3 mol/L) caused a s gn f cant decrease n the contract le responses evoked by EFS at all frequenc es, whereas no s gn f cant effect was determ ned for lower concentrat ons (P = 0.001-0.004) [F gure 1]. As an example, the max mal contract le response evoked by EFS at 5 Hz was found elevated at a h gh concentrat on of propofol (10−3 mol/L) when compared w th sal ne adm n strat on (71.8 ± 5.7 vs 47.2 ± 11.8% of max mal contract on, P < 0.003).{F gure 1}
Ketam n d d not s gn f cantly change the contract le responses evoked by EFS at concentrat ons of 10−5 to 10−3 mol/L when compared w th the control values.
H gh concentrat on of m dazolam (10−3 mol/L) n the bath reduced the contract on responses of rat detrusor smooth muscle evoked by all frequenc es of EFS when compared w th the control values (P = 0.000-0.013), whereas moderate concentrat on of m dazolam (10−4 mol/L) reduced the contract le responses to EFS s gn f cantly only at low frequenc es (5 and 10 Hz) [F gure 2]. The max mal contract le response evoked by EFS at 5 Hz was found to be decreased at a moderate concentrat on of m dazolam (10−4 mol/L) when compared w th sal ne adm n strat on (54.3 ± 6.5 vs 72.7 ± 7.4% of max mal contract on, P < 0.002).{F gure 2}
Effect of ntravenous anesthet cs on carbachol- nduced detrusor contract ons
Propofol d d not s gn f cantly change the contract le responses nduced by carbachol at concentrat ons of 10−5 to 10−3 mol/L when compared w th the control values.
H gh concentrat on of ketam n (10−3 mol/L) caused s gn f cant decrease n the contract le responses nduced by carbachol at 10−7 and 10−6 mol/L concentrat ons (P=0.001-0.034) [F gure 3]. The add t on of 10−3 mol/L ketam n to the organ baths caused decreases n carbachol- nduced contract le responses from 13.3 ± 4.2 to 4.6±2.2% of max mal contract on at 10−7 mol/L carbachol (P < 0.001), and from 57.8 ± 9.2 to 23.8±5.1% of max mal contract on at 10−6 mol/L carbachol (P < 0.034).{F gure 3}
Moderate to h gh concentrat ons of m dazolam (10−4 to 10−3 mol/L) reduced the carbachol- nduced contract le responses of rat detrusor smooth muscle cumulat vely, w th s gn f cant decreases between 10−6 and 10−4 mol/L concentrat ons of carbachol (P = 0.006-0.046) [F gure 4]. The max mal contract on nduced by 10 -6 mol/L carbachol (47.5 ± 7.2%) was found to be decreased to 27.1 ± 3.6 and 20.6 ± 7.7% after add t on of 10−4 mol/L and 10−3 mol/L m dazolam to the organ baths, respect vely (P < 0.015). The max mal contract on nduced by 10−5 mol/L carbachol (97.5 ± 11.3%) was found to be decreased to 60.5 ± 7.2 and 52.1 ± 13.1% after add t on of 10−4 and 10−3 mol/L m dazolam to the organ baths, respect vely (P < 0.015). The max mal contract on nduced by 10−4 mol/L carbachol (107.2 ± 21.3%) was found to be decreased to 70.0 ± 24.2 and 57.8 ± 24.8% after add t on of 10−4 and 10−3 mol/L m dazolam to the organ baths, respect vely (P < 0.015).{F gure 4}
Discussion
Th s study nvest gated the n v tro effects of 3 ntravenous anesthet cs, m dazolam, ketam ne, and propofol, on nerve-med ated and carbachol- nduced contract ons of rat detrusor smooth muscles. Although all the 3 drugs reduced the contract le responses of the rat detrusor smooth muscle el c ted by EFS and/or carbachol n d fferent degrees, some of these results were not stat st cally s gn f cant. It was observed that 10−3 mol/L m dazolam reduced evoked contract le responses at 5, 10, 20, 30, 40, and 50 Hz and 10−4 mol/L m dazolam reduced EFS-evoked contract le responses el c ted at 5 and 10 Hz. M dazolam (10−4 to 10−3 mol/L) also reduced carbachol- nduced contract le responses at 10−8 to 10−4 mol/L concentrat ons s gn f cantly. Propofol at a concentrat on of 10−3 mol/L has s gn f cantly reduced EFS-evoked contract le responses but not the carbachol- nduced ones. In contrast, 10−3 mol/L ketam n has s gn f cantly decreased the carbachol- nduced contract le responses, but not the EFS-evoked ones.
Urodynam c stud es of the lower ur nary tract prov de useful cl n cal nformat on about the funct on of the ur nary bladder, the sph ncter mechan sm, and the vo d ng pattern tself. As the appl cat on s nvas ve and uncomfortable, sedat on s somet mes needed, espec ally n nfants and toddlers. Relat vely short-act ng anesthet c agents, such as propofol, ketam ne, and m dazolam, are matter of cho ce for such ntervent ons. However, there s very l m ted data about the effects of these agents on the bladder contract l ty. In order to evaluate these effects, an
n v tro study w th l m ted number of an mals was performed.
The contract le responses ga ned from the appl cat on of EFS to a muscular str p g ve nformat on about the whole neuromuscular junct on (NMJ), nclud ng presynapt c and postsynapt c area. Appl cat on of exogenous carbachol, a chol nerg c agon st, causes a contract le response v a postsynapt c muscar n c receptors. Therefore, an appropr ate response to the exogenous chol nerg c agon st advocates a v gorous postsynapt c area. [15] In th s study, we appl ed EFS and carbachol to the muscular str ps n order to evaluate the contract le act v ty of detrusor muscle and KCl n order to cons der the reference response.
Propofol, ketam ne, and m dazolam are commonly used anesthet c agents for sedat on dur ng d agnost c or endoscop c procedures. The r usage s advantageous because they have not only short act on durat on but also rap d onset of act on. [16],[17],[18] Bes des the r well-known central nervous system depressant effects, there s l m ted data n the l terature about the effects of these anesthet c agents on the autonom c nervous system.
As an anesthet c agent, propofol s known to produce parasympathet c predom nance n the body. Its relaxant effects on tracheal smooth muscle, gastr c or colon c muscle, pregnant uter ne muscles, and d aphragm have been presented n the l terature. M lls et al. found that propofol decreased the bladder compl ance n p gs and atrop ne antagon zed th s act on. [14] They concluded that the decrease n compl ance seen n the p g bladder after sedat on w th propofol s med ated v a muscar n c exc tat on. Th s study showed that a h gh concentrat on of propofol (10−3 mol/L) reduced EFS-evoked contract le responses s gn f cantly. But no d fference on contract le responses was observed dur ng carbachol- nduced contract ons. Further rad ol gand stud es are needed n order to conf rm these changes on the molecular aspects and to prove the underly ng mechan sm.
Ketam ne s known to have sympathoexc tatory effects w th unexpla ned act on mechan sms. The effects of the drug are med ated by N-methyl-d-aspartate, op o d, muscar n c, and d fferent voltage-gated receptors. [17] Moreover, ts d rect effects on both α1- and β2 -adrenoreceptors of the ur nary bladder and urethra were demonstrated by Bevan et al. [21] In our study, we found that 10−3 mol/L ketam ne reduced carbachol- nduced contract le responses s gn f cantly, but d d not affect the contract le responses el c ted by EFS.
M dazolam decreases ton c sympathet c act v ty. [18] Its depressant effects on CaCl 2 , KCl, and Ach- nduced contract ons of the ur nary bladder were demonstrated by Mart -Cabrera et al. [12] Also, Symth et al. demonstrated the presence of per pheral-type benzod azep ne receptors n the ur nary bladder, wh ch are capable of alter ng contract l ty by the modulat on of Ca +2 act v ty n v tro. [13] In th s study, we found that a benzod azep ne der vat ve, m dazolam at moderate to h gh concentrat ons (10−4 to 10−3 mol/L) reduced both EFS-evoked and
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In an earl er study, Ghon em et al. performed a controlled study compar ng the effects of 2 anesthet cs (flurane and ketam ne) on urodynam cs n a pr mate model and found that anesthes a has a profound effect on the bladder funct ons and capac ty. [23] They proposed ketam ne as a su table agent for urodynam c stud es n nonhuman pr mates. Be ng comparable w th th s study, we too suggest ketam ne for urodynam c stud es as t has less depressant effects on detrusor contract l ty when compared w th the other anesthet c agents.
Bozkurt et al. nvest gated the effects of m dazolam on urodynam cs n ch ldren and reported that m dazolam adm n strat on has not changed the results. [24] In our study, we demonstrated that moderate to h gh concentrat ons of m dazolam reduced detrusor contract l ty s gn f cantly. Th s d vers ty can be attr buted to the heterogene ty of the cl n cal study group presented by Bozkurt et al. They have performed th s study on 20 pat ents, most of them hav ng anorectal malformat ons and the ch ldren w th anorectal malformat ons m ght have defect ve bladder funct ons due to e ther pr mary pathology or secondary to the operat ons.
Plasma levels needed for hypnos s and amnes a n humans are approx mately 100-200 ng/mL for m dazolam, 85-160 ng/mL for ketam ne, and 2-6 μg/mL for propofol. [22] When the fact that these drugs are s gn f cantly prote n-bound s also taken nto account, t s almost certa n that the concentrat ons used n th s study are relevant to cl n cal pract ce.
The l m tat on of th s study was the lack of appl cat on of receptor blockers, such as tetrodotox n to the organ baths, wh le evaluat ng the effects of anesthet cs. A further study evaluat ng such nteract ons would probably g ve more deta led nformat on about the effects of the anesthet cs at the NMJ and the type of the contract le response due to e ther nerve st mulat on or muscle depolar zat on.
In conclus on, we demonstrated that the anesthet c agents, espec ally m dazolam, depress the n v tro detrusor contract ons s gn f cantly. These results br ng to focus the effects of anesthet c agents on urodynam cs. Further stud es evaluat ng the effects of agon sts and antagon sts on the contract le responses n detrusor muscle under sedat on, the urodynam c changes n human be ngs under sedat on, or the effects of t trat on of the anesthet c agents used dur ng urodynam c stud es are needed to def ne the underly ng mechan sms of the
nh b tory effects of anesthet c agents on the detrusor muscle. We also th nk that the cl n c ans should bear n m nd the probable alterat ons due to ntravenous anesthet cs, wh le evaluat ng the results of urodynam c stud es n ch ldren under sedat on.
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