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Effectsofpremedicationon Salivary Secretionin OsakaOsakaOdontologicalSociety Odontological Society J Osaka Dent Univ 2009 (April) ;43 (1)[119-127. Effectsof premedication on salivary secretionin the rat submandibular gland Satoko Taniwa, Kenii Uchihashi*, Junichiro Kotani** and Yasuo Nishikawa* ' Graduate Schoo/ of Dentistr)t e4nesthesioJog;c), **Department ofAnesthesiologJt and Departrnent of Physioiog}c Osaka Dentat Univetsity, 8-1 Kuiuhahanazono-cho, Hirakata-shi, Osaka 57]-1121, .lapan. During anesthesia, muscarinic parasympathetic antagonists can be used as a preopera- tive medication on order to reduce salivary tlew, tracheobronchial secretions, and pha- ryngeal secretions, as well as to decrease the acidity ot gastric secretions. We did an in vivo study to examine whether muscarinic receptor subtypes play a role in the exocrine function of the rat submandibular gland. The effects ot muscarinic antagonists (piren- zepine, methoctramine, 4-diphenylacetoxy-N-dimethylpiperidinlum (4-DAMP) and gly- copyrroLate) were examined on secretion from the submandibular gland evoked by ace- tylcholine in pentobarbital-anesthetized rats. Glycopyrrolate caused less elevation in heart rate than the other anticholinergics. 4-DAMP and glycopyrrolate markedly inhibited the acety)choline-evoked fluid responses. Pirenzepine showed signiticantly ]ower inhibi- tory potency than 4-DAMP or glycopyrrolate, while methoctramine had even less of an in- hibitory effect. Pirenzepine, 4-DAMP and glycopyrrolate significantly inhibited both protein concentra- tion and amylase activity in the acetylcholine-evoked submandibular saliva, while methoctramine did not affect the responses. The reduction ot the protein concentration and amylase activity in submandibular saliva caused by pirenzepine, 4-DAMP anci gly- copyrrolate were inhibited by NG-nitro-L-arginine methyl ester (L-NAME). Thus, it might be etfective to administer anti-cholinergic drugs together with L-NAME as premedication. These results suggest that glycopyrrolate significantly decreases salivary secretion, and has significantly fewer side effects than other muscarinic parasympathetic antagonists. Further controlled studies are required to determine the satety, efficacy and patient toler- ance of glycopyrrolate. (J Osaka Dent Univ 2009 ; 43 : 119-127) Key words : Premedication ; Muscarinic receptor ; Salivary gland rat submandibular binding and mo[ecular INTRODUCTION gland, ex- periments have indicated that different subtypes of Parasympathetic antagonists are frequently used muscarinic receptors contribute to cholinergic re- 7 for premedication to reduce oral and respiratory se- sponses.S Currently, it is wondered whether mus- cretions and prevent bradycardia. Atropine is fre- carinic receptors other than muscarinic M3 recep- quently used as a premedication with both generai tors evoke secretory responses in the rat subman- and topical anesthesiat'2 to reduce bronchial secre- dibular gland. To investigate this issue, we used tions and prevent bradycardia,3 as well as to protect the muscarinic antagonists pirenzepine, methoctra- against the deleterious effects of the instrumenta- mine, 4-diphenylacetoxy-N-methylpiperidine methio- tion on pulmonary mechanics,4 [t is genera"y dide <4-DAMP)S and glycopyrrolate. While 4-DAMP agreed that an increase in water secretion in re- shows a conspicuous and similar inhibitory potency sponse to muscarinic agonists is attributable to acti- on muscarinic M 1 and M3 receptors, pirenzepine vation of muscarlnic M 3 receptor subtypes.5 ln the has a selectivity profiie for the muscarinic M 1 re- NII-Electronic Library Service OsakaOsakaOdontological Odontological Society 120 S, Taniwa et al . Joumal of Osaka Denta1 University, April 2009 ceptor,g Glycopyrrolate is said to have similar an- Chemicalassays tisialagogue effects, but is [ess likely to cause sig- Analysis tor amylase activa'ty nificant tachycardia than atropine, Different anti- Saliva was collected in pre-weighed, jce-chilled vi- -30eC muscarinic receptor selectivity patterns could ex- als and then weighed, frozen and stored at plain the differences, and its selective and pro- until they were analyzed for amylase actMty. The Ionged effect of decreasing salivary gland secre- amylase activity of saliva was analyzed by an enzy- tion. Glycopyrrolate, a quaternary ammonium com- matic colorimetric test (Boehringer GmbH, pound availab[e in both orai and parenteral forms, Mannheim, Germany) using cr-4-nitropheny[malto- has been used in the fie[d of anesthesiology as a heptaoside (4 NP-G7) as substrate.13 One unit (U) pre-anesthetic agent because of its $elective and of catalytic activity of a-amylase is detined as the prolenged effect on decreasing salivary gland se- hydrolysis oi 1yM of 4NP-G7 per min per mL, cretion,iO This compound, which is structurally simi- which is equivalent to the definition of one interna- iar to atropine, affects the peripheral muscarinic re- tional unit. ceptors and has long-[asting inhibition of salivation and respiratory tract secretions."" Analysis for protein concentTation This in vivo study attempted to examine whether The protein content of the fluid responses was ana- muscarinic receptor subtypes other than muscarinic Iyzed by the method of Lowry.i" M3 receptors exert exocrine functiona[ roles in the rat submandibular gland. Since different antimus- MOasurement of biood pressure carinic receptor selectivity patterns could explain Blood pressure was measured continuously via a the differences, the effects of pirenzepine, methoc- catheter placed into the femoral artety, and heart tramine, 4-diphenylacetoxy-N-methylpiperidine-rate was measured using the tail-cuff method.'5 methiodine (4-DAMP) and glycopyrrolate were ex- amined on secretion from the major saljvary glands DrugsThe evoked by acetylcholine in pentobarbita]-anesthe- drugs employed were acetylcholine chloride tized rats. (Sigma, St. Louis, MO, US) ; pirenzepine dihydro- chloride (Wako, Osaka, Japan), methoctramine MATERIALS AND METHODS hemihydrate (Sigma), 4-diphenylacetoxy-N-methyl- Animals piperidine methiodide (4-DAMP ; Sigma), glycopyr- Male Wistar rats weighing 250-320g were used, rolate (Sigma), and NG-Nitro-L-arginine methyl es- Food but not water was withheld from the rats for ter, hydrochloride (L-NAME ; Sigma, St. Louis, US). 24h before each experiment. The present study A cannula placed in the femoral vein was used for was conduced with approval from the Animal Study all drug administrations. Initial[y, five doses of ace- Committee, and in accordance with the Osaka Den- ty[choline were administered. These secretory re- tal University Animal Study Guidefiines (approvalsponses were used as control values for response$ number: 07-08002). obtained in the presence of muscarinic antagonists, and in the presence of the nitric oxide synthase in- naeasurement of salivar]t flove rate hibitor L-NAME. In the first series of experiments, Saliva samples, were collected from the submandi- acetylcholine was injected intravenously either in bular gland through polyethylene tubing (lntramedicsuccessively increasing doses, or before admini- PE-10; Becton & Dickinson, Franklin Lakes, NJ, stration of the mu$carinic antagonists. USA) inserted into the oral opening of the main duct. Fluid weight of coliected saliva was then Ftinctional studies Measured,i2 The animals were anaesthetized with sodium pen- NII-Electronic Library Service OsakaOsakaOdontological Odontological Society Vol. 43, No. 1 Effect of premedication on salivary secretlon I2i 1OO tobarbital (50 mg kg i.p.) followed by supplementary i6Eo doses injected intravenously as required. The tra- chea was cannulated and the body temperature 80o([Eb was maintained at 38'C, The duct of the submandi- bular vvas cannulated, All saliva secreted in ' gland 60a response to adminlstration of acety[choline was col- lected and weighed. The saliva was collected in small trays, which were immediately weighed in or- der to minimize evaporation. In additional experi- ments, the effects of p[renzepine, methoctramine, ili;:1 8 4-DAMP and glycopyrrolate were examined on '/1OO acetylcholine-evoked salivary flow rate. In each ani- o 200 300 400 500 mal, only one gland of each pair was tested. A can- Acetylcho[ineconcentration(ltglkg} nula placed in the femoral vein was used for all Fig. 1 Salivary secretlon of rat submandibular gland evoked drug administrations. In the experiments, acetyl- by intravenous administration of acetylcholine of between 1OO choline was injected repeatedly beginning at 100 ;tg and 500"g, The secretory flow rate was calculated as the salivary flow rate measured in the units oi mgfkg and the dose was increased by another 100 "gfminllOO mg. The data are presented as mean values ± SE. mgfkg each time until 500 mglkg was reached. In- itially, five doses of acetylcholine were adm[nistered 1oo in the absence of the muscarinic antagonist. These AaE secretoty responses were u$ed as contror values 1 80oog.gE'." for responses obtained in the presence of the mus- carinic antagonist. Pirenzepine, methoctoramine, 4- -･-100 mg DAMP'6 and glycopyrrolate were used at doses that 60'vx --- 1O mg were above the threshold dose for etfect, ln order +1.0 mg to collect adequate amounts of saliva for analysis, 9N ÷ O] mg 40)8k +Centrol several responses were occasionally pooled. Ace- tylcholine was given at least twice in $uccession in 2okco order to evacuate the dead space of the cannula and avoid contamination with secretion elicited by --T 1 any previous procedure. The second sample was o- T 100 200 300 400 500 analyzed for protein.
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