Naunyn-Schmiedeberg's
Naunyn-Schmiedeberg's Arch Pharmacol (1992) 346: 219- 225
Archivesof Pharmacology © Springer-Verlag 1992
Blood pressure and gastric motor responses to bradykinin and hydrochloric acid injected into somatic or visceral tissues Ulrike Holzer-Petsche Institut ftir Experimentelleund KlinischePharmakologie,Karl-Franzens-Universit/itGraz, Universitfitsplatz4, A-S010 Graz, Austria Received September 30, 1991/AcceptedMarch 25, 1992
Summary. Both visceral and somatic nociceptive stimuli elicit reflex changes in blood pressure and gastric motor activity, but the exact type of response varies with the type of nociceptive stimulus and its site of application. Therefore, the present study compared the effects of visceral (i. p. or i.a.) and somatic (s.c.) administration of bradykinin and HC1 on both mean arterial blood pressure (MAP) and intragastric pressure in anaesthetized rats. The nervous pathways mediating these responses were investigated by surgical or pharmacological inhibition of the possible reflex arcs. Bradykinin (i. a. - into the aortic arch, i.p., and s.c.), and HC1 (i. p. and s.c.), elicited a fall in MAP followed by a transient increase. Intragastric pressure decreased in response to administration of these chemicals. Acute coeliac ganglionectomy reduced the gastric relaxations in response to both bradykinin and HC1, whereas vagotomy reduced only the gastric relaxations induced by HC1. Neither lesion influenced the changes in MAP after either chemical. Ablation of small diameter afferents by capsaicin or chemical sympathectomy by guanethidine reduced the changes in MAP after both chemicals, except that which occurred after i.a. injection of bradykinin. The secondary increase in MAP after i.a. and i.p. administration of algesics was increased after guanethidine. Both pretreatments reduced gastric relaxations in response to either chemical. Pretreatment of the rats with the bradykinin antagonist Hoe-140 reduced the responses to bradykinin but not to HC1. The results show that both visceral and somatic administration of painful chemicals elicit reflex falls in MAP and intragastric pressure. In general, the responses are stronger after "visceral" than after "somatic" administration. Both the splanchnic and vagal pathways seem to be involved in mediating the gastric motor responses. However, the effects of different algesics are not necessarily mediated by the same mechanisms. Key words: Pain (somatic/visceral) - Nociception Bradykinin - Capsaicin
Introduction Nociceptive stimuli are known to elicit reflex responses in a number of organ systems such as the cardiovascular, the respiratory and the gastrointestinal systems (Lembeck and Skofitsch 1982; Ordway et al. 1983, 1988; Radhakrishnan et al. 1985; Sj6qvist et al. t985; Hallerb/ick et al. 1987; Mizutani et al. 1990). Both visceral and somatic stimuli have been described to elicit changes in blood pressure and gastric motor activity (Kametani et al. 1979; Cervero and McRitchie 1982 a, b; Ordway and Longhurst 1983; Waldrop and Ordway 1986). Since the type of response seems to vary with the type of nociceptive stimulus used as well as with its site of application, the present study was designed to compare, in one model, the effects on blood pressure and gastrointestinal motility of two painful chemicals applied at different sites and by different routes (s. c., i.p., and i.a.). Furthermore, the nervous pathways mediating these reflex responses were investigated by means of surgical or pharmacological inhibition of parts of the possible reflex arcs. Two algogens were used. Bradykinin is one of the most potent stimuli of nociceptive nerve endings (Juan and Lembeck 1974). However, different studies have yielded differing observations as to its specificity for a given receptor type. Whereas Szolcs/myi (1987) reported bradykinin to excite only polymodal nociceptive C-fibres in the rabbit ear, Beck and Handwerker (1974) found no specificity, with regard to fibre type and diameter, in cat skin. In kat knee joint, bradykinin excited most group III and IV afferent units regardless of their sensitivity to active or passive noxious or non-noxious mechanical stimulation (Kanaka et al. 1985). Injected into the peritoneal cavity or into the splenic artery, bradykinin has been shown to stimulate pain-related behaviour effectively in various animal species (Dickerson et al. 1965). The second algogen tested was hydrochloric acid (HC1), since a reduction of the pH has long been known to activate nociceptors (Lindahl 1962).
220
Methods
Animalpreparation. Sprague-Dawley rats of either sex (200-300 g body weight; Versuchstierzuchtanstalt Himberg, Austria) were fasted over night with free access to tap water. Under phenobarbitone anaesthesia (250 mg/kg i.p.) the trachea was cannulated to keep a patent airway and the oesophagus was ligated in the neck. The left carotid artery was cannulated for measurement of blood pressure by means of a pressure transducer and heart rate via a ratemeter. Another catheter was inserted into the right carotid artery and advanced about 3 cm centrally for injection of bradykinin into the aortic arch (i. a.). In order to keep this catheter patent a glucosebicarbonate buffer (556mmol 1- t glucose and 100mmol 1-1 NaHCO3) was continuously infused at a rate of 1.5 ml/h. Changes in intragastric pressure were recorded as described previously (Cervero and McRitchie 1982a, b; Holzer-Petsche et al. 1987). A pressure transducer was attached to a catheter inserted into the stomach through an incision in the duodenum and fixed by a ligation around the pylorus. The catheter was connected to a syringe by means of a T-shaped adapter and the stomach was filled with 5 ml isotonic saline. The signals were recorded on a pen recorder. After this procedure intragastric pressure stabilized at 0.8 ± 0.1 kPa (n = 11). A similar catheter was introduced into the colon descendens via the anus and secured by a suprapubic ligature. Another ligature was placed at the left colonic flexure and the colon descendens was filled with I ml isotonic saline. Otherwise, the registration of intracolonic pressure was the same as for intragastric pressure. At a filling volume of ] ml, intracolonic pressure stabilized at 0.2 + 0.06 kPa (n = 9). For injection of algesic chemicals, two PE-]0 catheters were inserted at each site into the peritoneal cavity between folds of the mesentery and into the abdominal subcutis. Care was taken to avoid direct contact of the tips of the i.p. catheters with the stomach or intestine. Body temperature was kept at 3 7 , 3 8 ° C by means of a heating pad. Each rat received one injection of bradykinin through the i.a. cannula, one injection through one of the i.p. and one through one of the s.c. catheters. HC1 was injected through one i.p. and one s.c. catheter. All solutions were administered in a volume of 100 pL The injections were given in random order and each injection site was used only once in order to avoid sensitization or desensitization.
,g -r E
150~ 100 5O
a.
Naunyn-Schmiedeberg's Arch Pharmacol (1992) 346: 219- 225
Archivesof Pharmacology © Springer-Verlag 1992
Blood pressure and gastric motor responses to bradykinin and hydrochloric acid injected into somatic or visceral tissues Ulrike Holzer-Petsche Institut ftir Experimentelleund KlinischePharmakologie,Karl-Franzens-Universit/itGraz, Universitfitsplatz4, A-S010 Graz, Austria Received September 30, 1991/AcceptedMarch 25, 1992
Summary. Both visceral and somatic nociceptive stimuli elicit reflex changes in blood pressure and gastric motor activity, but the exact type of response varies with the type of nociceptive stimulus and its site of application. Therefore, the present study compared the effects of visceral (i. p. or i.a.) and somatic (s.c.) administration of bradykinin and HC1 on both mean arterial blood pressure (MAP) and intragastric pressure in anaesthetized rats. The nervous pathways mediating these responses were investigated by surgical or pharmacological inhibition of the possible reflex arcs. Bradykinin (i. a. - into the aortic arch, i.p., and s.c.), and HC1 (i. p. and s.c.), elicited a fall in MAP followed by a transient increase. Intragastric pressure decreased in response to administration of these chemicals. Acute coeliac ganglionectomy reduced the gastric relaxations in response to both bradykinin and HC1, whereas vagotomy reduced only the gastric relaxations induced by HC1. Neither lesion influenced the changes in MAP after either chemical. Ablation of small diameter afferents by capsaicin or chemical sympathectomy by guanethidine reduced the changes in MAP after both chemicals, except that which occurred after i.a. injection of bradykinin. The secondary increase in MAP after i.a. and i.p. administration of algesics was increased after guanethidine. Both pretreatments reduced gastric relaxations in response to either chemical. Pretreatment of the rats with the bradykinin antagonist Hoe-140 reduced the responses to bradykinin but not to HC1. The results show that both visceral and somatic administration of painful chemicals elicit reflex falls in MAP and intragastric pressure. In general, the responses are stronger after "visceral" than after "somatic" administration. Both the splanchnic and vagal pathways seem to be involved in mediating the gastric motor responses. However, the effects of different algesics are not necessarily mediated by the same mechanisms. Key words: Pain (somatic/visceral) - Nociception Bradykinin - Capsaicin
Introduction Nociceptive stimuli are known to elicit reflex responses in a number of organ systems such as the cardiovascular, the respiratory and the gastrointestinal systems (Lembeck and Skofitsch 1982; Ordway et al. 1983, 1988; Radhakrishnan et al. 1985; Sj6qvist et al. t985; Hallerb/ick et al. 1987; Mizutani et al. 1990). Both visceral and somatic stimuli have been described to elicit changes in blood pressure and gastric motor activity (Kametani et al. 1979; Cervero and McRitchie 1982 a, b; Ordway and Longhurst 1983; Waldrop and Ordway 1986). Since the type of response seems to vary with the type of nociceptive stimulus used as well as with its site of application, the present study was designed to compare, in one model, the effects on blood pressure and gastrointestinal motility of two painful chemicals applied at different sites and by different routes (s. c., i.p., and i.a.). Furthermore, the nervous pathways mediating these reflex responses were investigated by means of surgical or pharmacological inhibition of parts of the possible reflex arcs. Two algogens were used. Bradykinin is one of the most potent stimuli of nociceptive nerve endings (Juan and Lembeck 1974). However, different studies have yielded differing observations as to its specificity for a given receptor type. Whereas Szolcs/myi (1987) reported bradykinin to excite only polymodal nociceptive C-fibres in the rabbit ear, Beck and Handwerker (1974) found no specificity, with regard to fibre type and diameter, in cat skin. In kat knee joint, bradykinin excited most group III and IV afferent units regardless of their sensitivity to active or passive noxious or non-noxious mechanical stimulation (Kanaka et al. 1985). Injected into the peritoneal cavity or into the splenic artery, bradykinin has been shown to stimulate pain-related behaviour effectively in various animal species (Dickerson et al. 1965). The second algogen tested was hydrochloric acid (HC1), since a reduction of the pH has long been known to activate nociceptors (Lindahl 1962).
220
Methods
Animalpreparation. Sprague-Dawley rats of either sex (200-300 g body weight; Versuchstierzuchtanstalt Himberg, Austria) were fasted over night with free access to tap water. Under phenobarbitone anaesthesia (250 mg/kg i.p.) the trachea was cannulated to keep a patent airway and the oesophagus was ligated in the neck. The left carotid artery was cannulated for measurement of blood pressure by means of a pressure transducer and heart rate via a ratemeter. Another catheter was inserted into the right carotid artery and advanced about 3 cm centrally for injection of bradykinin into the aortic arch (i. a.). In order to keep this catheter patent a glucosebicarbonate buffer (556mmol 1- t glucose and 100mmol 1-1 NaHCO3) was continuously infused at a rate of 1.5 ml/h. Changes in intragastric pressure were recorded as described previously (Cervero and McRitchie 1982a, b; Holzer-Petsche et al. 1987). A pressure transducer was attached to a catheter inserted into the stomach through an incision in the duodenum and fixed by a ligation around the pylorus. The catheter was connected to a syringe by means of a T-shaped adapter and the stomach was filled with 5 ml isotonic saline. The signals were recorded on a pen recorder. After this procedure intragastric pressure stabilized at 0.8 ± 0.1 kPa (n = 11). A similar catheter was introduced into the colon descendens via the anus and secured by a suprapubic ligature. Another ligature was placed at the left colonic flexure and the colon descendens was filled with I ml isotonic saline. Otherwise, the registration of intracolonic pressure was the same as for intragastric pressure. At a filling volume of ] ml, intracolonic pressure stabilized at 0.2 + 0.06 kPa (n = 9). For injection of algesic chemicals, two PE-]0 catheters were inserted at each site into the peritoneal cavity between folds of the mesentery and into the abdominal subcutis. Care was taken to avoid direct contact of the tips of the i.p. catheters with the stomach or intestine. Body temperature was kept at 3 7 , 3 8 ° C by means of a heating pad. Each rat received one injection of bradykinin through the i.a. cannula, one injection through one of the i.p. and one through one of the s.c. catheters. HC1 was injected through one i.p. and one s.c. catheter. All solutions were administered in a volume of 100 pL The injections were given in random order and each injection site was used only once in order to avoid sensitization or desensitization.
,g -r E
150~ 100 5O
a.
