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1. The current study addressed how acute colitis, induced in male Sprague-Dawley rats by the administration of dextran sulphate sodium (DSS) in their drinking water, may affect some functional properties of the longitudinal muscle layer of the distal colon. 2. Dextran sulphate sodium was provided at a concentration of 3% for 3 or 7 days, or 5% for 7 days, and the rats were thereafter killed. Specimens of the distal colon were taken for histology or for organ bath experiments. 3. The colitis score increased significantly with increasing dose of DSS administered. At 5% concentration, there was sometimes even transmural inflammation. Functionally, there was a progressive increase in optimal preload (P(o)) for the contractile response to carbachol (1 microM), in relation to the severity of the colitis. At 5% DSS, the magnitude of the response to carbachol at P(o) was significantly increased compared with control rats. Such an effect could not be verified when, instead, K+ (60 mM) was used as a spasmogen. 4. It is concluded, that the colitis score increased in severity progressively with increasing amounts of DSS administered. The longitudinal muscle layer was functionally affected by the inflammation. Thus, there was a progressive increase in optimal preload for muscle contraction. Moreover, severe colitis resulted in an increase of the contractile response to carbachol, while a significant increase in the response to depolarization with K+ could not be found.

Ionized calcium (Ca2+) and bicarbonate (HCO(3)-) are important ions for gallstone formation. In the present study the effect of indomethacin and vasoactive intestinal peptide-antiserum (VIP-antiserum) on the Ca2+, HCO(3)- and fluid secretion in the inflamed gallbladder were tested in a validated experimental model in cats. The animals were studied in acute experiments 6 weeks after cystic duct ligation and gallstone implantation. During basal conditions there was a continuous secretion of Ca2+, HCO(3)- and fluid into the lumen of the inflamed gallbladder. Indomethacin and VIP-antiserum inhibited the Ca2+, HCO(3)- and fluid secretion across the inflamed gallbladder mucosa. Intraluminal amiloride inhibited the absorption of Ca2+, HCO(3)- and fluid after indomethacin infusion. An impaired absorption of Ca2+, HCO(3)- and fluid in the inflamed gallbladder is probably important for the solubility of calcium salts in the early stages of inflammation in the gallbladder mucosa.

Experiments were performed in chloralosed cats where gastric motility was recorded by the "volume method". Mucosal and serosal nociceptive stimulations were accomplished by local heating to 45-52 degrees C. Heating generally elicited gastric relaxations, mainly due to activation of extrinsic inhibitory reflexes, but mucosal heating sometimes caused contractile responses which were resistant to nicotinic and adrenergic blockade. The contractions were, however, blocked by atropine and, further, could not be demonstrated after degeneration of splanchnic afferents. On the basis of these and earlier results it is suggested that the gastric contractions induced by mucosal nociceptive stimulation are due to axon reflexes, conveyed by splanchnic afferents that, possibly via release of substance P, make non-nicotinic reflex contacts with intramural excitatory cholinergic neurons.

In chloralose-anesthetized, adrenalectomized cats, the sympathetically conveyed effects of topical hypothalamic stimulations on gastric volume, blood pressure and heart rate were systematically explored. The vagal nerves were cut but could be kept active by graded efferent stimulation. In the absence of such vagal activity, hypothalamic stimulation had no appreciable influence on gastric volume, even though the stomach maintained considerable myogenic tone. When, however, a vagal excitatory activity was present, hypothalamic stimulation could markedly affect gastric tone, indicating that the sympathetic fibres exert their inhibitory influence on the stomach via its cholinergic intramural neurons. Hypothalamic stimulations that induced reductions in pressure or heart rate also usually caused an enhancement of gastric tone. Similarly, pressor responses were associated with decreases in gastric volume whereas stimulation-induced tachycardia was not linked to any particular type of gastric response. Thus, the hypothalamic sympathoinhibitory influences on the cardiovascular system seem closely connected to a supression of the sympathetic outflow to the stomach. There is, on the other hand, no regular association between hypothalamic sympathoexcitatory influences on the cardiovascular and gastrointestinal systems; in fact, there is in many areas even a suppression of sympathetic discharge to the stomach in association with cardiovascular stimulation.

Experiments were performed on chloralosed cats with ligated adrenals. The peripheral ends of the preganglionic sympathetic nerves to the colon were stimulated and colonic motility was monitored by a volumetric method. Electric nerve stimulation with various intensities elicited inhibitory motor responses and occasionally contractions. Hexamethonium and/or guanethidine blocked all inhibitory actions and revealed pure excitatory responses at high stimulation intensities. These colonic contractions were inhibited by atropine. However, atropine-resistant contractions were sometimes observed, predominantly in the colorectal region. Thoracic sympathetic nerves affected the motility in the proximal colon only, while lumbar sympathetic nerves acted on both proximal and distal parts. Strength-duration relationships and sensitivity to local heating suggest that the excitatory responses are due to an antidromic activation of thin, possibly afferent nerve fibres. Small doses of substance P injected close i.a. induced colonic contractions unchanged by hexamethonium and/or guanethidine but sensitive to atropine. The neurally-induced colonic contractions are suggested to be due to an antidromic activation of thin sensory neurons which in the periphery release substance P, in turn activating cholinergic motor neurons, thus constituting an axon reflex arrangement. The possibility of a similar axon reflex mechanism, associated to thin afferents, activating adrenergic inhibitory neurons at the prevertebral ganglionic level is discussed.

In pentobarbitone-chloralose anaesthetized rats, the effects of aortic administration of various purine compounds on systemic arterial pressure were investigated. All animals were pretreated with atropine and guanethidine to (largely) eliminate reflex neurogenic cardiovascular adjustments, and drugs influencing purine receptors, prostaglandin synthesis, etc. were used for analytical purposes. The compounds used were adenosine (AD) and its slowly degradable analogue, 2-chloroadenosine (2-chloro), adenosine-5'-triphosphate (ATP) and its slowly degradable analogues beta, gamma-methyleneATP (beta,gamma-meATP) and alpha,beta-methyleneATP (alpha,beta-meATP). Control cardiac output measurements before, at and after the peak pressure changes in some experiments revealed that they were at least 80% due to changes in systemic resistance, i.e. dominated by shifts in resistance vascular tone. Adenosine, 2-chloro, ATP and beta,gamma-meATP all elicited depressor (vasodilator) responses. 2-chloro was more potent than AD. Furthermore, the results suggest that the depressor action of ATP involves P1-purinoceptors, following the rapid degradation of ATP to AD, and probably also other mechanisms. The stable ATP analogues caused prompt pressor (vasoconstrictor) responses, where alpha,beta-meATP was more potent than beta,gamma-meATP. The latter compound also produced delayed (probably P1-purinoceptormediated) depressor actions, presumably via slow degradation to AD.

Experiments were performed in chloralosed cats, laparotomized with ligated adrenals and spinalized in the cervical region. Blood pressure, heart rate and gastric motility were monitored. Stimulations were performed in two brain stem regions, viz. a "control region" including the nucleus ambiguous and a "dorsal region" approximately corresponding to the dorsal vagal nucleus and the solitarius complex. From both regions were regularly elicited gastric motor responses that were either excitatory, biphasic or inhibitory in direction, and always associated with prompt bradycardia and hypotension. After hexamethonium blockade of the "conventional" efferent vagal excitatory and relaxatory fibres to the stomach, stimulation of the control region no longer augmented gastric motility, while gastric contractions which could be abolished by atropine or vagotomy were produced from the dorsal region. The bradycardia and hypotension responses from both regions were also blocked by hexamethonium and then stimulations often led to delayed pressor responses, resistant to both vagotomy and atropine. The present results, together with previous findings (Delbro et al. 1981, 1982) suggest that the hexamethonium-resistant gastric contractions, elicited by stimulation of the mentioned dorsal region of the brain stem, are due to antidromic activation of afferent gastric vagal fibres with excitatory collaterals to intramural cholinergic neurons.

Experiments were performed in chloralosed cats with ligated adrenals with recording of arterial blood pressure, heat rate and gastric volume, the latter with a balloon method. Electric activation of the peripheral cut vagus at low and high intensity induced gastric excitatory and relaxatory responses, respectively. Hexamethonium blocked the stimulation-bound bradycardia but now high intensities induced excitatory gastric responses, resistant to alpha- and beta-adrenergic blocking agents and naloxone but sensitive to atropine. Heating of the intact vagus, to selectively activate thin afferents, resulted in gastric inhibition, due to vago-vagal reflex activation. When the nerve had been proximally cut, local nerve heating induced excitatory gastric responses, with the same pharmacological characteristics as those caused by electric nerve stimulation. The observations suggest that the hexamethonium-resistant gastric excitatory responses to peripheral vagal stimulation are due to antidromic activation of thin afferents which are proposed to function in axon reflexes affecting gastric motility.

A method to study electrically induced distal colonic motility in the rat in vivo is reported. The animals were anaesthetized with methohexital and chloralose and were artificially ventilated. Motility of a segment (2 cm) of the distal colon was monitored as volume changes of an intraluminal balloon, introduced via the anus. Local electrical stimulation of the wall of the segment was achieved by means of a bipolar electrode folded around the gut. Stimulations produced reproducible contractile responses in a frequency dependent fashion. Stimulation characteristics resembled those of other autonomic neuro-effector systems. The adrenergic neuron-blocker, guanethidine, significantly lowered colonic tone, but had no other effects on spontaneous or electrically induced motility. Atropine significantly lowered colonic tone. After the administration of this compound the electrically induced contractions were significantly smaller with a shorter duration and, furthermore, appeared upon the cessation of stimulation ('off' or 'rebound' contraction). Following the administration of tetrodotoxin (TTX, given close i.a. via a cannula with its tip in distal aorta) basal colonic tone and the number of spontaneously occurring contractions increased. The amplitude and duration of the electrically induced responses were significantly attenuated and, furthermore, appeared as 'rebound' contractions which were preceded by a relaxation. Such TTX-resistant responses may be myogenic, but a neurogenic origin cannot be excluded. The present study showed that local electrical stimulation of the distal colon elicits cholinergic contractions, but also atropine- and TTX-resistant motor responses.

In chloralosed cats, usually with ligated adrenals and paralysed with gallamine, the thoracic dorsal roots were electrically stimulated and gastric motor responses were recorded. Thoracic dorsal root stimulation regularly elicited gastric contractions after pretreatment with guanethidine and/or hexamethonium which were readily blocked by atropine. It was established that these gastric motor responses were due to peripheral stimulation of the dorsal root and not to spread to the ventral roots. Together with other results (Delbro & Lisander 1980) the findings suggest an antidromic activation of thin afferent fibres with excitatory collaterals to intramural cholinergic neurons which convey the gastric contractions.

Experiments were performed on chloralosed, adrenalectomized cats, paralysed with gallamine and artificially ventilated. Gastric motility was recorded by the balloon method. Efferent stimulation of the cut greater splanchnic nerve, well proximal to the celiac ganglion, could either increase or decrease gastric tone. The excitatory responses called for higher stimulation intensities than the inhibitory ones but were as a rule observed at lower frequencies only (1-4 Hz). They could be abolished by atropine but were not prevented by bilateral vagotomy, hexamethonium nor guanethidine. The latter two drugs rather reversed inhibitory responses to excitatory ones which exhibited a hyperbolic frequency-response relationship with maximal effects already at 2-4 Hz. Heating of a nerve trunk selectively activates thin afferents of the delta group and C-class. Heating of the greater splanchnic nerve caused an increase in gastric motility which, like that caused by electric stimulation, was not prevented by hexamethonium nor guanethidine; nor was it eliminated by cutting the nerve centrally, nor by vagotomy, while it was abolished by atropine. These results suggest that the excitatory gastric responses to efferent splanchnic nerve stimulation are due to antidromic activation of thin afferent fibres. Their functional significance remains obscure but their peripheral arborizations may convey 'axon reflexes' influencing gastrointestinal motility.

Gastric motor responses, recorded as volume changes of an intragastric balloon, were induced by the close i.a. administration of bradykinin (0.75-4 micrograms) in chloralose-anaesthetized cats. The animals were vagotomized and the adrenals were ligated at the outset of the experiments. Prior to autonomic blocking agents bradykinin elicited relaxatory or biphasic motor responses. Following nicotinic ganglionic receptor blockade bradykinin caused predominantly gastric contractions. Such excitatory responses were antagonized by 80-100% by atropine, suggesting a dominant neurogenic component. An hypothesis is put forward that the observed gastric contractions result from a bradykinin-induced activation of an axon reflex arrangement confined to thin sensory nerve fibres which, by substance P release from intramural collaterals, excite postganglionic cholinergic motor neurones.

Experiments were performed on chloralosed cats, pretreated with guanethidine and hexamethonium and with ligated adrenals. The motility of an arterially isolated colonic segment was monitored by a volumetric method. Colonic contractions were induced either by electric stimulation of the centrally cut lumbar splanchnic nerves, or by close i.a. injections of acetylcholine (ACh). Close i.a. injections of substance P (SP) were performed in order to test the degree of SP-receptor blockade. Blockade of colonic SP-receptors, either by close i.a. administration of large amounts of SP itself or by Spantide, a competitive SP-receptor antagonist, markedly reduced or abolished the neurally induced colonic contractions, while responses to ACh were unchanged. These results indicate a role for SP, or a closely related peptide, as an intermediate neurotransmitter in the neurally induced colonic responses. Thus, the present study gives support to the hypothesis that non-nicotinic, non-adrenergic colonic contractions, in response to electric stimulation of sympathetic nerves, are due to an antidromic activation of sensory neurons with peripheral excitatory collaterals which release SP, in turn activating the colonic smooth muscle, mainly via a muscarinic mechanism.

Electrical stimulation of the feline vagal or splanchnic nerves after hexamethonium blockade of nicotinic ganglionic transmission produces gastric contractions, suggesting antidromic activation of thin afferents. The present experiments were performed to examine whether substance P is involved as a transmitter in such gastric responses. Cats were anesthetized with chloralose, laparotomized and the adrenals were ligated. The left greater splanchnic nerve, proximal to the celiac ganglion, and the left or right cervical vagal nerve were dissected, cut and placed on electrodes for peripheral stimulation. Gastric motility was monitored with a balloon. Hexamethonium was administered i.v. as well as i.a. to the stomach. Nerve stimulations produced powerful gastric contractions, which were antagonized by large doses (approximately 0.8 mumol) of substance P administered i.a. to the stomach. Similarly, the gastric contractions elicited by vagal or splanchnic nerve stimulations were reduced to at least 60% of control by the specific substance P antagonist (D-Pro2, D-Trp7,9)-SP administered i.a. (0.4-1.3 mumol). The present results support the concept that substance P is associated with gastric excitatory motor responses, possibly elicited by antidromic activation of thin afferent nerve fibres.

Experiments were performed on cats anaesthetized with chloralose and treated with adrenoceptor blocking agents. Distal colonic and rectal motility were selectively recorded by a volumetric method. The effects of muscarinic and ganglionic nicotine receptor blockade on motor responses induced by graded efferent electrical pelvic nerve stimulation (PNS) were studied. Stimulation at low current strength evoked contractions in both the colon and the rectum, which were sensitive to atropine and to hexamethonium. High intensity stimulation elicited distal colonic contractions resistant to both atropine and hexamethonium. Similar excitatory responses to high strength PNS were also observed in the rectum, though not in all experiments. Stimulation at intermediate intensities evoked distal colonic and rectal relaxations which were resistant to atropine but blocked by hexamethonium. The results indicate that PNS influences colonic and rectal motility by activation of at least three discrete non-adrenergic nervous pathways: (1) low-threshold excitatory fibres involving nicotinic and muscarinic transmission, (2) high-threshold excitatory fibres with a non-muscarinic, non-nicotinic transmission mechanism, (3) inhibitory fibres with an intermediate stimulus intensity threshold, exerting their effect by a non-muscarinic mechanism involving a nicotinic step.

Experiments were performed on chloralose-anaesthetized cats, pretreated with guanethidine and with ligated adrenals and sectioned splanchnic nerves. The animals were paralysed and artificially ventilated. Jejunal motility was recorded by an intraluminal balloon, as volume changes at a constant pressure. Cervical or abdominal vagal afferent stimulation was performed before and after the administration of atropine. In both circumstances jejunal contractions were elicited. The latency of onset and the duration of the responses were significantly shorter before than after atropine. Strength-duration and frequency-response relationships, respectively, did not differ significantly prior and subsequent to atropine. Naloxone (0.05-0.5 mg kg-1 i.v.) blocked these reflexly induced atropine-resistant jejunal contractions, as did section of the contralateral vagus. Possible mechanisms of action of these putative opioid receptor-mediated neurogenic effects are discussed. The present study demonstrates that non-adrenergic, non-cholinergic, naloxone-sensitive jejunal contractions can be elicited as a vago-vagal reflex, where the receptive field seems to be located within the abdominal cavity.

The possible involvement of purinoceptors in the parasympathetic nervous control of large intestinal motility was investigated in cats anaesthetized with chloralose and treated with adrenolytics. Distal colonic and rectal motor responses to efferent pelvic nerve stimulation (PNS) and drugs injected close i.a., were recorded by a volumetric method. Single dose i.a. injections of alpha, beta-methylene ATP (mATP) induced colonic and rectal contractions which were resistant to atropine, hexamethonium and indomethacin, as well as to the nerve blocking agent tetrodotoxin. Repeated injections of mATP were followed by attenuated motor responses and eventually complete tachyphylaxis to the compound developed. In the presence of atropine, or a combination of hexamethonium and atropine, contractions elicited by PNS were inhibited during mATP tachyphylaxis. In contrast, prior to such anticholinergic drugs, or in the presence of hexamethonium alone, pelvic nerve mediated contractions persisted despite mATP tachyphylaxis, which did not affect the colonic and rectal contractions evoked by acetylcholine or histamine. The results suggest that P2-purinoceptors are involved in non-adrenergic, non-cholinergic large intestinal excitatory motor responses to PNS.

In pentobarbital-chloralose-anaesthetized rats, pretreated with hexamethonium and atropine the mechanism by which substance P (SP) causes tachycardia was analysed. Substance P, when infused i.v. at doses between 0.49 nmol and 1.52 nmol elicited a marked, dose-dependent tachycardia, which was reduced to less than half by propranolol, 0.1 mg kg-1. Furthermore, the SP-induced tachycardia was reduced to about 1/10 of control by guanethidine. Further, the tachycardia, which could also be elicited in pithed rats, was antagonized by the SP-receptor blocker Spantide, but these results must be taken with care since Spantide itself caused a pronounced and long-lasting depressor response. It is hypothesized that SP causes tachycardia by exciting specific receptors on the stellate ganglia, which leads to an activation of adrenergic fibres to the sinus node.