veratrine and phenyl-biguanide

The effect on the nociceptive tail-flick (TF) reflex of cardiopulmonary chemoreceptor and arterial baroreceptor activation, producing Bezold-Jarisch like- and baro-reflex responses, respectively, was analysed in lightly halothane-anaesthetized rats. Intra-cardiac administration of phenylbiguanide (5-100 microg/kg, into the right atrium) or veratrine (30-150 microg/kg, into the left ventricle), which both elicited the characteristic Bezold-Jarisch-like cardiovascular reflex responses (hypotension and bradycardia), produced a dose-dependent increase in TF latency. A similar inhibitory influence on the TF reflex was noted upon baroreflex activation by acute administration of phenylephrine (15-50 microg/kg i.v.) or aortic depressor nerve stimulation (100-400 microA). As expected from the involvement of local excitatory amino acid receptors in both vagally mediated cardiovascular reflex responses and inhibition of the TF reflex, microinjections of kynurenic acid (3 nmol/0.1 microl), an N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonist, into the nucleus tractus solitarius, prevented the cardiovascular responses as well as the concomitant increase in TF latency produced by cardiopulmonary chemoreceptor and baroreceptor stimulations. The present data show that induction of the cardiopulmonary chemoreceptor and baroreceptor reflexes produces an antinociceptive effect which can be assessed using the TF test, and that glutamate ionotropic receptors within the nucleus tractus solitarius mediate this effect.

Topics: Analgesics; Animals; Aorta; Atropine; Baroreflex; Biguanides; Chemoreceptor Cells; Electric Stimulation; Excitatory Amino Acid Antagonists; Kynurenic Acid; Male; Nociceptors; Parasympatholytics; Phenylephrine; Rats; Rats, Sprague-Dawley; Skin Temperature; Solitary Nucleus; Sympathomimetics; Tail; Veratrine

Cardiovascular responses to intravenous bolus doses of certain exogenous substances (capsaicin, phenyldiguanide, cryptenamine, veratrine sulphate) which act on chemoreceptors in the pulmonary or proximal arterial circulation were compared to the naturally occurring chemoreceptor agonist, leucineenkephalin (Leu5-ENK) in the conscious dog. Capsaicin (40 micrograms/kg) and phenyldiguanide (40 micrograms/kg) produced hypotension and bradycardia 5 to 12 sec after injection (P less than 0.05) followed by hypertension (P less than 0.05). Cryptenamine (5 micrograms/kg) produced only hypotension and bradycardia (P less than 0.05) whereas Leu5-ENK (35 micrograms/kg) produced only hypertension and tachycardia (P less than 0.05). The hypotension and bradycardia produced by capsaicin and phenyldiguanide occurred earlier than the pressor response to Leu5-ENK, capsaicin, and phenyldiguanide and the depressor response to veratrine (P less than 0.05). Cryptenamine (5 micrograms/kg) and Leu5-ENK (35 micrograms/kg) when given together had additive effects on heart rate but interacted significantly in influencing blood pressure (P less than 0.05). It is concluded that the early response to capsaicin and phenyldiguanide are compatible with stimulation of known pulmonary chemoreceptors (including J receptors) whereas the pressor effect of phenyldiguanide and Leu5-ENK and the depressor response to veratrum alkaloids are due to activation of receptors in the proximal arterial circulation. The influence of Leu5-ENK on the haemodynamic response to veratrine suggest that ENK may modulate the Bezold-Jarisch reflex.

Topics: Animals; Biguanides; Blood Pressure; Bradycardia; Capsaicin; Cardiovascular System; Chemoreceptor Cells; Dogs; Drug Combinations; Drug Interactions; Enkephalin, Leucine; Female; Heart Rate; Hypotension; Injections, Intravenous; Male; Protoveratrines; Veratrine

The proposal that some post-prandially released alimentary hormones modify ingestive behaviour and gastric emptying by altering impulse activity in alimentary enteroceptors has been tested using a number of gastrointestinal peptide hormone analogues. These and other drugs were applied to single-unit afferent preparations of duodenal tension receptors in chloralose-anaesthetized sheep. In separate experiments the effect of pentagastrin and cholecystokinin on duodenal motor activity was recorded without unitary afferent activity measurements. Local intra-arterial bolus injections of pentagastrin, cholecystokinin, insulin, prostaglandin, acetylcholine, phenylbiguanide, veratrine, 5-hydroxytryptamine and bradykinin aroused or enhanced activity in tension receptors. With the exception of a short-latency effect of insulin B.P., these responses occurred together with local increases in tension and electromyographic activity of the duodenum. Combinations of atropine and hexamethonium reduced duodenal motor activity and abolished most drug-evoked afferent responses. Intracarotid bolus injections of pentagastrin at first increased, then reduced duodenal tension, electromyographic activity and impulse activity of tension receptors. Cholecystokinin (CCK-8) injected by this route caused similar alterations of these parameters, and the response was characterized by periods of reduced activity followed by a prolonged excitation of duodenal motility. From the responses to bolus injections of humoral agents it is concluded that some alimentary hormones released after a meal may have a peripheral excitatory action on the tension receptor environment which causes increased afferent activity. The mechanism probably involves both an alteration in duodenal motility and a sensitization of the receptor ending. In addition, the peptide hormones gastrin and cholecystokinin may act centrally to alter duodenal motor control and thus may influence gastric emptying and post-prandial satiety mechanisms.

Topics: Action Potentials; Animals; Atropine; Biguanides; Bradykinin; Cholecystokinin; Dose-Response Relationship, Drug; Duodenum; Electromyography; Hexamethonium Compounds; In Vitro Techniques; Insulin; Mechanoreceptors; Neurotransmitter Agents; Pentagastrin; Prostaglandins; Serotonin; Sheep; Veratrine

The effects of capsaicin applied perineurally to the cervical vagus nerves have been studied on cardiovascular and respiratory functions in urethane anaesthetized cats. Application of capsaicin resulted in a moderate but significant decrease in the mean arterial blood pressure and in changes of the heart rate whose direction and magnitude depended on the initial cardiac frequency. Subsequent to these alterations, which may be attributed to a direct stimulation by capsaicin of vagal afferents, a transient block of impulse propagation was observed. Three to five days after pre-treatment of the cervical vagus nerves with capsaicin, phenyldiguanidine and veratrine given intravenously invariably evoked bradycardia, hypotension and apnoea, while the reflex responses to intravenous injection of capsaicin and some of its pungent congeners were greatly reduced or even abolished. It is suggested that vagal afferent fibres mediating cardiovascular and respiratory chemo-reflexes are separated into chemo-specifically different populations. Perineural application of capsaicin may be a useful tool for elucidating the role of different populations of peptide-containing vagal afferent fibres in the regulation of cardiovascular and respiratory functions.

Topics: Animals; Biguanides; Blood Pressure; Capsaicin; Cats; Electric Stimulation; Heart Rate; Neurons, Afferent; Reflex; Respiration; Vagus Nerve; Veratrine