bemesetron and phenyl-biguanide

To determine the role of central serotonin 5-HT(3) receptors in respiratory motor control, respiratory motor bursts were recorded from hypoglossal (XII) nerve rootlets on isolated adult turtle brainstems during bath-application of 5-HT(3) receptor agonists and antagonists. mCPBG and PBG (5-HT(3) receptor agonists) acutely increased XII burst frequency and regularity, and decreased bursts/episode. Tropisetron and MDL72222 (5-HT(3) antagonists) increased bursts/episode, suggesting endogenous 5-HT(3) receptor activation modulates burst timing in vitro. Tropisetron blocked all mCPBG effects, and the PBG-induced reduction in bursts/episode. Tropisetron application following mCPBG application did not reverse the long-lasting (2h) mCPBG-induced decrease in bursts/episode. We conclude that endogenous 5-HT(3) receptor activation regulates respiratory frequency, regularity, and episodicity in turtles and may induce a form of respiratory plasticity with the long-lasting changes in respiratory regularity.

Topics: Action Potentials; Afferent Pathways; Animals; Biguanides; Dose-Response Relationship, Drug; Hypoglossal Nerve; In Vitro Techniques; Indoles; Physical Stimulation; Receptors, Serotonin, 5-HT3; Respiration; Respiratory Center; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin Agents; Time Factors; Tropanes; Tropisetron; Turtles

The present study was performed to examine neuroprotective effects of 5-hydroxytryptamine (5-HT)(3) receptor antagonists against beta-amyloid protein (25--35)-, a synthetic 25--35 amyloid peptide, induced neurotoxicity using cultured rat cortical neurons. beta-Amyloid protein (25--35) produced a concentration-dependent reduction of cell viability, which was significantly reduced by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist, verapamil, an L-type Ca(2+) channel blocker, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. The 5-HT(3) receptor antagonists, tropanyl-3,5-dichlorobenzoate (MDL-72222, 0.1--10 microM) and N-(1-azabicyclo[2.2.2.]oct-3-yl)-6-chloro-4-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride (Y 25130, 0.05--5 microM), decreased the beta-amyloid protein (25--35) (10 microM)-induced neuronal cell death as assessed by a colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and the number of apoptotic nuclei, evidenced by Hoechst 33342 staining. MDL 72222 and Y 25130 inhibited the beta-amyloid protein (25--35) (10 microM)-induced elevation of cytosolic Ca(2+) concentration ([Ca(2+)](c)) and glutamate release, generation of reactive oxygen species, and caspase-3 activity. These neuroprotective effects of MDL 72222 (10 microM) and Y 25130 (5 microM) were completely blocked by the simultaneous treatment with 100 microM 1-phenylbiguanide, a 5-HT(3) receptor agonist, indicating that the protective effects of these compounds were due to 5-HT(3) receptor blockade. These results suggest that the activation of the 5-HT(3) receptor may be partially involved in beta-amyloid protein-induced neurotoxicity, by membrane depolarization for Ca(2+) influx. Therefore, the blockade of 5-HT(3) receptor with MDL 72222 and Y 25130, may ameliorate the beta-amyloid protein-induced neurotoxicity by interfering with the increase of [Ca(2+)](c), and then by inhibiting glutamate release, generation of reactive oxygen species and caspase-3 activity.

Topics: Amyloid beta-Peptides; Animals; Biguanides; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Caspase 3; Caspases; Cell Death; Cells, Cultured; Cerebral Cortex; Dose-Response Relationship, Drug; Female; Glutamic Acid; Neurons; Neuroprotective Agents; Oxazines; Peptide Fragments; Pregnancy; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Serotonin Receptor Agonists; Tropanes

1 The role of peripheral 5-hydroxytryptamine (5-HT(3)) receptors and cholecystokinin type 1 (CCK(1)) receptors in the inhibitory effects of phenylbiguanide (PBG) and CCK on arterial blood pressure, heart rate and the discharge of presympathetic vasomotor neurones of the rostral ventrolateral medulla (RVLM) was studied in alpha-chloralose-anaesthetized rats. 2 CCK (1 and 4 micro g kg(-1), i.v.) and PBG (2 and 10 micro g kg(-1), i.v.) reduced arterial blood pressure and heart rate, and inhibited the discharge of single RVLM presympathetic vasomotor neurones in a dose-related manner. 3 Devazepide (0.5 mg kg(-1), i.v.), a selective CCK(1) receptor antagonist, blocked the effects of CCK on arterial blood pressure, heart rate and neuronal discharge but did not significantly alter these responses to PBG. MDL72222 (0.1 mg kg(-1), i.v.), a selective 5-HT(3) receptor antagonist, blocked the effects of PBG on arterial blood pressure, heart rate and presympathetic neuronal discharge. MDL72222 attenuated the effects of CCK on arterial blood pressure, heart rate and RVLM presympathetic neuronal discharge. Vehicle did not significantly alter any of the responses to CCK or PBG. 4 These experiments suggest that systemically administered CCK acts directly through CCK(1) receptors to modulate sympathetic vasomotor function. In addition, the actions of CCK also are partly dependent on activation of 5-HT(3) receptors. CCK may release 5-HT which then acts at 5-HT(3) receptors to produce sympathetic vasomotor inhibition. In contrast, the actions of PBG are entirely dependent on 5-HT(3) receptors and are independent of any actions at the CCK(1) receptor.

Topics: Animals; Biguanides; Blood Pressure; Cholecystokinin; Dose-Response Relationship, Drug; Heart Rate; Male; Medulla Oblongata; Membrane Potentials; Neurons; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Tropanes; Vasomotor System

We have studied the effects of serotonin (5-HT) 5-HT3 receptor agonists 1-phenylbiguanide (1-PBG) and 1-(m-chlorophenyl)biguanide (mCPBG), and antagonists 3-tropanyl-3,5-dichlorobenzoate (MDL-72222) and tropisetron (3-tropanyl-indole-3-carboxylate HCl; ICS-205930) on apomorphine-induced aggressive behaviour in normal or DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] pre-treated male Wistar rats. DSP-4 (50 mg/kg) pre-treatment significantly accelerated the development of apomorphine-induced aggressive behaviour. mCPBG (1.0 and 10 mg/kg) did not modify the aggressiveness, but 1-PBG (3.0 and 30 mg/kg) attenuated the aggressiveness in normal but not DSP-4 pre-treated rats. MDL-72222 (0.4 and 4.0 mg/kg) attenuated the aggressive behaviour in normal rats, tropisetron (0.3 mg/kg) had an antiaggressive effect only by citalopram (10 mg/kg) challenge. MDL-72222 and tropisetron were ineffective in DSP-4 pre-treated rats. In conclusion, our results indicate that the 5-HT3 receptors modulate the apomorphine-induced aggressive behaviour and the 5-HT3 receptor antagonists have moderate antiaggressive effect in this test.

Topics: Aggression; Animals; Apomorphine; Behavior, Animal; Benzylamines; Biguanides; Citalopram; Dopamine Agonists; Dose-Response Relationship, Drug; Male; Rats; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Receptor Agonists; Sympathomimetics; Time Factors; Tropanes

The crystal and molecular structures of the following serotoninergic drugs have been determined: (1) 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide hemihydrate (NAN-190.HBr), C23H28N3O3+.Br-.1/2H2O, M(r) = 483.42, monoclinic, C2/c, a = 21.916 (4), b = 15.207 (2), c = 14.052 (2) A, beta = 101.56 (1) degree, V = 4588 (1) A3, Z = 8, Dx = 1.40 Mgm-3, lambda (Mo K alpha) = 0.71069 A, mu = 1.823 mm-1, F(000) = 2008, T = 295 K, R = 0.035 for 2617 observed reflections; (2) N-phenylimidocarbonimidic diamide (1-phenylbiguanide), C8H11N5, M(r) = 177.21, monoclinic, P2(1)/c, a = 9.781 (2), b = 35.040(5), c = 11.000 (2) A, beta = 97.72(1) degree, V = 3736(1)A3, Z = 16, Dx = 1.26 Mg m-3, lambda (Mo K alpha) = 0.71069 A, mu = 0.084 mm-1, F(000) = 1504, T = 295 K, R = 0.070 for 3407 observed reflections; (3) 8-methyl-8-azabicyclo[3.2.1]oct-3yl 3,5-dicholorobenzoate (MDL 72222), C15H17Cl2NO2, M(r) = 314.21, triclinic, P1, alpha = 8.480 (3), b = 9.840 (3), c = 10.158 (4) A, alpha = 90.04 (3), beta = 111.77 (3), gamma = 105.07(3) degrees, V = 755.6(5) A3, Z = 2, Dx = 1.38 Mg m-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.430 mm-1, F(000) = 328, T = 295 K, R = 0.070 for 1685 observed reflections; (4) 1, 2, 3, 4, 10, 14b-hexahydro-2-methyldibenzo[c.f]pyrizino[1, 2-alpha]azepine hydrochloride (mianserin. HCl), C18H21N2+. Cl-, M(r) = 300.83, monoclinic, P2(1)/a, a = 9.014 (2), b = 14.917 (2), c = 12.412 (2) A, beta = 108.84 (1) degree, V = 1579.5 (5) A3, Z = 4, Dx = 1.26 Mg m-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.237 mm-1, F(000) = 640, T = 295 K, R = 0.063 for 1493 observed reflections. A systematic structural analysis of the present compounds and others known to interact with the 5-HT1, 5-HT2 and 5-HT3 receptors allows to identify their similarities with the endogenous ligand serotonin (5-HT) and the stereochemical differences which determine selectivity for the various receptor subtypes. The pharmacophoric feature for 5-HT receptor binding is identified in a constant-length vector linking an aromatic ring with a protonated nitrogen, while specific affinities for receptorial subtypes and the nature of the effect appear to be modulated by the dimensions of the substituents at nitrogen.

Topics: Biguanides; Crystallography, X-Ray; Ligands; Mianserin; Piperazines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serotonin Receptor Agonists; Stereoisomerism; Tropanes

The effects of serotonin (5-hydroxytryptamine) on ventilation were investigated by continuous measurements of intrabuccal pressure in unrestrained eel. Intravenous administration of 5-hydroxytryptamine (30 micrograms.kg-1) caused a large increase in ventilatory frequency (+ 100%) and amplitude (+ 140%). The 5-hydroxytryptamine-induced hyperventilation was blocked by the 5-HT3-receptor antagonists metoclopramide (1.0 mg.kg-1) or MDL72222 (1.0 mg.kg-1), and was insensitive to the 5-HT1/2-receptor antagonist methysergide (3.0 mg.kg-1) and to the 5-HT4-receptor antagonist DAU 6285 CL (3.0 mg.kg-1). The hyperventilatory response to 5-hydroxytryptamine could be mimicked by the 5-HT3 receptor agonist 1-phenylbiguanide (300 micrograms.kg-1). These results strongly implicate the 5-HT3-receptor as the mediator of the 5-hydroxytryptamine-induced hyperventilation in eel.

Topics: Anguilla; Animals; Benzimidazoles; Biguanides; Bridged Bicyclo Compounds, Heterocyclic; Hyperventilation; Injections, Intravenous; Methysergide; Metoclopramide; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Respiration; Serotonin; Serotonin Antagonists; Tropanes

1. In vivo microdialysis was used to study the effect of phenylbiguanide (PBG), a 5-hydroxytryptamine3 receptor agonist, on the extracellular output of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the corpus striatum. 2. PBG produced a dose-related (10-500 microM) increase in the release of dopamine (280-2000%). DOPAC and HVA output decreased with the perfusion of PBG. This decrease was similar with 50-500 microM PBG. 5-HIAA output was not affected by any PBG concentration used. 3. When nomifensine (5 microM) was included in the Ringer solution, the effect of PBG on the release of dopamine was ameliorated or inhibited. However, the effect of PBG (50-500 microM) on the extracellular output of DOPAC and HVA was similar in the absence and in the presence of nomifensine (5 microM). 4. Perfusion of MDL 72222, a 5-hydroxytryptamine3 receptor antagonist, at doses of 50 and 100 microM produced similar decreases (50% of controls) and increases (120% of controls) in the extracellular output of dopamine and DOPAC, respectively. HVA and 5-HIAA output levels were not affected by either concentration of MDL 72222. MDL 72222 (10 microM) produced a slight and transient increase in the release of dopamine and a decrease in the extracellular output of DOPAC. HVA and 5-HIAA extracellular output was not affected by MDL 72222 (10 microM) perfusion. 5. Co-perfusion of MDL 72222 (10 and 100 microM) or tetrodotoxin (1 microM) with PBG (50 microM) did not modify the effect produced by PBG (50 microM) alone on the release of dopamine. 6 These results suggest that the effect of PBG on the release of dopamine is mainly carrier-mediated.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Biguanides; Corpus Striatum; Dialysis; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Extracellular Space; Hydroxyindoleacetic Acid; Male; Microchemistry; Nomifensine; Rats; Rats, Wistar; Serotonin Antagonists; Serotonin Receptor Agonists; Sodium Channels; Tetrodotoxin; Tropanes

The 5-HT3-receptor antagonist, ondansetron, has been shown to have positive effects in selected in-vivo models of memory impairment and anxiety. The exact mechanisms underlying such bioactivities are unknown. In the present work, an 86Rb efflux bioassay was used to show that ondansetron has a unique ability to block voltage-gated potassium channels in TE671 human neuroblastoma cells. This intrinsic potassium-channel-blocking (KCB) property is relatively weak (IC50 20 microM), but is not shared by other 5-HT3-receptor ligands including zatosetron, MDL 72222, LY 278, 584, zacopride, 1-phenylbiguanide, and ICS 205-930 (tropisetron). Pre-incubation of the target neuroblastoma cells with several 5-HT-receptor ligands including 5-hydroxytryptamine, 8-OH-DPAT, ketanserin, 2-methyl-5-HT, as well as a number of potent 5-HT3 agonists and antagonists and two selective neurotoxins, failed to abolish the KCB action of ondansetron. A preliminary structure-activity relationship analysis indicates that the KCB activity of ondansetron is almost entirely attributable to its structural nucleus, 2,3-dihyro-9-methyl-4(1H)-carbazolone. It is hypothesized that the KCB action of ondansetron is mediated through receptors other than 5-HT3 receptors. The KCB activity of ondansetron may be a significant factor in the in-vivo cognition-enhancing activities of this compound, conceivably due to depolarization of the hippocampal synaptic membranes and a consequent augmentation of neurotransmission.

Topics: Anti-Anxiety Agents; Benzamides; Benzofurans; Biguanides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Hypoglycemic Agents; Indazoles; Indoles; Neuroblastoma; Neurotoxins; Ondansetron; Potassium Channels; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Rubidium Radioisotopes; Serotonin Antagonists; Serotonin Receptor Agonists; Structure-Activity Relationship; Tropanes; Tropisetron; Tumor Cells, Cultured

Our work has focused on identifying the type of serotonin receptor through which serotonin acts as a developmental signal in the central nervous system. Previously, we have found that the regulation of development of ascending serotonergic neurons is through the balance of two serotonin receptors. One, the 5-HT1a receptor, releases a growth factor from astroglial cells. The other receptor is related to a release-regulating autoreceptor and can be stimulated indirectly by serotonin releasers such as fenfluramine. In the present study, we examined the receptors which regulate development of the descending neurons by treating pregnant rats with selective serotonergic drugs, from gestation day 12 until birth. Pups were subsequently tested for alterations in development by nociceptive testing (tail-flick latency) and by determining the binding of 3H-paroxetine, an indicator of serotonin terminal density, in spinal cord. Our results show that agents stimulating the 5-HT1a receptor (8-OH-DPAT) or the 5-HT1b receptor (TFMPP) or substances which release serotonin (fenfluramine) had no effect on the development of spinal serotonergic pathways. However, agents acting on the 5-HT3 receptor did--the agonist phenylbiguanide (PG) increased latency on tail-flick testing (postnatal days 10 and 30), while the antagonist, MDL 72222, decreased latency (postnatal days 10 and 18). Interestingly, both the agonist and the antagonist significantly increased 3H-paroxetine binding on postnatal day 18. Our results are discussed in terms of a possible mechanism by which 5-HT3 receptors may influence development.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aging; Animals; Biguanides; Female; Fenfluramine; Hypoglycemic Agents; Maternal-Fetal Exchange; Neurons; Pain; Paroxetine; Piperazines; Piperidines; Pregnancy; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Spinal Cord; Tetrahydronaphthalenes; Tropanes

The locations of serotonin-3 (5-HT3) receptors involved in initiating vomiting (emesis) were assessed by cutting visceral afferents or lesioning the area postrema. The 5-HT3 receptor agonists phenylbiguanide (PBG) and 2-methyl-5-HT were shown to induce vomiting and related prodromal signs (e.g., licking, swallowing) in nonoperated cats. Two-methyl-5-HT, but not PBG, also usually produced defecation and sometimes urination. Most studies were conducted using PBG, which induced vomiting in 40/49 (82%) cats at doses of 8.0 mg/kg i.p. or less (thresholds ranged from 2-8 mg/kg, median 5 mg/kg). Latencies to the first episode ranged from 4 to 21 min (median 7.5 min). PBG-induced vomiting was blocked by the 5-HT3 receptor antagonist MDL 72222. Lesions of the area postrema had no apparent effect on vomiting induced by PBG or by electrical stimulation of abdominal vagal afferents. In contrast, the threshold of PBG-induced vomiting was increased by supradiaphragmatic vagotomy and greatly increased by splanchnic nerve section. Thus, abdominal visceral afferents, but not the area postrema, play an important role in mediating vomiting induced by i.p. injection of the 5-HT3 receptor agonist PBG. The mechanisms by which vomiting is induced by PBG as compared to the cancer chemotherapeutic drug cisplatin are discussed.

Topics: Animals; Biguanides; Cats; Cerebral Ventricles; Female; Male; Serotonin; Serotonin Antagonists; Splanchnic Nerves; Tropanes; Vagotomy; Vomiting

1. We have tested in unanaesthetized rabbits two hypotheses regarding a physiological role for cardiogenic chemoreflexes in acute central hypovolaemia. 2. In rabbits, the sympathoinhibitory phase of acute central hypovolaemia depends on the activation of a brain-stem delta-opioid receptor mechanism by a signal from the heart. Blockade of this by fourth ventricular injection of the delta-receptor antagonist ICI 174864 had no effect on the reflex haemodynamic responses to left atrial phenylbiguanide or intrapericardial nicotine. 3. Intravenous administration of the 5-HT3 receptor antagonist MDL 72222, or intrapericardial administration of the nicotinic ganglionic cholinoceptor antagonist mecamylamine HCl, had no effect on the haemodynamic response to acute central hypovolaemia. 4. We conclude that phenylbiguanide-sensitive myocardial afferents and nicotine-sensitive epicardial afferents play no part in the response to acute hypovolaemia in rabbits, and that the reflex effects evoked by chemically exciting these afferents do not depend on a brain-stem delta-opioid mechanism.

Topics: Afferent Pathways; Animals; Biguanides; Chemoreceptor Cells; Enkephalin, Leucine; Heart; Hemodynamics; Mecamylamine; Narcotic Antagonists; Nicotine; Rabbits; Receptors, Opioid, delta; Serotonin Antagonists; Tropanes

1. When phenylbiguanide (1-PBG) (6.25-400 micrograms) was injected into the left atrium, right atrium or pulmonary artery of unanesthetized rabbits it caused dose-dependent falls of heart rate and arterial pressure, and short-lived hypopnoea or apnoea. The threshold dose was 50-100 micrograms. Maximal falls of heart rate (86-108 beats/min) and arterial pressure (33-35 mmHg) occurred at a dose of 200 micrograms. The latency between injection and onset of the bradycardia was 2.2-2.6 s and did not depend on the route. Cardiac output fell transiently with heart rate, but at the time of the maximal fall of arterial pressure it had returned to normal. All effects were abolished by intrapericardial procaine. The haemodynamic effects were exaggerated by sino-aortic barodenervation. Intrapericardial 1-PBG (200-400 micrograms) was without effect. Injection of 1-PBG (greater than 50-100 micrograms) into the aortic arch caused a variable increase in heart rate and arterial pressure. 2. When both cervical vagus nerves were crushed the depressor effects of atrial 1-PBG were reduced by only 76-84%. 3. The dose-response curves for left atrial and pulmonary artery injection of 1-PBG were shifted successively to the right by intravenous infusion of the 5-HT3 antagonist MDL72222 (0.1 and 1.0 mg/kg). 4. We conclude that in unanesthetized rabbits left atrial 1-PBG selectively excites myocardial afferents, whereas right atrial or pulmonary artery 1-PBG excites afferents that originate close to the pulmonary vasculature. In each case 1-PBG acts through pharmacologically specific 5-HT3 receptors. The afferents run mainly, but not exclusively, in the vagus nerves. The reflex fall of arterial pressure is accounted for almost entirely by a decrease in peripheral resistance.

Topics: Animals; Biguanides; Cardiovascular Agents; Denervation; Heart; Hematocrit; Hemodynamics; Lung; Neural Conduction; Pressoreceptors; Procaine; Rabbits; Receptors, Serotonin; Reflex; Respiration; Serotonin Antagonists; Tropanes; Vagus Nerve

The effect of ketanserin (3 mg/kg i.v.) on the baroreceptor heart rate reflex and the Bezold-Jarisch reflex was examined in conscious Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the control situation (before ketanserin treatment), reflex bradycardia in response to phenylephrine (baroreflex) and phenyldiguanide (Bezold-Jarisch reflex) were impaired in SHR as compared with WKY, while reflex tachycardia in response to nitroprusside was similar in the two groups. However, after ketanserin administration in SHR, there was a reversal of the baroreflex-mediated tachycardia in response to nitroprusside into a bradycardic response. The nitroprusside-induced bradycardia was not caused by the release of 5-HT stimulating chemosensitive vagal afferents since the 5-HT3 receptor antagonist MDL 72222 did not block this response. In the same SHR, the Bezold-Jarisch reflex evoked by phenyldiguanide and the phenylephrine-induced bradycardia were potentiated by ketanserin. All the above effects of ketanserin were less evident in the WKY. Ketanserin did not alter vagal efferent function in anaesthetized SHR since it did not affect bradycardia induced by electrical stimulation of the vagus nerve. Therefore, it is suggested that ketanserin has sensitised cardiac vagal afferent mechanisms in SHR, which led to a normalization of reflex bradycardic function to a level normally observed in conscious normotensive WKY (i.e. prior to ketanserin treatment).

Topics: Animals; Atropine; Biguanides; Blood Pressure; Cardiovascular System; Dose-Response Relationship, Drug; Electric Stimulation; Female; Heart Rate; Hypoglycemic Agents; Ketanserin; Nitroprusside; Pressoreceptors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reflex; Tropanes; Vagus Nerve

To investigate cardiac chemoreceptors in rats a catheter was chronically implanted into the pericardial sac via the thymus. Intrapericardial (ipc) injection of 200 microliters isotonic saline vehicle did not alter arterial blood pressure, heart rate, right atrial pressure, or respiratory rate. Phenyl biguanide (PBG) and nicotine (NIC) were injected into the pericardial sac. In intact rats anesthetized with methohexital sodium, 90 micrograms PBG ipc decreased blood pressure (BP), heart rate (HR), and renal nerve activity (RNA), whereas 300 micrograms NIC ipc increased BP and decreased HR and RNA. Sinoaortic baroreceptor denervation (SAD) did not affect the responses to PBG and abolished only the HR response to NIC. When vagotomy was added to SAD, all responses to intrapericardial PBG were abolished, but the increase in BP and decrease in RNA resulting from intrapericardial NIC persisted. In SAD rats anesthetized with methohexital, PBG produced dose-dependent decreases in BP and RNA, whereas NIC produced dose-dependent increases in BP and decreases in RNA; the serotonin (5-HT3) antagonist MDL 72222 (80 micrograms ipc) abolished the responses to PBG but not to NIC. MDL 72222 inhibited BP and RNA responses to PBG to a similar extent in conscious and anesthetized SAD rats. Anesthesia attenuated the magnitude and time course of BP and RNA responses to PBG compared with the conscious state. In conclusion, 1) sympathoinhibitory responses to intrapericardial PBG and NIC are mediated by epicardial receptors with different afferent neural pathways, PBG by cardiac vagal afferents and NIC by nonvagal, possibly cardiac sympathetic afferents; 2) PBG exerts its effects via epicardial 5-HT3 receptors; 3) anesthesia attenuates the responses to PBG.

Topics: Animals; Biguanides; Blood Circulation; Blood Pressure; Denervation; Heart Rate; Kidney; Nervous System Physiological Phenomena; Nicotine; Pericardium; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Sinus of Valsalva; Tropanes; Vagotomy

The pulmonary chemoreflexes evoked by phenylbiguanide (PBG), phenyldiguanide (PDG), phenylguanidine (PG) and 5-hydroxytryptamine (5-HT) have been investigated in the pentobarbitone-anaesthetized rabbit. The rank order of potency was 5-HT greater than PBG greater than PG greater than PDG. The responses evoked by all agonists were antagonized by pre-treatment with the selective 5-HT3 receptor antagonist MDL 72222, suggesting that their reflex effects are mediated by 5-HT3 receptors located on pulmonary vagal afferents. Furthermore, considering the low potency and long injection response time of PDG compared to PBG, we conclude that previous workers have used PBG and not PDG to identify non-myelinated pulmonary vagal afferents and to evoke the pulmonary chemoreflex.

Topics: Animals; Biguanides; Blood Pressure; Guanidines; Heart Rate; Lung; Male; Rabbits; Receptors, Serotonin; Reflex; Respiration; Serotonin; Serotonin Antagonists; Structure-Activity Relationship; Tidal Volume; Tropanes