Muscle pressor reflex: potential role of vanilloid type 1 receptor and acid-sensing ion channel.

Reflex cardiovascular responses to muscle contraction are mediated by mechanical and metabolic stimulation of thin muscle afferent fibers. Metabolic stimulants and receptors involved in responses are uncertain. Capsaicin depolarizes thin sensory afferent nerves that have vanilloid type 1 receptors (VR1). Among potential endogenous ligands of thin fibers, H+ has been suggested as a metabolite mediating the reflex muscle response as well as a potential stimulant of VR1. It has also been suggested that acid-sensing ion channels (ASIC) mediate H+, evoking afferent nerve excitation. We have examined the roles of VR1 and ASIC in mediating cardiovascular reflex responses to acid stimulation of muscle afferents in a rat model. In anesthetized rats, injections of capsaicin into the arterial blood supply of triceps surae muscles evoked a biphasic response (n = 6). An initial fall in mean arterial pressure (from baseline of 95.8 +/- 9.5 to 70.4 +/- 4.5 mmHg, P < 0.05 vs. baseline) was followed by an increase (to 131.6 +/- 11.3 mmHg, P < 0.05 vs. baseline). Anandamide (an endogenous substance that activates VR1) induced the same change in blood pressure as did capsaicin. The pressor (but not depressor) component of the response was blocked by capsazepine (a VR1 antagonist) and section of afferent nerves. In decerebrate rats (n = 8), H+ evoked a pressor response that was not blocked by capsazepine but was attenuated by amiloride (an ASIC blocker). In rats (n = 12) pretreated with resiniferatoxin to destroy muscle afferents containing VR1, capsaicin and H+ responses were blunted. We conclude that H+ stimulates ASIC, evoking the reflex response, and that ASIC are likely to be frequently found on afferents containing VR1. The data also suggest that VR1 and ASIC may play a role in processing of muscle afferent signals, evoking the muscle pressor reflex.     

Vagal afferent responses to fatty acids of different chain length in the rat

The role of cholecystokinin (CCK) in the effect of dietary lipid on proximal gastrointestinal function and satiety is controversial. Recent work suggests that fatty acid chain length may be a determining factor. We investigated the mechanism by which long- and short-chain fatty acids activate jejunal afferent nerves in rats. Whole mesenteric afferent nerve discharge was recorded in anaesthetized male Wistar rats during luminal perfusion of saline, sodium oleate, and sodium butyrate (both 10 mM). Both fatty acids evoked characteristic afferent nerve responses, distinct from the mechanical response to saline, that were abolished in rats following chronic subdiaphragmatic vagotomy. The effect of oleate was abolished by the CCK-A receptor antagonist Devazepide (0.5 mg/kg), whereas the effect of butyrate persisted despite pretreatment with either Devazepide or a combination of the calcium channel inhibitors nifedipine (1 mg/kg) and the omega-conotoxins GVIA and SVIB (each 25 microg/kg). In summary, long- and short-chain fatty acids activate intestinal vagal afferents by different mechanisms; oleate acts via a CCK-mediated mechanism and butyrate appears to have a direct effect on afferent terminals.     

The actions of serotonin on frog primary afferent terminals and cell bodies

The actions of serotonin (5-HT) were studied in the isolated frog spinal cord and dorsal root ganglion preparations. In the spinal cord, 5-HT increased the spontaneous activity recorded from dorsal roots, facilitated evoked spinal reflexes and produced fast and slow primary afferent depolarization (PAD). A direct action of 5-HT on primary afferent terminals is likely since 5-HT induced PAD remained in the presence of 1 microM tetrodotoxin and 2 mM Mn2+. The direct action of 5-HT on primary afferent terminals was blocked by methysergide and attenuated by concentrations of Mn2+ in excess of that required to block transmitter release. Cell bodies of the dorsal root ganglion were also depolarized by 5-HT. A slow hyperpolarization occasionally followed the initial depolarization. The depolarizing action of 5-HT in the dorsal root ganglion was also attenuated by treatment with Mn2+. It is concluded that 5-HT acts directly on frog primary afferents and that this influence may involve a calcium sensitive process. The dorsal root ganglion response to 5-HT appears to be a suitable model of the afferent terminal response.     

Lipopolysaccharide-induced changes in mesenteric afferent sensitivity of rat jejunum in vitro: role of prostaglandins

Bacterial translocation across the intestinal mucosal barrier leads to a macrophage-mediated inflammatory response, visceral hyperalgesia, and ileus. Our aim was to examine how mediators released into mesenteric lymph following LPS treatment influence intestinal afferent sensitivity and the role played by prostanoids in any sensitization. Intestinal lymph was collected from awake rats following treatment with either saline or LPS (5 mg/kg ip). Extracellular multiunit afferent recordings were made from paravascular mesenteric nerve bundles supplying the rat jejunum in vitro following arterial administration of control lymph, LPS lymph, and LPS. Mesenteric afferent discharge increased significantly after LPS lymph compared with control lymph. Peak discharge occurred within 2 min and remained elevated for 5 to 8 min. This response was attenuated by pretreatment with naproxen (10 microM), and restored upon addition of prostaglandin E(2) (5 microM) in the presence of naproxen, but AH6809 (5 microM), an EP(1)/EP(2) receptor(s) antagonist, failed to decrease the magnitude of LPS lymph-induced response. LPS itself also stimulated mesenteric afferent discharge but was unaffected by naproxen. TNF-alpha was significantly increased in LPS lymph compared with control lymph (1,583 +/- 197 vs. 169 +/- 38 pg/ml, P < 0.01) but exogenous TNF-alpha failed to evoke any afferent nerve discharge. We concluded that inflammatory mediators released from the gut into mesenteric lymph during endotoxemia have a profound effect on afferent discharge. These mediators influence afferent firing via the release of local prostaglandins.     

Serotonin induced vasodilatation in the human forearm is antagonized by the selective 5-HT3 receptor antagonist ICS 205-930

The role of 5-HT3 receptors in the biphasic vasodilator response to serotonin (5-hydroxytryptamine; 5-HT) was investigated in the forearm of 7 young healthy volunteers (aged 22-32 years). Single dose infusions of 5-HT (1 ng/kg/min) and of acetylcholine (ACh, 500 ng/kg/min) were administered into the brachial artery. Subsequently combined infusions of 5-HT together with the selective 5-HT3 receptor antagonist ICS 205-930 (350 and 700 ng/kg/min), and ACh together with ICS 205-930 (700 ng/kg/min) were given. After a pause of at least 1 hour the single infusions of 5-HT and ACh were repeated. Subsequently, 5-HT and ACh were infused together with atropine (100 ng/kg/min). Forearm blood flow (FBF) was measured by R-wave triggered venous occlusion plethysmography. Heart rate (HR) and i.a. blood pressure (BP) were recorded semi-continuously. None of the drugs in the doses used did induce systemic hemodynamic effects. After an initial rapid transient increase in FBF of 316 +/- 55%, 5-HT elicited a persistent increase in FBF of 90 +/- 22% (mean +/- SEM, p less than 0.05 for both). ACh induced a monophasic vasodilatation of 475 +/- 123% (p less than 0.05). Both the initial transient and the persistent dilatator response to 5-HT were attenuated by ICS 205-930 350 ng/kg/min (p = 0.057, n = 5) and 700 ng/kg/min (p less than 0.05, n = 7). The highest dose of ICS 205-930 did not significantly influence the dilatator response to ACh. Atropine abolished the ACh induced vasodilatation (p less than 0.05), but did not influence the biphasic dilatator response to 5-HT. Thus the 5-HT induced biphasic vasodilatation was antagonized by ICS 205-930, indicating that this response was mediated by 5-HT3 receptor activation. The fact that atropine did not influence the vascular response to 5-HT suggests that 5-HT did not induce vascular relaxation indirectly by the release of ACh from cholinergic nerve endings.     

Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying

Intestinal perfusion with carbohydrates inhibits gastric emptying via vagal and spinal capsaicin-sensitive afferent pathways. The aim of the present study was to determine the role of 1) 5-hydroxytryptamine (5-HT)(3) receptors (5-HT(3)R) in mediating glucose-induced inhibition of gastric emptying and 2) 5-HT(3)R expression in vagal and spinal afferents in innervating the duodenum. In awake rats fitted with gastric and duodenal cannulas, perfusion of the duodenum with glucose (50 and 100 mg) inhibited gastric emptying. Intestinal perfusion of mannitol inhibited gastric emptying only at the highest concentration (990 mosm/kgH(2)O). Pretreatment with the 5-HT(3)R antagonist tropisetron abolished both glucose- and mannitol-induced inhibition of gastric emptying. Retrograde labeling of visceral afferents by injection of dextran-conjugated Texas Red into the duodenal wall was used to identify extrinsic primary afferents. Immunoreactivity for 5-HT(3)R, visualized with an antibody directed to the COOH terminus of the rat 5-HT(3)R, was found in >80% of duodenal vagal and spinal afferents. These results show that duodenal extrinsic afferents express 5-HT(3)R and that the receptor mediates specific glucose-induced inhibition of gastric emptying. These findings support the hypothesis that enterochromaffin cells in the intestinal mucosa release 5-HT in response to glucose, which activates 5-HT(3)R on afferent nerve terminals to evoke reflex changes in gastric motility. The primary glucose sensors of the intestine may be mucosal enterochromaffin cells.     

EVIDENCE FOR THE SYNTHESIS AND STORAGE OF 5-HYDROXYTRYPTAMINE IN TWO SEPARATE POOLS IN THE BRAIN

Abstract— Evidence is presented to support the hypothesis that 5-hydroxytryptamine (5-HT) in the rat brain is synthesized by two separate pathways and stored in two or more compartments. Lysergic acid diethylamide in doses down to 50 μg/kg was shown to reduce the formation of 5-[³H]HT from [³H]tryptophan in the presence of a monoamine oxidase inhibitor, although the total rate of accumulation of 5-HT was unchanged. Conversely, adrenalectomy was found to increase the total synthesis of 5-HT measured in the same way, although the amount of 5-[³H]HT formed suggested that there was no increase in the synthesis of the amine. In a third experiment it was found that electrical stimulation of 5-HT-containing nerves following labelling of 5-HT stores with [³H]tryptophan led to a biphasic disappearance of 5-[³H]HT. It is suggested that the method of measuring 5-HT synthesis by measuring 5-[³H]HT formed from[³H]tryptophan in the presence of a monoamine oxidase inhibitor may be a way of selectively measuring the turnover of the functional pool of 5-HT.     

The inhibitory actions of acebutolol and propranolol on the contractile response to 5-hydroxytryptamine in various isolated vascular smooth muscles

Pretreatment with acebutolol or propranolol at high concentrations had an inhibitory effect on the contractile response to 5-hydroxytryptamine (5-HT) in most vascular smooth muscles such as rabbit aorta and basilar, mesenteric, renal, femoral arteries and cat coronary artery. The inhibitory actions of both agents were generally greater than on the responses to excess Ca2+ and potassium. In rabbit renal arteries, acebutolol had no effect on the response to 5-HT but inhibited the responses to excess Ca2+ and potassium. Propranolol had a marked inhibitory effect on the response to 5-HT. In all preparations used, the contractions induced by norepinephrine (NE) and histamine showed a much greater resistance to the effect of acebutolol and propranolol than the contractions induced by 5-HT, Ca2+ and potassium. Nifedipine had no inhibitory effect on the response to 5-HT in most of the preparations. Nifedipine inhibited the response to 5-HT only in the basilar arteries. The inhibitory actions of propranolol on the response to 5-HT was greater than that of acebutolol. The inhibitory action of acebutolol and propranolol on the response to 5-HT may be related to mechanisms other than the beta-adrenoceptor blocking action of the drugs. The possible mechanisms of inhibitory action of both beta-adrenoceptor antagonists on 5-HT are discussed.     

Laryngeal C-fiber afferents are not involved in the apneic response to laryngeal wood smoke in anesthetized rats

Laryngeal exposure to wood smoke in rats evokes a reflex apnea which is mediated through superior laryngeal afferents (J. Appl. Physiol. 83: 723-730, 1997). To study the role of laryngeal C-fiber afferents in eliciting this response, capsaicin aerosol (0.05 - 0.2 microg/ml) and 5 ml of wood smoke were delivered separately into a functionally isolated larynx of anesthetized Sprague-Dawley rats at a constant flow rate of 1.4 ml/s, while animals breathed spontaneously. Studies were repeated after either an intravenous injection of ruthenium red (2 mg/kg; n = 8), a perineural capsaicin treatment (200 microg/ml for 5 min; n = 8) of the superior laryngeal nerves, or a perineural sham treatment (n = 8); Ruthenium red inhibits the stimulation of afferent C-fiber nerve endings by capsaicin, whereas perineural capsaicin treatment selective blocks the conduction of C-fiber afferents. Either ruthenium red or perineural capsaicin treatment abolished the apneic response to laryngeal capsaicin, but did not significantly affect the apneic response to laryngeal wood smoke. Furthermore, the apneic responses to both types of irritants were not significantly altered by perineural sham treatment, yet were completely eliminated by a subsequent denervation of superior laryngeal nerves. Our results suggest that superior laryngeal C-fiber afferents are not involved in eliciting the reflex apneic response to laryngeal wood smoke in anesthetized rats. It is speculated that this response may result mainly from the stimulation of myelinated afferents, possibly laryngeal irritant receptors.     

Differential effects of airway afferent nerve subtypes on cough and respiration in anesthetized guinea pigs

The hypothesis that respiratory reflexes, such as cough, reflect the net and often opposing effects of activation of multiple afferent nerve subpopulations throughout the airways was evaluated. Laryngeal and tracheal mucosal challenge with either citric acid or mechanical probing reliably evoked coughing in anesthetized guinea pigs. No other stimulus reliably evoked coughing in these animals, regardless of route of administration and despite some profound effects on respiration. Selectively activating vagal C-fibers arising from the nodose ganglia with either adenosine or 2-methyl-5-HT evoked only tachypnea. Selectively activating vagal afferents arising from the jugular ganglia induced respiratory slowing and apnea. Nasal afferent nerve activation by capsaicin, citric acid, hypertonic saline, or histamine evoked only respiratory slowing. Histamine, which activates intrapulmonary rapidly adapting receptors but not airway or lung C-fibers or tracheal bronchial cough receptors induced bronchospasm and tachypnea, but no coughing. The results indicate that the reflexes initiated by stimuli thought to be selective for some afferent nerve subtypes will likely depend on the net and potentially opposing effects of multiple afferent nerve subpopulations throughout the airways. The data also provide further evidence that the afferent nerves regulating cough in anesthetized guinea pigs are distinct from either C-fibers or intrapulmonary rapidly adapting receptors.     

The response of alpha-motoneurons of different size to stretch and vibration of extensor muscles after injection of 5-hydroxytryptophan in spinal cats.

1. Vibration of the GS muscle at 100/sec, and the peak-to-peak amplitude of about 100 mu, produced slight reflex activity of homonymous and heteronymous alpha-motoneurons in the spinal, unanesthetized cat. 2. Intravenous injection of the 5-HT precursor 5-HTP (25 mg/kg, L-form) performed in the spinal preparation facilitated the responses of single extensor alpha-motoneurons to both vibration and stretch of the corresponding muscle. The 5-HT antagonist methysergide (0-5 mg/kg i. v.) blocked almost completely the facilitation of the vibration and stretch induced motoneuronal discharges produced by 5-HTP in the spinal cat, indicating that the facilitation was 5-HT specific. 4. A comparison of the types of alpha-motoneurons participating in the reflex responses elicited by the different stimuli in the spinal cat following injection of 5-HTP showed that both small-tonic and large-phasic alpha-motoneurons take part in both stretch and vibration reflexes. 5. It is concluded that the alpha-motoneuron pool of the GS muscle represents an homogenous population, no matter what kind of synaptic drive is used for its activation, and that the susceptibility of a motoneuron to discharge depends on the amount of the afferent excitatory input rather than on the modalities of sensory stimulation.     

TRPV1 marks synaptic segregation of multiple convergent afferents at the rat medial solitary tract nucleus

TRPV1 receptors are expressed on most but not all central terminals of cranial visceral afferents in the caudal solitary tract nucleus (NTS). TRPV1 is associated with unmyelinated C-fiber afferents. Both TRPV1+ and TRPV1- afferents enter NTS but their precise organization remains poorly understood. In horizontal brainstem slices, we activated solitary tract (ST) afferents and recorded ST-evoked glutamatergic excitatory synaptic currents (ST-EPSCs) under whole cell voltage clamp conditions from neurons of the medial subnucleus. Electrical shocks to the ST produced fixed latency EPSCs (jitter<200 μs) that identified direct ST afferent innervation. Graded increases in shock intensity often recruited more than one ST afferent and ST-EPSCs had consistent threshold intensity, latency to onset, and unique EPSC waveforms that characterized each unitary ST afferent contact. The TRPV1 agonist capsaicin (100 nM) blocked the evoked TRPV1+ ST-EPSCs and defined them as either TRPV1+ or TRPV1- inputs. No partial responses to capsaicin were observed so that in NTS neurons that received one or multiple (2-5) direct ST afferent inputs--all were either blocked by capsaicin or were unaltered. Since TRPV1 mediates asynchronous release following TRPV1+ ST-evoked EPSCs, we likewise found that recruiting more than one ST afferent further augmented the asynchronous response and was eliminated by capsaicin. Thus, TRPV1+ and TRPV1- afferents are completely segregated to separate NTS neurons. As a result, the TRPV1 receptor augments glutamate release only within unmyelinated afferent pathways in caudal medial NTS and our work indicates a complete separation of C-type from A-type afferent information at these first central neurons.     

Indirect mechanism of histamine-induced nociception in temporomandibular joint of rats

A considerable amount of evidence suggests that temporomandibular joint (TMJ) pain associated with temporomandibular disorder results, at least in part, from an inflammatory episode. Although histamine can cause pain, it is not clear whether this mediator induces nociception in the TMJ. In this study, we investigated the contribution of endogenous histamine to formalin-induced nociception in the TMJ of rats. We also investigated whether the administration of histamine induces nociception in the TMJ and, if so, whether this effect is mediated by an indirect action on primary afferent nociceptors. Local administration of the H1-receptor antagonist pyrilamine prevented formalin-induced nociception in the TMJ in a dose-dependent manner. Local administration of histamine (250 microg) in the TMJ induced nociceptive behavior that was inhibited by co-administration of the lidocaine N-ethyl bromide quaternary salt QX-314 (2%) or the selective H1-receptor antagonist pyrilamine (400 microg). Nociception induced by histamine was also inhibited by pre-treatment with sodium cromoglycate (800 microg) and by co-administration of the 5-HT(3) receptor antagonist tropisetron (400 mug), while pyrilamine (400 mug) did not inhibit nociception induced by 5-hydroxytryptamine (5-HT, 250 microg) in the TMJ. Furthermore, histamine, in a dose that did not induce nociception by itself, strongly enhanced 5-HT-induced nociception. Finally, the administration of a sub-threshold dose of 5-HT (100 microg), but not of histamine (100 microg), elicited nociception in the TMJ previously challenged with the inflammatory agent carrageenan (100 microg). In conclusion, these data suggest that histamine induces TMJ nociception by an indirect mechanism involving endogenous release of 5-HT and activation of 5-HT(3) receptors on sensory afferents. It is proposed that histamine activates the H1 receptor to induce the release of 5-HT which depolarizes the nociceptor by activating 5-HT(3) receptor.     

炎症介质在内毒素引起大鼠肠系膜血管床降钙素基因相关肽释放中的作用

本研究在离体大鼠肠系膜血管床灌流模型上,采用特异放免法测定灌流液中的降钙素基因相关肽（ＣＧＲＰ）,观察几种常见炎症介质在内毒素引起ＣＧＲＰ释放中的作用。结果显示：前列腺素合成酶抑制剂地塞米松、布洛芬与消炎痛,缓激肽受体Ｂ２拮抗剂ＨＯＥ１４０,血小板激活因子拮抗剂ＷＥＢ２０８６,组胺Ｈ１受体拮抗剂苯海拉明以及和组胺Ｈ２受体拮抗剂西咪替丁,均能明显抑剂制内毒素引起的ＣＧＲＰ释放,５羟色胺受体拮抗剂ＩＣＳ２０５９３０却无明显作用。从而提示：内毒素引起ＣＧＲＰ释放是通过炎症介质前列腺素、缓激肽、血小板激活因子和组胺介导的,阻断或减少炎症介质的产生可望减轻内毒素血症时ＣＧＲＰ的过量释放。     

Increased 5-HT3-mediated signalling in pelvic afferent neurons from mice deficient in P2X2 and/or P2X3 receptor subunits

Extracellular ATP and 5-hydroxytryptamine (5-HT) are both involved in visceral sensory pathways by interacting with P2X and 5-HT₃ receptors, respectively. We have investigated the changes in P2X and 5-HT₃-mediated signalling in pelvic afferent neurons in mice deficient in P2X₂ and/or P2X₃ subunits by whole-cell recording of L₆–S₂ dorsal root ganglion (DRG) neurons and by multi-unit recording of pelvic afferents of the colorectum. In wildtype DRG neurons, ATP evoked transient, sustained or mixed (biphasic) inward currents. Transient currents were absent in P2X₃ ^−/− neurons, whereas sustained currents were absent in P2X₂ ^−/− DRG neurons. Neither transient nor sustained currents were observed following application of ATP or α,β-methylene ATP (α,β-meATP) in P2X₂/P2X₃ ^Dbl−/− DRG neurons. 5-HT was found to induce a fast inward current in 63% of DRG neurons from wildtype mice, which was blocked by tropisetron, a 5-HT₃ receptor antagonist. The percentage of DRG neurons responding to 5-HT was significantly increased in P2X ₂ ^−/−, P2X₃ ^−/− and P2X₂/P2X₃ ^Dbl−/− mice, and the amplitude of 5-HT response was significantly increased in P2X₂/P2X₃ ^Dbl−/− mice. The pelvic afferent response to colorectal distension was attenuated in P2X₂/P2X₃ ^Dbl−/− mice, but the response to serosal application of 5-HT was enhanced. Furthermore, tropisetron resulted in a greater reduction in pelvic afferent responses to colorectal distension in the P2X₂/P2X₃ ^Dbl−/− preparations. These data suggest that P2X receptors containing the P2X₂ and/or P2X₃ subunits mediate purinergic activation of colorectal afferents and that 5-HT signalling in pelvic afferent neurons is up-regulated in mice lacking P2X₂ or P2X₃ receptor genes. This effect is more pronounced when both subunits are absent.     

刺激中缝背核对大鼠小脑皮层下核团神经元电活动的影响

我们首次观察了电刺激大鼠中缝背核（ＤＲ）对小脑核团（ＤＣＮ）──内侧核（ＭＮ）,间位核（ＩＮ）和外侧核（ＬＮ）神经元电活动的影响。结果表明：刺激ＤＲ可引起ＤＣＮ神经元的抑制、兴奋和双相（兴奋－抑制、抑制－兴奋）三种不同类型的反应,其中以抑制性反应为主（７６％－９０％）;反应的潜伏期为１０—８４ｍｓ,但大多数细胞呈现小于３０ｍｓ的短潜伏期反应;ＤＣＮ细胞的自发放电频率为５－１２０Ｈｚ,自发放电频率高的神经元群体对ＤＲ刺激的反应比率却比自发放电频率低的群体低;静脉注射５－ＨＴ２／１ｃ受体阻断剂ｍｅｔｈｙｓｅｒｇｉｄｅ可以阻断ＤＣＮ细胞对ＤＲ刺激的抑制性反应（６６．７％－８３．３％）。这些结果提示中缝－小脑５－ＨＴ能纤维传入系统可能通过对ＤＣＮ细胞电活动的调制作用参予小脑的感觉运动整合过程。     

Increase in tissue concentrations of histamine and 5-hydroxytryptamine following capsaicin treatment of newborn rats

Treatment of newborn rats with capsaicin is known to result in a permanent deficit of unmyelinated afferent neurones. The present study was concerned with the effect of neonatal capsaicin (50 mg kg^?1 s.c.) on tissue concentrations of histamine and 5-hydroxytryptamine (5-HT) in the adult rat. The amines were determined at the age of 5 to 6 months using high performance liquid chromatography. Histamine and 5-HT concentrations were significantly increased in the dorsal skin of the hind paw and the dorsal spinal cord. Histamine concentrations were also increased in lungs and ventral spinal cord while 5-HT concentrations were unaltered in these tissues. Both histamine and 5-HT concentrations were unchanged in the ventral skin of the hind paw, gastrointestinal tract and brain. It is proposed that the changes in the amine concentrations reflect a secondary response of histamine and 5-HT containing mast cells and neurones to the irreversible degeneration of unmyelinated afferent neurones caused by neonatal capsaicin treatment.     

Effect of LY53857, a selective 5HT2 receptor antagonist, on 5HT-induced increases in cutaneous vascular permeability in rats

Both serotonin and histamine increased cutaneous vascular permeability in rats; however, serotonin was approximately 100-fold more potent than histamine. LY53857 (0.1 and 1.0 mg/kg, i.p.), a selective 5HT2 receptor antagonist, blocked serotonin- but not histamine-induced increases in cutaneous vascular permeability. the alpha 1 receptor antagonist, prazosin, did not significantly affect increases in vascular permeability produced by serotonin. These data extend previous studies with LY53857 by further documenting its selectivity as a 5HT2 receptor antagonist. In addition, these results with a selective 5HT2 receptor antagonist provide evidence that 5HT2 receptor activation may be the predominant mechanism associated with vascular permeability changes induced by serotonin.     

Phenyldiguanide activates cardiac receptors to produce responses by involving three different efferent pathways in anaesthetized rats

The present study was undertaken to determine the afferent and efferent pathways involved in the phenyldiguanide (PDG)-induced reflex response in rats. Intravenous (iv) injection of PDG (10 microg/kg), produced hypotension, bradycardia and apnea over a period of time. Bilateral vagotomy abolished the PDG-induced reflex changes. Atropine (2 mg/kg; iv) blocked only the bradycardiac response produced by PDG, while prazosin (0.5 mg/kg; iv) blocked the hypotensive response, and bilateral vagotomy in these animals abolished the apneic response. In separate series of experiments, intrapericardial injection of lignocaine abolished the hypotensive and bradycardiac responses evoked by PDG in artificially ventilated rats. The results reveal that the PDG-induced reflex is mediated through vagal afferents originating from the heart and efferents involve three different pathways. The bradycardiac response was through the muscarinic receptors, the hypotension is mediated through alpha1 adrenoceptors and the apnea presumably through the spinal motoneurones supplying the respiratory muscles.     

Mechanisms underlying mechanosensitivity of mesenteric afferent fibers to vascular flow

Spinal afferent neurons, with endings in the intestinal mesenteries, have been shown to respond to changes in vascular perfusion rates. The mechanisms underlying this sensitivity were investigated in an in vitro preparation of the mesenteric fan devoid of connections with the gut wall. Afferent discharge increased when vascular perfusion was stopped ("flow off"), a response localized to the terminal vessels just prior to where they entered the gut wall. The flow-off response was compared following pharmacological manipulations designed to determine direct mechanical activation from indirect mechanisms via the vascular endothelium or muscle. Under Ca(2+)-free conditions, responses to flow off were significantly augmented. In contrast, the myosin light chain kinase inhibitor wortmannin (1 microM, 20 min) did not affect the flow-off response despite blocking the vasoconstriction evoked by 10 microM l-phenylephrine. This ruled out active tension, generated by vascular smooth muscle, in the response to flow off. Passive changes caused by vessel collapse during flow off were speculated to affect sensory nerve terminals directly. The flow-off response was not affected by the N-, P-, and Q-type Ca(2+) channel blocker omega-conotoxin MVIIC (1 muM intra-arterially) or the P2X receptor/ion channel blocker PPADS (50 microM). However, ruthenium red (50 microM), a blocker of nonselective cation channels, greatly reduced the flow-off response and also abolished the vasodilator response to capsaicin. Our data support the concept that mesenteric afferents sense changes in vascular flow during flow off through direct mechanisms, possibly involving nonselective cation channels. Passive distortion in the fan, caused by changes in blood flow, may represent a natural stimulus for these afferents in vivo.