Neural modulation of cephalexin intestinal absorption through the di- and tripeptide brush border transporter of rat jejunum in vivo.
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Intestinal absorption of beta-lactamine antibiotics (e.g., cefixime and cephalexin) has been shown to proceed through the dipeptide carrier system. In a previous study, nifedipine (NFP), an L-type calcium channel blocker, enhanced the absorption of cefixime in vivo but not in vitro, and it was suggested that neural mechanisms might be involved in the effect of NFP. The aim of the present study was to assess the involvement of the nervous system on the intestinal absorption of cephalexin (CFX). To investigate this, we used a single-pass jejunal perfusion technique in rats. NFP and diltiazem enhanced approximately 2-fold the plasma levels of CFX in treated rats versus untreated controls. NFP also increased approximately 2-fold the CFX level in portal plasma and increased urinary excretion of CFX, thus indicating that CFX did effectively increase CFX intestinal absorption. Perfusing high concentrations of dipeptides in the jejunal lumen competitively reduced CFX absorption and inhibited the enhancement of CFX absorption produced by NFP. Hexamethonium and lidocaine inhibited the effect of NFP, whereas atropine, capsaicin, clonidine, and isoproterenol enhanced CFX absorption by the same order of magnitude as NFP. Thus, complex neural networks can modulate the function of the intestinal di- and tripeptide transporter. Sympathetic noradrenergic fibers, intestinal sensory neurons, and nicotinic synapses are involved in the increase of CFX absorption produced by NFP. (+info)
Nitric oxide mediates sympathetic vasoconstriction at supraspinal, spinal, and synaptic levels.
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The purposes of this study were to investigate the level of the sympathetic nervous system in which nitric oxide (NO) mediates regional sympathetic vasoconstriction and to determine whether neural mechanisms are involved in vasoconstriction after NO inhibition. Ganglionic blockade (hexamethonium), alpha1-receptor blockade (prazosin), and spinal section at T1 were used to study sympathetic involvement. NO was blocked with Nomega-nitro-L-arginine methyl ester (L-NAME). Regional blood flow in the mesenteric and renal arteries and terminal aorta was monitored by electromagnetic flowmetry in conscious rats. L-NAME (3-5 mg/kg iv) increased arterial pressure and peripheral resistance. Ganglionic blockade (25 mg/kg iv) significantly reduced the increase in resistance in the mesentery and kidney in intact and spinal-sectioned rats. Ganglionic blockade significantly decreased hindquarter resistance in intact rats but not in spinal-sectioned rats. Prazosin (200 micrograms/kg iv) significantly reduced the increased hindquarter resistance. We concluded that NO suppresses sympathetic vasoconstriction in the mesentery and kidney at the spinal level, whereas hindquarter tone is mediated at supraspinal and synaptic levels. (+info)
Mechanisms of acute cardiovascular response to periodic apneas in sedated pigs.
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This study was designed to evaluate the importance of sympathoadrenal activation in the acute cardiovascular response to apneas and the role of hypoxemia in this response. In addition, we evaluated the contribution of the vagus nerve to apnea responses after chemical sympathectomy. In six pigs preinstrumented with an electromagnetic flow probe and five nonpreinstrumented pigs, effects of periodic nonobstructive apneas were tested under the following six conditions: room air breathing, 100% O2 supplementation, both repeated after administration of hexamethonium (Hex), and both repeated again after bilateral vagotomy in addition to Hex. With room air apneas, during the apnea cycle, there were increases in mean arterial pressure (MAP; from baseline of 108 +/- 4 to 124 +/- 6 Torr, P < 0.01), plasma norepinephrine (from 681 +/- 99 to 1,825 +/- 578 pg/ml, P < 0.05), and epinephrine (from 191 +/- 67 to 1,245 +/- 685 pg/ml, P < 0.05) but decreases in cardiac output (CO; from 3.3 +/- 0.6 to 2.4 +/- 0.3 l/min, P < 0.01) and cervical sympathetic nerve activity. With O2 supplementation relative to baseline, apneas were associated with small increases in MAP (from 112 +/- 4 to 118 +/- 3 Torr, P < 0.01) and norepinephrine (from 675 +/- 97 to 861 +/- 170 pg/ml, P < 0.05). After Hex, apneas with room air were associated with small increases in MAP (from 103 +/- 6 to 109 +/- 6 Torr, P < 0.05) and epinephrine (from 136 +/- 45 to 666 +/- 467 pg/ml, P < 0.05) and decreases in CO (from 3.6 +/- 0.4 to 3.2 +/- 0. 5 l/min, P < 0.05). After Hex, apneas with O2 supplementation were associated with decreased MAP (from 107 +/- 5 to 100 +/- 5 Torr, P < 0.05) and no other changes. After vagotomy + Hex, with room air and O2 supplementation, apneas were associated with decreased MAP (from 98 +/- 6 to 76 +/- 7 and from 103 +/- 7 to 95 +/- 6 Torr, respectively, both P < 0.01) but increased CO [from 2.7 +/- 0.3 to 3. 2 +/- 0.4 l/min (P < 0.05) and from 2.4 +/- 0.2 to 2.7 +/- 0.2 l/min (P < 0.01), respectively]. We conclude that sympathoadrenal activation is the major pressor mechanism during apneas. Cervical sympathetic nerve activity does not reflect overall sympathoadrenal activity during apneas. Hypoxemia is an important but not the sole trigger factor for sympathoadrenal activation. There is an important vagally mediated reflex that contributes to the pressor response to apneas. (+info)
Single channel properties of human alpha3 AChRs: impact of beta2, beta4 and alpha5 subunits.
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1. We performed single channel analysis on human alpha3 acetylcholine receptors (AChRs) in Xenopus oocytes and native AChRs from the human neuroblastoma cell line IMR-32. alpha3 AChRs exhibit channel properties that reflect subunit composition. 2. alpha3beta2 AChR open times were 0.71 +/- 0.14 and 3.5 +/- 0.4 ms with a predominant conductance of 26 pS. alpha3beta4 AChRs had open times of 1.4 +/- 0.2 and 6.5 +/- 0.8 ms and a predominant conductance of 31 pS. Burst times were 0.82 +/- 0.12 and 5.3 +/- 0.7 ms for alpha3beta2 and 1.7 +/- 0.1 and 16 +/- 1 ms for alpha3beta4. Desensitization was faster for AChRs with the beta2 subunit than for those with the beta4 subunit. 3. One open time for alpha3alpha5beta2 AChRs (5.5 +/- 0.3 ms) was different from those of alpha3beta2 AChRs. For alpha3alpha5beta4 AChRs, an additional conductance, open time and burst time (36 pS, 22 +/- 3 ms and 43 +/- 4 ms, respectively) were different from those for alpha3beta4 AChRs. 4. alpha3 AChRs were inhibited by hexamethonium or mecamylamine. The rate constants for block of alpha3beta4 by hexamethonium and of alpha3beta2 by mecamylamine were 1.2 x 107 and 4.6 x 107 M-1 s-1, respectively. 5. AChRs from IMR-32 cells had a predominant conductance of 32 pS and open times of 1.5 +/- 0.3 and 9.6 +/- 1.2 ms. These properties were most similar to those of alpha3beta4 AChRs expressed in oocytes. Antibodies revealed that 5 +/- 2 % of IMR-32 alpha3 AChRs contained alpha5 subunits and 6 +/- 2 % contained beta2 subunits. IMR-32 alpha3 AChRs are primarily alpha3beta4 AChRs. (+info)
Subtypes of muscarinic receptors regulating gallbladder cholinergic contractions.
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The aim of this study was to determine the functional role of muscarinic receptor subtypes regulating gallbladder cholinergic contractions. Electrical field stimulation (EFS; 16 Hz) produced contractile responses of guinea pig gallbladder muscle strips in vitro that were inhibited by 1 microM tetrodotoxin (2 +/- 2% of control) and 1 microM atropine (1 +/- 1% of control), indicating activation of intrinsic cholinergic nerves. Exogenous ACh (5 microM)-induced contractions were inhibited by atropine (1 +/- 1% of control) but not tetrodotoxin (102 +/- 1% of control), indicating a direct effect on smooth muscle. The M1 receptor antagonist pirenzepine (10 nM) had no effect on ACh-induced contractions but inhibited EFS-induced contractions by 11 +/- 3%. The M2 antagonist methoctramine (10 nM) had no effect on ACh-induced contractions but augmented EFS-induced contractions by 5 +/- 2%. The M3 antagonist 4-DAMP (10 nM) inhibited ACh-induced contractions by 14 +/- 4% and EFS-induced contractions by 22 +/- 5%. In conclusion, specific M1, M2, and M3 receptors modulate gallbladder muscle contractions by regulating ACh release from cholinergic nerves and mediating the contraction. Cholinergic contractions are mediated by M3 receptors directly on the smooth muscle. M2 receptors are on cholinergic nerves and function as prejunctional inhibitory autoreceptors. M1 receptors are on cholinergic nerves and function as prejunctional facilitatory autoreceptors. (+info)
Peptidyl inhibitors of shaker-type Kv1 channels elicit twitches in guinea pig ileum by blocking kv1.1 at enteric nervous system and enhancing acetylcholine release.
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Potent and selective peptidyl blockers of the Shaker-type (Kv1) voltage-gated potassium channels were used to determine the role of these channels in regulating the spontaneous motility of smooth muscle preparations. Margatoxin (MgTX), kaliotoxin, and agitoxin-2 at 1 to 10 nM and agitoxin-1 at 50 to 100 nM induce twitches in guinea pig ileum strips. These twitches are abolished by tetrodotoxin (TTX, 0.5 microM), atropine (1 microM), hexamethonium (10 microM), or nifedipine (0.1 microM). It is proposed that blockade of Kv1 channels by MgTX, kaliotoxin, or the agitoxins increases excitability of intramural nerve plexuses in the ileum, promoting release of acetylcholine from excitatory motor nerve terminals. This, in turn, leads to Ca2+-dependent action potentials and twitching of the muscle fibers. MgTX does not induce twitches in several other guinea pig and/or rat vascular, genitourinary, or gastrointestinal smooth muscles, although small increases in spontaneous myogenic activity may be seen in detrusor muscle exposed to >30 nM MgTX. This effect is not reversed by TTX or atropine. The TTX- and atropine-sensitive twitches of guinea pig ileum are also induced by nanomolar concentrations of alpha-dendrotoxin, a selective blocker of Shaker Kv1.1 and 1.2 subtypes, or stichodactylatoxin, a peptide isolated from sea anemone that displays high affinity for Kv1.1 and 1.3, but not by charybdotoxin, which blocks Kv1.2 and 1.3 but not 1.1. The data taken together suggest that high-affinity blockade of Kv1.1 underlies the ability of MgTX, kaliotoxin, agitoxin-1, agitoxin-2, alpha-dendrotoxin, and stichodactylatoxin to elicit TTX-sensitive twitches in guinea pig ileum. (+info)
Topographical and electrophysiological characteristics of highly excitable S neurones in the myenteric plexus of the guinea-pig ileum.
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1. Most intracellular electrical recordings from myenteric neurones have been made from the centre of large ganglia. In this study, we examined the electrophysiological properties of neurones at the corners of large ganglia close to internodal strands and in microganglia. 2. Of 150 neurones in these locations: 111 were tonic S neurones; 9 were phasic S neurones and 30 were AH neurones. 3. Tonic S neurones were characterized by: (i) low resting membrane potentials (-50 +/- 1 mV, mean +/- s.e.m.); (ii) high input impedance (522 +/- 23 MOmega); (iii) low threshold for action potential (AP) generation (0.012 +/- 0.004 nA); (iv) firing of APs throughout a depolarizing pulse (duration <= 1 s) and one to four APs following a hyperpolarizing pulse and (v) spontaneous fast excitatory postsynaptic potentials (FEPSPs). A substantial proportion of tonic S neurones (43 %) also fired APs spontaneously (7.6 +/- 0.6 Hz; range, 0.3-19 Hz). All APs were blocked by tetrodotoxin (1 microM). 4. Tonic S neurones were subclassified, according to their post-stimulus responses, as SAH or SAD neurones. Following a burst of APs, SAH neurones exhibited a prominent after-hyperpolarization (duration, 711 +/- 10 ms) and SAD neurones an after-depolarization (duration, 170 +/- 10 ms). The after-hyperpolarization was reduced in four of ten neurones by apamin (0.3 microM). 5. FEPSPs were evoked in 20 of 38 S neurones by electrical stimulation applied both oral and anal to the recording site. Repetitive stimuli evoked slow excitatory postsynaptic potentials (SEPSPs) in some tonic S neurones. 6. Three functional classes of S neurones were identified after injection of neurobiotin through the recording microelectrode: (i) longitudinal muscle motor neurones, (ii) short circular muscle motor neurones, and (iii) ascending interneurones. 7. In conclusion, there appears to be topographical organization of highly excitable, tonic S neurones within the myenteric plexus, since, in contrast to other S neurones, they can be readily impaled in myenteric ganglia close to internodal strands and in microganglia. (+info)
Does the guinea-pig ileum obey the 'law of the intestine'?
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1. We report the first simultaneous mechanical reflex responses of the longitudinal muscle (LM) and circular muscle (CM) layers of the guinea-pig ileum following mucosal stimulation and distension in vitro. 2. Dissection techniques were used to prevent mechanical interaction between the LM and CM layers both oral and anal to a stimulus site. 3. All graded stimuli produced graded contractions of both the LM and CM orally and anally to the stimulus. Contractions occurred synchronously in the LM and CM and under no circumstances were inhibitory responses recorded in either muscle layer, despite the presence of ongoing cholinergic tone in both the LM and CM. Contractions were abolished by tetrodotoxin (1.6 microM). 4. Local brush stroking of the mucosa evoked a peristaltic wave which readily conducted distally over 13 cm, without the presence of fluid in the lumen. No descending relaxation was observed. 5. Apamin (300 nM) disrupted evoked peristaltic waves and significantly increased the rate-of-rise of the LM and CM contractions anal to a stimulus, and the LM oral to a stimulus. 6. Nomega-nitro-L-arginine (100 microM), a nitric oxide synthesis inhibitor, had no overall significant effect on the characteristics of the LM and CM contractions, although on occasion an enhancement in their peak amplitude was noted. 7. It is suggested that the guinea-pig ileum does not conform to the 'law of the intestine' as postulated by Bayliss & Starling (1899). Rather, local physiological stimulation of the ileum elicits a contraction both orally and anally to a stimulus, which occurs synchronously in both the CM and LM layers. Apamin-sensitive inhibitory neurotransmission modulates the rate-of-rise of the anal contraction of the CM, possibly to generate distal propulsion. (+info)