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)
Antiadrenergic effect of chronic amiodarone therapy in human heart failure.
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OBJECTIVES: The aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure. BACKGROUND: Unlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect. METHODS: To evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity. RESULTS: Amiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22 +/- 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart. CONCLUSIONS: These data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective. (+info)
Involvement of cGMP-dependent protein kinase in adrenergic potentiation of transmitter release from the calyx-type presynaptic terminal.
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I have previously reported that norepinephrine (NE) induces a sustained potentiation of transmitter release in the chick ciliary ganglion through a mechanism pharmacologically distinct from any known adrenergic receptors. Here I report that the adrenergic potentiation of transmitter release was enhanced by a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) and by zaprinast, an inhibitor of cGMP-selective phosphodiesterase. Exogenous application of the membrane-permeable cGMP, 8-bromo-cGMP (8Br-cGMP), potentiated the quantal transmitter release, and after potentiation, the addition of NE was no longer effective. On the other hand, 8Br-cAMP neither potentiated the transmitter release nor occluded the NE-induced potentiation. The NE-induced potentiation was blocked by neither nitric oxide (NO) synthase inhibitor nor NO scavenger. The quantal transmitter release was not potentiated by NO donors, e.g., sodium nitroprusside. The NE-induced potentiation and its enhancement by IBMX was antagonized by two inhibitors of protein kinase G (PKG), Rp isomer of 8-(4-chlorophenylthio) guanosine-3', 5'-cyclic monophosphorothioate and KT5823. As with NE-induced potentiation, the effects of 8Br-cGMP on both the resting intraterminal [Ca2+] ([Ca2+]i) and the action potential-dependent increment of [Ca2+]i (DeltaCa) in the presynaptic terminal were negligible. The reduction of the paired pulse ratio of EPSC is consistent with the notion that the NE- and cGMP-dependent potentiation of transmitter release was attributable mainly to an increase of the exocytotic fusion probability. These results indicate that NE binds to a novel adrenergic receptor that activates guanylyl cyclase and that accumulation of cGMP activates PKG, which may phosphorylate a target protein involved in the exocytosis of synaptic vesicles. (+info)
Venous hydrostatic indifference point as a marker of postnatal adaptation to orthostasis in swine.
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The postulate that venous adaptation assists postural baroreflex regulation by shifting the hydrostatic indifference point (HIP) toward the heart was investigated in eight midazolam-sedated newborn piglets. Whole body head-up (+15, +30, and +45 degrees ) and head-down (-15 and -30 degrees ) tilt provided a physiological range of orthostatic strain. HIP for all positive tilts shifted toward the heart (P < 0.05), +45 degrees HIP shifted most [6.7 +/- 0.3, 5.9 +/- 0.5, and 3.6 +/- 0.3 (SE) cm caudal to right atrium on days 1, 3, and 6, respectively]. HIP for negative tilts (3.0 +/- 0.2 cm caudal to right atrium) did not shift with postnatal age. Euthanasia on day 6 caused 2.1 +/- 0.3-cm caudal displacement of HIP for positive and negative tilts (P < 0.05). HIP proximity to right atrium was not altered by alpha-, beta-adrenoceptor and cholinoceptor blockade on day 5. It is concluded that early HIP migration reflects enhancement of venous pressure control to head-up orthostatic strain. The effect is independent of baroreflex-mediated adrenoceptor and cholinoceptor mechanisms. (+info)
Stimulation by transforming growth factor-alpha of DNA synthesis and proliferation of adult rat hepatocytes in primary cultures: modulation by alpha- and beta-adrenoceptor agonists.
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We investigated the effects of transforming growth factor alpha (TGF-alpha) on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes and examined the influence of alpha and beta adrenoceptor agonists on the TGF-alpha-induced responses. TGF-alpha (1.0 ng/ml) produced a 4.1-fold elevation of DNA synthesis during 3 h of culture and a 1.2-fold increase in the nucleus number (proliferation) during 4 h of culture at a cell density of 3.3 x 10(4) cells/cm(2). The TGF-alpha-induced hepatocyte DNA synthesis and proliferation were dose-dependent at EC(50) values of 0.36 ng/ml and 0.45 ng/ml, respectively. Hepatocyte DNA synthesis and proliferation induced by 1.0 ng/ml TGF-alpha did not reduce even at higher initial plating densities (5.0 x 10(4) and 1.0 x 10(5) cells/cm(2)). Increasing concentrations of the beta(2) adrenoceptor agonist metaproterenol (10(-7)-10(-6) M) markedly reduced the proliferative effects of TGF-alpha, whereas those of the alpha(2) adrenoceptor agonist 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline (UK-14304; 10(-6)-10(-5) M) and the alpha(1) adrenoceptor agonist phenylephrine (10(-7)-10(-6) M) significantly potentiated the TGF-alpha action. The proliferative effects of TGF-alpha (1.0 ng/ml) were not affected significantly by a monoclonal antiepidermal growth factor receptor antibody (1-100 ng/ml) and were almost completely blocked by specific inhibitors of signal transducers such as genistein (10(-5) M), 1-6[[17beta-3methoxyestra-1,3, 5(10)-trien-17-yl]amino]hexyl]-1H-pyrrol2,5-dione (U-73122; 0(-5) M), wortmannin (5 x 10(-7) M), sphingosine (5 x 10(-6) M), 2'-amino-3'-methoxyflavone (PD98059; 5 x 10(-5) M), and rapamycin (10 ng/ml). These results suggest that among the elements that link signals of cell surface receptor to the nucleus, the proliferative action of TGF-alpha is mediated, at least, by tyrosine kinase, phospholipase C, phosphatidylinositol 3-kinase, protein kinase C, mitogen-activated protein kinase kinase, and ribosomal protein p70 S6 kinase. (+info)
Mechanisms of action of OPC-28326, a selective hindlimb vasodilator.
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The unique cardiovascular profile of OPC-28326 [4-(N-methyl-2-phenylethylamino)-1-(3, 5-dimethyl-4-propionylaminobenzoyl)piperidine hydrochloride monohydrate] provides insight into basic mechanisms of this new drug as determined by experiments in dogs and rats. In anesthetized open-chest dogs, an i.v. administration of a low dose (0.3 and 1.0 microg/kg) of OPC-28326 selectively increased femoral artery blood flow with only minimal action on systemic blood pressure, heart rate and coronary, carotid, vertebral, renal, and mesenteric blood flows. Biochemical study suggests that OPC-28326 had no effect on phosphodiesterase-3 and -5. OPC-28326 dose-dependently inhibited phenylephrine-induced increases in blood pressure in spinally anesthetized dogs. The potency of OPC-28326 was, however, about 180 times lower than that of prazosin. Although binding studies have revealed an affinity of OPC-28326 to serotonin 5-HT(2) receptors, the drug is without effect, except at very high concentrations, on serotonin-induced contraction in an isolated canine femoral artery preparation. The potency of OPC-28326 on the increase in femoral artery blood flow was about 14 times higher than that of prazosin but was at about the same level as that obtained with yohimbine in canine autoperfused femoral artery preparations. In perfused rat hindlimb preparations, OPC-28326 inhibited the decrease in perfusion flow induced by brimonidine, a selective alpha(2)-adrenoceptor agonist. The potency of OPC-28326 was at least 10 times less than that of yohimbine. Taken together, the results show that at low doses, OPC-28326 selectively exerts a potent vasodilating effect on the femoral arterial bed, in part due to an alpha(2)-adrenoceptor-blocking activity. (+info)
Adrenergic and purinergic components in bisected vas deferens from spontaneously hypertensive rats.
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1. Purinergic and adrenergic components of the contractile response to electrical field stimulation (EFS) have been investigated in epididymal and prostatic portions of Wystar Kyoto (WKY) and spontaneously hypertensive rat (SHR) vas deferens. 2. In both halves of SHR and WKY vas deferens, EFS (40 V, 0.5 ms for 30 s, 0.5-32 Hz) evoked frequency-related contractions. The neurogenic responses were biphasic, consisting of a rapid non-adrenergic response, dominant in the prostatic portion, followed by a slow tonic adrenergic component, dominant in the epididymal half. 3. Phasic and tonic components of the frequency-response curves evoked by EFS were significantly higher in the epididymal but not in the prostatic portion of vas deferens from SHR compared to WKY rats. 4. The alpha1-adrenoceptor antagonist prazosin (0.1 microM) was more effective against both components of the contractile response in the epididymal end of SHR than in WKY rats. 5. Inhibition by alpha, beta-methylene adenosine 5'-triphosphate (alpha,beta-meATP 3 and 30 microM) was higher in both components of the contractile responses in WKY preparations than in SHR. 6. Combined alpha1-adrenoceptor and P2x-purinoceptor antagonism virtually abolished the EFS-evoked contractile response in both strains. The degree of inhibition by prazosin (0.1 microM) after P2x-purinoceptor blockade was higher in SHR than in WKY rats. 7. These results demonstrate a modification in the purinergic and noradrenergic contribution to neurogenic responses in SHR and WKY animals besides a co-participation of ATP and noradrenaline in both contractile components of the response to EFS. (+info)
S18327 (1-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperid-1-yl]ethyl]3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1)- and alpha(2)-adrenergic receptors: I. Receptorial, neurochemical, and electrophysiological profile.
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S18327 displayed modest affinity for human (h)D(2) and hD(3) receptors and high affinity for hD(4) receptors. At each, S18327 antagonized stimulation of [(35)S]guanosine-5'-O-(3-thio)triphosphate binding by dopamine (DA). It also blocked activation of mitogen-activated protein kinase at hD(3) receptors. The affinity of S18327 at hD(1) and hD(5) sites was modest. S18327 showed pronounced affinity for human serotonin (h5-HT)(2A) receptors and human alpha(1A)-adrenergic receptors (hARs), at which it antagonized increases in intracellular Ca(2+) concentration levels elicited by 5-HT and norepinephrine (NE), respectively. S18327 presented significant affinity for halpha(2A)-ARs and antagonized NE-induced[(35)S]guanosine-5'-O-(3-thio)triphosphate binding both at these sites and at alpha(2)-ARs in rat amygdala. Reflecting blockade of alpha(2)-autoreceptors, S18327 enhanced firing of adrenergic neurons in locus ceruleus, accelerated hippocampal synthesis of NE, and increased dialysate levels of NE in hippocampus, accumbens, and frontal cortex. S18327 abolished inhibition of ventrotegmental area-localized dopaminergic neurons by apomorphine. However, S18327 alone did not affect their activity and only modestly enhanced cerebral turnover of DA and dialysate levels of DA in striatum and accumbens. In contrast, S18327 markedly increased dialysate levels of DA in frontal cortex, an action abolished by the selective alpha(2)-AR agonist, S18616. Finally, S18327 reduced synthesis and dialysate levels of 5-HT in striatum and suppressed firing of dorsal raphe-localized serotonergic neurons, an action attenuated by the alpha(1)-AR agonist cirazoline. In conclusion, S18327 possesses marked antagonist activity at alpha(1)-ARs and D(4) and 5-HT(2A) receptors and less potent antagonist activity at alpha(2)-ARs and D(1) and D(2) receptors. Antagonism by S18327 of alpha(2)-ARs enhances adrenergic transmission and reinforces frontocortical dopaminergic transmission, whereas blockade of alpha(1)-ARs inhibits dorsal raphe-derived serotonergic pathways. As further described in the accompanying paper, this profile of activity may contribute to the potential antipsychotic properties of S18327. (+info)