The action of dexmedetomidine on rat locus coeruleus neurones was examined using intracellular recordings from the in vitro brain slice preparation. Concentrations of dexmedetomidine from 1 to 1000 nM were tested. At 30 nM, dexmedetomidine produced complete inhibition of firing of all neurones tested (n = 21); this was associated with a 13 mV hyperpolarization (range 2.2-29.7 mV, n = 21) and a 27% reduction in input resistance (range 11.1-46.2%, n = 17). The dexmedetomidine responses reached a plateau phase between 100 and 1000 nM. Based on single-cell recordings, the hyperpolarizing potency of dexmedetomidine was found to be 6 times greater than that of clonidine (n = 10). The reversal potential for the dexmedetomidine-induced hyperpolarization was -106.9 +/- 1.7 mV (n = 9), a value similar to the K+ equilibrium potential; hyperpolarization was blocked by both CsCl and BaCl2. The effect of dexmedetomidine was antagonized by yohimbine, with a dissociation equilibrium constant of 30 nM. In contrast, prazosin, the alpha 1-, alpha 2B- and alpha 2C-adrenoceptor subtype-preferring ligand, did not inhibit the dexmedetomidine effect. Our results also show that low concentrations of oxymetazoline (10-300 nM), an alpha 2A-adrenoceptor subtype-selective drug, cause profound inhibition of neuronal activity in the locus coeruleus. These data therefore suggest that dexmedetomidine binds to alpha 2A-adrenoceptors on the cell membrane of neurones of the locus coeruleus and that this leads to opening of the inwardly rectifying K+ channels, resulting in the observed hyperpolarization of the membrane.
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Adrenergic stimulation of the heart leads to activation of the phospholipase D signal transduction pathway with formation of the intracellular second messengers phosphatidic acid and diacylglycerol, which may play a role in the development of myocardial hypertrophy by activating mitogen-activated protein kinases and protein kinase C. So far, the adrenergic receptor subtypes mediating activation of cardiac phospholipase D are not known.
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The numbers of fully adherent (20/40 versus 21/45), partially nonadherent (13/40 versus 20/45), or completely nonadherent patients (7/40 versus 4/45) to antihypertensive treatment were not different in the renal denervation and the control groups, respectively (P=0.3605). The difference in the change in daytime ambulatory systolic blood pressure from baseline to 6 months between the 2 groups was -6.7 mm Hg (P=0.0461) in fully adherent and -7.8 mm Hg (P=0.0996) in nonadherent (partially nonadherent plus completely nonadherent) patients. The between-patient variability of daytime ambulatory systolic blood pressure was greater for nonadherent than for fully adherent patients.
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Using a number of agonist and antagonist compounds, we attempted to characterize the responses and receptors involved in the effects of 5-hydroxytryptamine (5-HT) in the in situ autoperfused rat kidney. An intra-arterial (i.a.) bolus injection of 5-HT (0.0125 to 0.1 microg/kg) increased renal perfusion pressure in a dose-dependent way but did not change the systemic blood pressure. The 5-HT2 receptor agonist, (1-(3-chlorophenyl) piperazine), m-CPP, caused a local vasoconstrictor effect in the autoperfused rat kidney. An intra-arterial injection of 5-carboxamidotryptamine, 5-CT and 1-(m-chlorophenyl)-biguanide (m-CPBG) did not modify the renal perfusion pressure. The vasoconstrictor effect elicited by 5-HT and m-CPP was significantly decreased by ritanserin, enalapril and losartan but was not modified by prazosin, propranolol or indomethacin pretreatment. Our data suggest that the vasoconstrictor serotonergic response induced in the in situ autoperfused rat kidney is mediated through angiotensin II activation by a local 5-HT2 receptor mechanism.
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The concept of a tonic drive activating respiratory muscle in wakefulness but not sleep has been an important and enduring notion in respiratory medicine, not least because it is useful in modeling sleep effects on breathing and understanding the pathogenesis of sleep-related breathing disorders such as obstructive sleep apnea. However, a neurotransmitter substrate mediating respiratory muscle activation across sleep-wake states has not been identified.
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Ten healthy subjects were investigated in a randomized, single-blind, three-way cross-over design and received a single dose of 0.4 mg tamsulosin, 5 mg terazosin or placebo on 3 study days at least 1 week apart. Before and 1, 3, 5, 7, 10 and 23.5 h after drug intake, alterations of diastolic blood pressure and other haemodynamic parameters in response to a graded infusion of the alpha1-adrenoceptor agonist phenylephrine were determined non-invasively.
Controlled clinical studies have demonstrated that blockade of alpha 1-adrenergic receptors relaxes prostatic muscle tone and decreases the symptoms of benign prostatic hyperplasia (BPH). Doxazosin, a once-daily quinazoline derivative and postsynaptic alpha 1-adrenoceptor antagonist, proven as treatment for hypertension, was evaluated in the treatment of BPH in dosages of 1-16 mg. 456 BPH patients (287 doxazosin-treated and 169 placebo-treated) were evaluated for efficacy and safety in five double-blind, placebo-controlled clinical studies. Doxazosin treatment resulted in improvements in both urodynamic and symptomatic parameters associated with BPH. Efficacy was only assessed in 1, 2 and 4 mg. Adverse experiences were reported in 127 (44.3%) of the patients treated with doxazosin and in 49 (29%) of the patients treated with placebo. Fifteen (5.2%) doxazosin patients and 4 (2.4%) placebo patients withdrew from the studies due to adverse effects. Results from these five clinical trials demonstrate doxazosin is effective and safe and well tolerated in both normotensive and hypertensive patients with BPH.
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Using constant infusion technique and a water-loading procedure, we investigated renal hemodynamic and excretional variables in 15 essential hypertensive patients [diastolic blood pressure (DBP) 102 +/- 10 mm Hg] after 3 weeks of placebo and after 16 weeks of treatment with a postjunctional alpha 1-adrenoceptor-antagonist, doxazosin (1-16 mg) once daily. A minor decrease in supine DBP (p less than 0.05) but no significant changes in systolic BP (SBP) and heart rate (HR) were observed. No significant changes were noted in glomerular filtration rate (GFR), renal plasma flow (RPF), and renal vascular resistance (RVR). The mean renal excretion rate of sodium, potassium, uric acid, and albumin for the entire group was unaffected by the treatment, but the individual changes in sodium clearance correlated significantly with changes in mean BP (r = 0.64, n = 15, p less than 0.05). Six patients showed an increase in sodium excretion after treatment, whereas nine showed a decrease. No decrease in mean body weight was noted, but the BP reduction after 5 months of treatment correlated significantly with the changes in body weight (r = 0.62, n = 15, p less than 0.01). The results indicate that long-term treatment with doxazosin had no deleterious effect on renal function, but the effects on BP were rather modest. The individual BP response is probably determined by the degree of fluid retention even if an intact pressure-natriuresis relationship could still be demonstrated during chronic therapy.
Patients' perceptions of the usefulness of information.
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After chronic treatment with imipramine (20 mg/kg, i.p., twice daily for 14 days) the pressor dose-response curves to phenylephrine, methoxamine and cirazoline (alpha 1-adrenoceptor agonists) significantly shifted to the left with decreased PD50 values in pithed rats; however, the dose-response curve to Sgd 101/75, a selective alpha 1-adrenoceptor agonist was not affected. On the other hand, the alpha 2-adrenoceptor agonists such as B-HT 920, xylazine and clonidine produced a rightward shift for both the pressor (increased PD50) and cardioinhibition (increased ID50) dose-response curves in these rats. These results required treatment with imipramine over 2 weeks. Chronic treatment with imipramine has reduced the antagonism by prazosin of the pressor effect of phenylephrine when compared with the dose-ratios between the 2 groups. On the contrary, the antagonism by piperoxan of the cardioinhibitory effect of B-HT 920 was rather enhanced by the treatment, but that of the pressor effect of B-HT 920 was little changed. In cerebrocortical membrane fractions obtained from rats pretreated with imipramine, Ki of phenylephrine to displace [3H]prazosin was decreased, whereas that of clonidine and yohimbine to displace [3H]yohimbine was increased. In conclusion, it is demonstrated that after chronic imipramine treatment the peripheral alpha 2-adrenoceptors (both presynaptic and postsynaptic sites) as well as central alpha 2-adrenoceptors respond with a decreased sensitivity to the alpha 2-adrenoceptor agonists, and moreover, this treatment produces an increased sensitivity of the central and peripheral alpha 1-adrenoceptors to the alpha 1-adrenoceptor full agonists.
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Methamphetamine (METH) is a psychostimulant that damages nigrostriatal dopaminergic terminals, primarily by enhancing dopamine and glutamate release. α₁-adrenergic receptor (AR) subtype involved in METH-induced neurotoxicity in rats was investigated using selective α₁-AR antagonists. METH neurotoxicity was evaluated by (1) measuring body temperature; (2) determining tyrosine hydroxylase (TH) immunoreactivity levels; (3) examining levels of dopamine and its metabolites; and (4) assessing glial fibrillary acidic protein (GFAP) and microglial immunoreactivity in the striatum. METH caused a decrease in dopamine and TH levels and induced hyperthermia which is an exacerbating factor of METH neurotoxicity. Concurrently, METH increased GFAP expression and the number of activated microglia. Pretreatment with prazosin, a nonselective α₁-AR antagonist, completely abolished METH-induced decrease in both dopamine and TH and caused a partial reduction in hyperthermia. Prazosin also prevented METH-induced increase in both GFAP expression and the number of activated microglia. In vivo microdialysis analysis revealed that prazosin, however, does not alter the METH-induced dopamine release in the striatum. The neuroprotective effects of prazosin could be mimicked by a selective α(1D) antagonist, BMY 7378, but not by selective α(1A) or α(1B) antagonists. These results suggest that the α(1D)-AR is involved in METH-induced hyperthermia and neurotoxicity in rats.
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Major variations in the consumption of cardiovascular drugs between healthcare areas, together with discreet variations in price mean there are big differences in pharmaceutical expenditure from one population to another.
Ventricular myocytes isolated from the hypertrophied hearts of thyrotoxic adult rats have an increase in mean protein content per myocyte (6.3 +/- 0.2 vs. 4.4 +/- 0.2 ng) compared with euthyroid cells. Viability and adenine nucleotide profiles are similar in both populations, but NAD content of the hyperthyroid myocytes is depressed (4.9 +/- 0.2 vs. 5.5 +/- 0.2 nmol/mg for controls) and UTP is higher (1.2 +/- 0.09 vs. 0.9 +/- 0.04 nmol/mg). Binding of (-)-[125I]iodocyanopindolol to intact hyperthyroid myocytes is increased by 42% compared with controls, with no change in the dissociation constant (Kd). This elevation in beta-receptor number is correlated to enhanced beta-agonist-induced adenosine 3',5'-cyclic monophosphate (cAMP) production. The half-maximal effective concentration (EC50) for the euthyroid isoproterenol dose-response curve is 2.14 x 10(-7) M but is decreased to 2.51 x 10(-8) M in hyperthyroid cardiac cells. Basal adenylate cyclase activity is apparently not affected by thyroid hormones, since basal cAMP levels for both groups are identical (5 pmol/mg) and both rise roughly twofold in the presence of a phosphodiesterase inhibitor. Forskolin-induced cAMP production and cAMP-specific phosphodiesterase activity are similar as well. In contrast to beta-adrenergic response, there are no significant differences in alpha 1-antagonist [3H]prazosin binding parameters between hyperthyroid and euthyroid cardiomyocytes.
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Human prostatic stromal cells were isolated from prostatectomy and cystoprostatectomy specimens. The cells were cultured in a selective medium supplemented with growth factors and steroid hormones. The culture flasks were coated with a viscous agent to allow cell contraction. Contractions were visualized by means of a cell-culture microscope fitted with a time-lapse video system. For quantitative analysis, the percentage of contracting cells was evaluated.
The effects of excitatory amino acid agonists on [3H]inositol phosphates (InsPs) levels have been examined in rabbit retinal tissues under basal conditions and after agonist stimulation. Quisqualate (QA) is the most effective excitatory amino acid agonist at stimulating InsPs accumulation with an EC50 value of 0.1 microM. The responses for maximally effective concentrations of QA with either ibotenate or kainate were not additive, which suggested that all the excitatory amino acid agonists which stimulate InsPs accumulation (quisqualate, kainate, NMDA, glutamate, ibotenate, aspartate) have a common site of action. None of the following antagonists: DL-2-amino-5-phosphonovalerate (APV), DL-2-amino-4-phosphonobutyrate (APB) and glutamate dimethyl ester (GDEE), prazosin, ketanserin or atropine influenced the excitatory amino agonist stimulation of InsPs. These data suggest the presence of a specific QA-receptor subtype in the retina. QA, and to a lesser extent other excitatory amino acid agonists, were also effective in stimulating InsPs accumulation and the mobilization of internal calcium levels in 3-5-day-old retinal cultures but not in the older cultures (25-30 days old), which lack neurones but contain Müller cells. The QA receptor subtypes linked to InsPs accumulation in the retina are therefore present on neurones. Kainate and NMDA had a weak inhibitory action on the effect of the carbachol-induced stimulation of InsPs at 50 microM. The NMDA action was abolished by APV, whereas this antagonist had no effect on the action of kainate.(ABSTRACT TRUNCATED AT 250 WORDS)
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Both treatment methods seemes to be effective in detrusor-sphincter discoordination. Selective alpha1-blockers alone are more effective than training and rehabilitation exercises.
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To examine the effect of adrenergic blockade on daily rhythms of rectal body temperature (T(b)), urine production rate, and melatonin (MEL; measured as urinary 6-sulfatoxymelatonin; 6-SMT), social voles Microtus socialis received a single intra-peritoneal injection of either prazosin (PRAZ, 1 mg/kg) or propranolol (PROP, 4.5 mg/kg); alpha- and beta-adrenergic blocking agents respectively, 1 h prior to scotophase onset (light/dark, 12L:12D; lights on 07:00 h). Both blockers caused significant decrease in T(b) values mainly during scotophase. Nocturnal urine production rates were higher for M. socialis treated with the drugs compared with controls. Overall, urine production rates were systematically higher in PROP-voles over the 24 h period when compared with PRAZ-voles; however these differences were not statistically significant. Interestingly, PROP caused significant elevation in urinary 6-SMT at the second half of the dark phase, whereas PRAZ had no effects. These data suggest that the mechanisms regulating MEL synthesis and thermoregulatory responses in M. socialis are different from those described in other rodents' species. Importantly, the data also suggest that the beta-blockade-induced elevation in MEL levels may be directly associated with increased urination in M. socialis.
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We attempted to determine which monoamine receptor subtypes are predominantly involved in antidepressant-induced antinociception. Antinociceptive effects were evaluated by using formalin tests with rats. Antidepressants acting as potent inhibitors of norepinephrine reuptake (nisoxetine, nortriptyline, and maprotiline) or inhibiting reuptake of both norepinephrine and serotonin (5-HT) (imipramine and milnacipran) induced dose-dependent antinociception. Simultaneous intraperitoneal administration of antidepressants and either prazosin (alpha(1) antagonist) or ketanserin (5-HT(2) antagonist) significantly antagonized antinociceptive effects. Fluvoxamine (selective serotonin reuptake inhibitor) induced antinociception less potently than other antidepressants and was significantly antagonized by ketanserin, but not prazosin. Ondansetron (5-HT(3) antagonist) significantly antagonized antinociception by 10 mg/kg of imipramine. In contrast, SDZ-205,557 (5-HT(4) antagonist) markedly enhanced antinociception by small-dose (2.5 mg/kg) imipramine. Imipramine-induced antinociception was significantly antagonized by intracerebroventricular administration of prazosin or ketanserin, but not by yohimbine (alpha(2) antagonist) or ondansetron, and was significantly enhanced by intracerebroventricularly administered SDZ-205,557. These findings suggest that alpha(1) adrenoceptors and 5-HT(2) receptors in the brain are involved in antidepressant-induced antinociception. In addition, the results suggested functional interactions between noradrenergic and serotonergic neurons as mechanisms for antidepressant-induced antinociception.
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We have recently reported that the responsiveness of adrenoceptors is decreased with aging in rat ventricular myocardium. Thus, the current study determined aging-dependent changes in: (a) characteristics of myocardial G proteins as determined by Western blot analysis; (b) steady-state levels of G protein mRNA as determined by Northern blot analysis; and (c) the intropic response to isoproterenol, a beta-adrenoceptor agonist. Cardiac preparations were isolated from male Wistar rats of 6 (adult) and 24 (old) months old. Compared with adults, aging decreased the combined level of the three Gs alpha subunits (45, 47 and 52 kDa) by a total of 23% in ventricular membrane preparations. In contrast, levels of Gi alpha (40/41 kDa), Gq alpha (42 kDa), Go alpha (39 kDa) and G common beta (35/36 kDa) immunoreactivity were not affected by aging in the same membrane preparations. In ventricular myocardium, steady-state levels of Gs alpha mRNA (1.9 kb) decreased by 20-28% between 6 and 24 months of age with no change in Gi alpha mRNA (2.4 kb). An aging-associated decline in beta-adrenergic stimulation was observed in the maximum positive inotropic effect elicited by isoproterenol in the presence of prazosin in left papillary muscles, with no change in ED50 values. These results suggest that age-related changes in cardiac excitation and contraction coupling following beta-adrenoceptor stimulation are mediated, at least in part, by Gs alpha protein dysfunction.
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By the introduction of the vasodilators into the therapy of the cardiac insufficiency particularly by the application of angiotensin-converting-enzyme (ACE) inhibitors advance could be obtained with regard the peripheral resistance which is always made evident as a sequel of the vasoconstriction in severe cardiac insufficiency the application of vasodilating substances (venous or arterial) leads to a relief of the heart with increase of the cardiac output, decrease of the congestion symptoms and partly amelioration of the exercise tolerance. Whereas all vasodilating substances show these effects in the acute experiment, in the long-term application due to the tolerance development no significant haemodynamic and clinical amelioration is to be made evident any more, with the exception of the ACE-inhibitors. Only the combination of nitrates and hydralazine showed favourable results with regard to the survival time. The therapy with ACE-inhibitors is, when they is used in an expert way and aimed, the hitherto most conducive one to success which has only slight side-effects. Because of the present knowledge all patients with a cardiac insufficiency of the degrees of severity III and IV, perhaps already beginning with degree of severity II, should, in addition to glycosides and diuretics, be treatment with ACE-inhibitors, so far as no contraindication or intolerability are present. Otherwise an experiment with nitrates plus hydralazine is justified.
The contributions of subtypes of alpha-adrenoceptor to contraction induced by agonists were studied in smooth muscles of isolated rat pulmonary arteries. The results showed that the antagonizing effects of prazosin on the contraction induced by norepinephrine (NE) or phenylephrine (Phe) were more potent than those of yohimbine. The effect of prazosin against Phe was more potent than against NE, and yohimbine was just the reverse. Preincubation of preparations with chlorethylclonidine (CEC) 50 mumol.L-1, after which only alpha 1A adrenoceptors were left, reduced the vascular contraction induced by NE to 36% of the control (P < 0.01). While in the presence of nifedipine 10 mumol.L-1, during which only the responses of alpha 1B adrenoceptors were left, the contraction was weakened to 70% (P < 0.05). The pKA values of alpha 1A subtype (3.37 +/- 0.34) were smaller than those of alpha 1B (6.64 +/- 0.40, P < 0.01). But the values of KA/EC50 were much higher in alpha 1A than those in alpha 1B. The results suggest that in smooth muscle of rat pulmonary artery both alpha 1 and alpha 2 adrenoceptors exist, but alpha 1 is superior functionally. Both subtypes of alpha 1 adrenoceptor are involved in the contraction induced by NE. Compared with alpha 1B subtype, alpha 1A subtype has a lower affinity but a more reserve and a higher efficacy for NE.
Central catecholamine depletion blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Caffeine provoked a hyperthermic response when the catecholamine releaser d-amphetamine (1 mg x kg(-1)) was combined with the 5-HT releaser D-fenfluramine (5 mg x kg(-1)) or the non-selective dopamine receptor agonist apomorphine (1 mg x kg(-1)) was combined with the 5-HT(2) receptor agonist DOI (2 mg x kg(-1)) but not following either agents alone. Pretreatment with the dopamine D(1) receptor antagonist Schering (SCH) 23390 (1 mg x kg(-1)), the 5-HT(2) receptor antagonist ketanserin (5 mg x kg(-1)) or alpha(1)-adreno- receptor antagonist prazosin (0.2 mg x kg(-1)) blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Co-administration of a combination of MDMA with the PDE-4 inhibitor rolipram (0.025 mg x kg(-1)) and the adenosine A(1/2) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-C]quinazolin-5-amine 15943 (10 mg x kg(-1)) or the A(2A) receptor antagonist SCH 58261 (2 mg x kg(-1)) but not the A(1) receptor antagonist DPCPX (10 mg x kg(-1)) exacerbated MDMA-induced hyperthermia.
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1. In pithed rats, the blood pressure effects of ATP, alpha,beta-methylene ATP (mATP), alpha-adrenoreceptor agonists and of electrical stimulation of the thoracolumbar sympathetic outflow were studied in the absence and presence of mATP, suramin and adrenoreceptor antagonists. 2. ATP elicited an initial rise in mean blood pressure followed by a decrease and a second increase. mATP produced a short-lived increase in blood pressure, whereas equieffective doses of noradrenaline, methoxamine and B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(5,4-d)-azepine) produced a more prolonged, biphasic pressor response. 3. In the presence of high doses of prazosin, rauwolscine plus propranolol, the initial vasopressor and the vasodepressor effect to ATP were not affected, whereas the delayed vasopressor response to ATP, the vasopressor response to electrical stimulation and even more so that to noradrenaline were suppressed. 4. Suramin, which by itself produced a short-lived decrease, followed by a persistent increase in blood pressure, decreased the pressor responses to ATP (initial phase), to mATP and to electrical stimulation without affecting the fall and second rise in blood pressure elicited by ATP and the pressor response to noradrenaline. 5. Desensitization of P2x receptors by a low dose of mATP abolished the initial vasopressor response to ATP but failed to affect the subsequent blood pressure effects of ATP as well as the pressor responses to noradrenaline and electrical stimulation. A high dose of mATP, in addition, decreased the vasopressor responses to noradrenaline, methoxamine, B-HT 920 and electrical stimulation; the delayed effects of ATP on blood pressure were not changed. 6. The electrically induced increase in blood pressure subsequent to administration of high doses of prazosin, rauwolscine plus propranolol was diminished by suramin and by the low and high dose of mATP. 7. The present study suggests that under certain circumstances ATP, which, added exogenously, has a triphasic effect on mean blood pressure, contributes to the electrically induced vasopressor response by activation of P2x receptors.
Previous studies suggest that noradrenaline may regulate serotonergic (5-HT) neurotransmission at the serotonin cell body and noradrenaline nerve terminal. Using microdialysis coupled to HPLC, we investigated the effects of alpha1-adrenoceptor manipulation on extracellular serotonin levels - in the ventral hippocampus, prefrontal cortex, and raphe nuclei - in the presence or absence of the serotonin reuptake inhibitor (SSRI), citalopram. Extracellular 5-HT levels from prefrontal cortex, ventral hippocampus and raphe nuclei were markedly increased following citalopram administration (3.0 mg/kg s.c.). In the prefrontal cortex and ventral hippocampus, local blockade of the alpha1-adrenoceptor (3.0 microM prazosin infusion) significantly decreased this citalopram-induced increase in serotonin, while cirazoline (alpha1-adrenoceptor agonist) and reboxetine (noradrenaline reuptake inhibitor) further increased extracellular serotonin levels when administered systemically (0.02 mg/kg i.p. and 5.0 mg/kg s.c. respectively) or locally infused (10.0 microM and 1.0 microM respectively). Moreover, prazosin pre-infusion into terminal areas prevented the increase in citalopram-induced increase in serotonin levels with systemic cirazoline or reboxetine administration. Prazosin also decreased the citalopram-induced increase in serotonin levels in the raphe nuclei; however no enhancement of the SSRI response was observed with systemic or local administration of cirazoline or reboxetine, suggesting that alpha1-adrenoceptors may already be maximally activated under these conditions. These data provide strong evidence that after acute citalopram administration, the alpha1-adrenoceptor exerts a modulatory role on serotonin levels.
The purpose of the present investigation was to examine the role of alpha adrenoceptors in the internal anal sphincter (IAS). Studies wer performed on alpha-chloralose anesthetized opossums. Resting pressure in the IAS (IASP) was recorded using low compliant continuously perfused catheters. The effects of the alpha-1 adrenoceptor agonist phenylephrine and alpha-2 adrenoceptor agonist clonidine and their corresponding selective antagonists, prazosin and yohimbine, respectively, were examined on the resting IASP, and on rectal balloon distension (RBD)-mediated IAS relaxation. Phenylephrine caused a rise in the IASP that was blocked by prazosin and not by yohimbine. Phenylephrine had no effect on IAS relaxation caused by RBD. Clonidine on the other hand caused significant suppression of IAS relaxation in response to RBD, but caused minimal changes in the resting IASP. The suppression of IAS relaxation by clonidine was selectively antagonized by yohimbine but not by prazosin. From these studies we conclude that alpha-2 adrenoceptors exert important neuromodulatory influences on rectoanal inhibitory reflex, while alpha-1 adrenoceptors may exert modulatory effects on the resting IAS tone.
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Some of antihypertensives, opiate antagonist and antifungal agent can interfere with sexual function in both men and women. Drug-related effects on sexual function may be difficult to distinguish from the direct action of gonadal function. Clinically well known those agents to have sexual dysfunction were selected and examined the direct effect on rat's testicular steroidogenesis in vitro. Donryu rats were decapitated at 11 weeks old and isolated testes were decapsulated and preincubated with Krebs-Ringer-phosphate buffer (KRP) added with 1 micrograms/flask of LH for 60 min at 37 degrees C. Then, incubation was made with prazosin (1 micrograms), clonidine (5 micrograms), verapamil (10 micrograms), naloxone (5 micrograms) and ketoconazole (150 micrograms), 37 degrees C for 180 min in fresh KRP-buffer, respectively. Steroids were analysed with RIA, and microfluorometry after purification with quantitative thin layer chromatography. Prazosin had a tendency to produce dihydrotestosterone (DHT) indicating a facilitation of 5 alpha-reductase, and clonidine showed a significant production of estradiol (E2) with a slight production of DHT indicating a significant facilitation of aromatase. Verapamil had a action to produce significantly E2 with a slight production of DHT, and naloxone showed a significant production of both DHT and E2. Thus, these two agents showed facilitation of both 5 alpha-reductase and aromatase. Ketoconazole had a significant production of both delta 4-androstenedione (delta 4-A) and E2 while it had a significant inhibition of DHT-production, thus this had a significant production of both aromatase and C17,20-lyase while had a significant inhibitory action of 5 alpha-reductase. These findings indicates that comparatively large doses of central-nervous system depressants are one of the factors that interfere with sexual function, but it is not necessary to have direct action to testicular function, however present study revealed that some of them can cause gonadal damage and consequently progressive loss of libido.
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Oxidative stress can induce cell mutations or proliferation which then can progress to carcinogenesis or remodeling. The same oxidative stress-mediated mechanism could participate in prostate cell proliferation and remodeling present in benign prostatic hyperplasia (BPH). Doxazosin induces prostate epithelial and stromal cell apoptosis through production of transforming growth factor-beta (TGF-beta), but cellular mechanisms are not completely clarified. In 10 prostate samples from BPH untreated patients who underwent TUR, we have assessed the gene and protein expression of: p22(phox) (subunit of NAD(P)H oxidase essential for O(2)(-) production); heme oxygenase-1 (HO-1) (induced by oxidative stress and antiapoptotic); TGF-beta (inhibitor of prostatic epithelial and stromal cell growth); the in vitro effect of doxazosin on expression of these markers.
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This was a randomized, double-blind, double-simulation control study. We equally assigned 60 men diagnosed with BPH of the kidney deficiency and blood stagnation type to an experimental and a control group, the former treated with mesylate doxazosin plus Longbishu Capsule and the latter with mesylate doxazosin plus placebo. We compared the International Prostate Symptom Score (IPSS), quality of life (QOL), Chinese symptom score (CSS), maximal urinary flow rate (Qmax), and prostate volume between the two groups of patients before and after 6 months of medication.