Previously, we showed that the blockade of α1-adrenoreceptors in the median raphe nucleus (MnR) increased food intake in free-feeding rats, indicating that adrenergic mechanisms in the MnR participate in the regulation of food intake. However, the impact of such a pharmacological manipulation on other neural circuits related to food intake remains unknown. In the current study, we sought to identify forebrain regions which are responsive to α1-adrenergic receptor blockade and presumably involved in the modulation of the feeding response. For this purpose, we examined the induction of c-Fos immunoreactivity in forebrain structures following injections of the α1-adrenoceptor antagonist prazosin into the MnR of free-feeding rats. To determine the chemical identity of hypothalamic c-Fos-positive cells, we then conducted double-label immunohistochemistry for Fos/orexin (OX) or Fos/melanin-concentrating hormone (MCH). Finally, we combined anterograde tracing from the MnR with immunohistochemical detection of orexin. Prazosin injections into the MnR significantly increased food intake. The ingestive response was accompanied by an increase in Fos expression in the basolateral amygdala (BLA) and lateral hypothalamic area (LHA). In the LHA, Fos expression occurred in neurons expressing OX, but not MCH. Combined anterograde tracing experiments revealed that LHA OX neurons are prominently targeted by MnR axons. These findings suggest that intra-MnR injection of prazosin, via activation of orexinergic neurons in the LHA and non-orexinergic neurons in the BLA, evoked a motivational response toward food intake.
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All patients had perspiration and cold extremities. Most of them had sting over extremities except two,having over the trunk. Shock was present in 48(53.3%), whereas myocarditis, encephalopathy, pulmonary edema and priapism were present in 38(42.2%), 32(35.5%), 34(37.8%), and 28(31.1%) children, respectively. Eight (8.9%) children had died. The mean value of blood pressure, sodium and potassium among survivors and non-survivors was insignificant. Mortality was significantly higher in children presented after 6 h of bite. Patients, who had metaboloic acidosis, tachpnea, myocarditis, APE, encephalopathy and priapism had significantly higher mortality (p < 0.05).
The present study assesses the antinociceptive effect of melatonin in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. Melatonin administered by intraperitoneal (i.p., 10-100 mg/kg), intracerebroventricular (i.c.v., 250-500 pmol/site) and intraplantar (i.pl., 30-100 ng/i.pl.) routes, reduced in a dose-dependent manner the nociception caused by i.pl. injection of glutamate (10 micromol/paw), with mean ID50 values of 32.6 mg/kg, 200 pmol/site and 59 ng/i.pl., respectively. Furthermore, melatonin in the dose range of 10-100 mg/kg, i.p., reduced the neurogenic pain caused by i.pl. injection of capsaicin (5.2 nmol/paw) with inhibition of 48 +/- 4%. The antinociceptive effect of melatonin (100 mg/kg, i.p.) on glutamate-induced nociception was completely prevented by the pretreatment of animals with naloxone (a nonselective opioid receptor antagonist, 1 mg/kg, i.p.), ketanserin (a preferential 5-HT2A receptor antagonist, 1 mg/kg, i.p.), sulpiride (a D2 receptor antagonist, 50 mg/kg, i.p.), L-arginine (a precursor of nitric oxide, 600 mg/kg, i.p.), yohimbine (an alpha2-adrenoceptor antagonist, 0.15 mg/kg, i.p.) and luzindole (a preferential MT2 receptor antagonist, 10 mg/kg, i.p.), but was not affected by the pretreatment with D-arginine (an inactive isomer of L-arginine, 600 mg/kg, i.p.), prazosin (an alpha1-adrenoceptor antagonist, 0.15 mg/kg, i.p.) or after bilateral adrenalectomy. Collectively, present results suggest that melatonin produces peripheral and central antinociception when assessed on capsaicin- or glutamate-induced pain in mice through mechanisms that are likely mediated by interaction with plasma membrane-bound melatonin receptors and modulated by opioid, serotonergic (5-HT2A receptors), dopaminergic (D2-receptors), adrenergic (alpha2-adrenoceptors) systems as well as the L-arginine-nitric oxide pathway.
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Spontaneous isometric contractions and field-evoked responses were recorded in vitro from strips of bovine mesenteric lymph node capsule. Field stimulation (0.3 ms pulses, 60 V nominal, 2 min trains) at frequencies > or = 2 Hz evoked a frequency-dependent increase in baseline tension which was maximum at frequencies > or = 16 Hz. Evoked contractions were significantly reduced (P = 0.02) by the neurotoxin tetrodotoxin (10(-6) M) although they were unaffected by the alpha-adrenoceptor antagonists phentolamine, rauwolscine and prazosin (3 x 10(-6) M). Similarly, responses were unaffected by the beta-adrenoceptor antagonist propranolol (10(-6) M), the cholinergic antagonist atropine (10(-6) M) or the uptake blocker cocaine (10(-6) M). Field-evoked contraction was also unaffected by a 30 min exposure to alpha,beta-methylene ATP (10(-6) M). The results suggest that bovine lymph node capsular smooth muscle is innervated by excitatory nerves which are non-adrenergic, non-cholinergic and non-purinergic in nature.
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An LC-MS method for the determination of metoclopramide in human plasma was developed and validated. Sample preparation involved extraction with ethyl acetate. Chromatographic separation was performed on a Thermo Hypersil-Hypurity C18 (150 mm x 2.1 mm, 5 microm) with the mobile phase consisting of 40 mM ammonium acetate-methanol-acetonitrile. A single-quadrupole mass spectrometer with an electrospray interface was operated in the selected-ion monitoring mode to detect the [M+H]+ ions at m/z 300 for metoclopramide and at m/z 384 for the internal standard (prazosin). The method was validated over 0.78-50.00 ng mL(-1) for metoclopramide. The recovery was 67.8-83.1%, and the limit of quantitation (LOQ) detection was 0.78 ng mL(-1) for metoclopramide. The intra- and inter-day precision of the method at three concentrations was 5.0-13.6% with accuracy of 99.2-104.0%. Stability of compounds was established in a battery of stability studies. The method was successfully applied to bioequivalence studies of metoclopramide hydrochloride tablets to obtain the pharmacokinetic parameters.
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Intravenously injected lipopolysaccharides (LPS) rapidly induce pulmonary platelet accumulation (PPA) and anaphylaxis-like shock (ALS) in mice. Macrophages reportedly release catecholamines rapidly upon stimulation with LPS. Here, we examined the involvement of macrophage-derived catecholamines in LPS-induced PPA and ALS. A catecholamine or Klebsiella O3 (KO3) LPS was intravenously injected into mice, with 5-hydroxytryptamine in the lung being measured as a platelet marker. The tested catecholamines induced PPA, leading to shock. Their minimum shock-inducing doses were at the nmol/kg level. The effects of epinephrine and norepinephrine were inhibited by prazosin (α1 antagonist) and by yohimbine (α2 antagonist), while dopamine's were inhibited only by prazosin. Use of synthetic adrenergic α1- and/or α2-agonists, platelet- or macrophage-depleted mice, a complement C5 inhibitor and C5-deficient mice revealed that (a) α2-receptor-mediated PPA and shock depend on both macrophages and complements, while α1-receptor-mediated PPA and shock depend on neither macrophages nor complements, (b) the PPA and ALS induced by KO3-LPS depend on α1- and α2-receptors, macrophages, and complements, and (c) KO3-LPS-induced PPA is preceded by catecholamines decreasing in serum. Together, these results suggest the following. (i) Catecholamines may stimulate macrophages and release complement C5 via α2-receptors. (ii) Macrophage-derived catecholamines may mediate LPS-induced PPA and ALS. (iii) Moderate PPA may serve as a defense mechanism to remove excess catecholamines from the circulation by promoting their rapid uptake, thus preventing excessive systemic effects. (iv) The present findings might provide an insight into possible future pharmacological strategies against such diseases as shock and acute respiratory distress syndrome.
The dorsal motor nucleus of the vagus (DMV) receives more noradrenergic terminals than any other medullary nucleus; few studies, however, have examined the effects of norepinephrine (NE) on DMV neurons. Using whole cell recordings in thin slices, we determined the effects of NE on identified gastric-projecting DMV neurons. Twenty-five percent of DMV neurons were unresponsive to NE, whereas the remaining 75% responded to NE with either an excitation (49%), an inhibition (26%), or an inhibition followed by an excitation (4%). Antrum/pylorus- and corpus-projecting neurons responded to NE with a similar percentage of excitatory (49 and 59%, respectively) and inhibitory (20% for both groups) responses. A lower percentage of excitatory (37%) and a higher percentage of inhibitory (36%) responses were, however, observed in fundus-projecting neurons. In all groups, pretreatment with prazosin or phenylephrine antagonized or mimicked the NE-induced excitation, respectively. Pretreatment with yohimbine or UK-14304 antagonized or mimicked the NE-induced inhibition, respectively. These data suggest that NE depolarization is mediated by alpha(1)-adrenoceptors, whereas NE hyperpolarization is mediated by alpha(2)-adrenoceptors. In 16 neurons depolarized by NE, amplitude of the action potential afterhyperpolarization (AHP) and its kinetics of decay (tau) were significantly reduced vs. control. No differences were found on the amplitude and tau of AHP in neurons hyperpolarized by NE. Using immunohistochemical techniques, we found that the distribution of tyrosine hydroxylase fibers within the DMV was significantly different within the mediolateral extent of DMV; however, distribution of cells responding to NE did not show a specific pattern of localization.
The antagonistic effect (pA2) of prazosin for norepinephrine was 7.76+/-0.13 in young dogs and 7.62+/-0.06 in aged dogs. The specific binding of [3H]-tamsulosin (a relatively selective alpha1A-adrenoceptor antagonist) was recognized diffusely in proximal urethras with in vitro autoradiography. The density of binding in smooth muscles was approximately 60 and 40% in circular longitudinal layers, respectively, for both dogs.
Posterior reversible encephalopathy syndrome (PRES) is a condition characterized by varying degrees of headache, nausea, vomiting, visual disturbances, focal neurologic deficit, and seizures due to severe systemic hypertension. The knowledge of secondary hypertension in children is most commonly due to renal abnormalities, suggesting that the leading cause of PRES in childhood is renal diseases.
Strips of canine saphenous vein, inferior vena cava, and femoral artery were studied isometrically in vitro to compare quantitatively the alpha 1- and postsynaptic alpha 2-adrenoceptor contributions to the contractile force generated by l-norepinephrine (NE). Effects mediated by each receptor type were measured independently by quantitative blockade of virtually all alpha 1-receptors with prazosin, or alpha 2-receptors with rauwolscine. Appropriate concentrations of the antagonists were calculated from dissociation constants previously determined by binding or competition with [3H]prazosin or [3H]rauwolscine in tissue homogenates. The contribution of alpha 1-adrenoceptors was larger than that of alpha 2-receptors in all vessels. The alpha 2-type was responsible for 38% of the maximum unblocked response to NE in saphenous vein, 32% in vena cava, and 28% in femoral artery. The occupation-response relationship for alpha 1-receptors was almost linear, without the marked upward convexity reported in some other vessels. alpha 2-Occupation-response curves were convex towards the occupation axis, with a relatively small response at low levels of occupation.
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The proportion of patients who reported treatment-emergent dizziness was not significantly different between the 2 treatment groups (tadalafil 7.0%; placebo 5.7%; P = .403). No difference between treatment groups was observed with respect to patients meeting the criteria for a positive orthostatic test (30 per treatment group, P = 1.00). The incidence of discontinuations was low among both treatment groups.
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This study evaluated the effect of prazosin in controlled mild hypertension and evaluated select metabolic changes that occurred with prazosin monotherapy. Various aspects of glucose, insulin, and lipid metabolism were studied before and after approximately 10 weeks of prazosin treatment in 12 patients with mild hypertension. Prazosin was well tolerated and induced a significant decrease (p less than 0.001) in both systolic and diastolic blood pressures, without any change in body weight. Plasma concentrations of glucose, free fatty acid, and lactate, which were measured hourly from 8 A.M. to 4 P.M. following meals consumed at 8 A.M. and noon, did not change with prazosin treatment. However, the plasma insulin response from 8 A.M. to 4 P.M. decreased significantly (p less than 0.001) following prazosin treatment. In addition, fasting plasma triglyceride and cholesterol concentrations were significantly lower (p less than 0.05) in prazosin-treated persons, as were postprandial triglyceride concentrations (p less than 0.001). Lower total plasma triglyceride and cholesterol concentrations were accounted for by decreases in very low-density lipoprotein cholesterol and triglyceride and low-density lipoprotein cholesterol and triglyceride, whereas both high-density lipoprotein triglyceride and high-density lipoprotein cholesterol concentrations increased following prazosin treatment. Finally, although both apolipoprotein A1 and apolipoprotein B concentrations decreased in association with prazosin treatment, the decrease in apolipoprotein B was much greater in magnitude, leading to an increase in the ratio of apolipoprotein A1 to apolipoprotein B. In this study, treatment of mild hypertension with prazosin led to lower blood pressures and changes in insulin and lipoprotein metabolism that are important in this patient population.
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The role of alpha-1 and alpha-2 adrenoceptors in the contractile response of the proximal urethra to agonists and antagonists was studies in female and male New Zealand White rabbits. The response pattern for alpha-1 agonists showed a sharp rise, while that for alpha-2 agonists showed a gradual increase to a maximum pressure. The duration of the response of alpha-2 agonists was significantly longer than that of alpha-1 agonists. A difference in the response between alpha-1 and alpha-2 would be produced mainly through different receptor functions. The magnitude of the response of alpha-1 adrenoceptors in the male rabbits was almost twice that of the female rabbits. In contrast, the response of alpha-2 in the male rabbits was less than that of the female rabbits. Our experimental findings indicate that alpha-2 stimulation mediates a slow and prolonged response that is essential for urinary continence in female rabbits.
1. We examined whether alpha 1-adrenoceptors in various blood vessels can be divided into subtypes by antagonist affinity or by susceptibility to chloroethylclonidine or nifedipine. 2. Noradrenaline or phenylephrine produced concentration-dependent contractions in all the tissues tested, which were competitively inhibited by phentolamine, yohimbine, prazosin, WB4101 and HV723. However, there were large differences between the tissues in the pA2 values for all the antagonists except phentolamine. 3. The blood vessels could be classified into three groups (I, II and III) on the basis of their affinity variation. In group I (dog mesenteric artery and vein, saphenous vein), the pA2 values for HV723 were greater than 9, and those for HV723 and WB4101 were approximately 1 log unit higher than for prazosin. This rank order of affinity reversed in group II (dog carotid artery and rat thoracic aorta), where prazosin was more potent (pA2 values greater than 9.5) than HV723 or WB4101. In group III (rabbit mesenteric artery, thoracic aorta and carotid artery and guinea-pig thoracic aorta), on the other hand, prazosin, HV723 and WB4101 inhibited the noradrenaline response with a similar affinity (pA2 values ranging from 8 to 9). 4. Yohimbine inhibited the responses to noradrenaline and phenylephrine with a lower affinity than prazosin, HV723 or WB4101. The pA2 values for yohimbine were similar in groups I and II (the values greater than 6.5), which were greater than those in group III (values less than 6.4). 5. The alpha l-adrenoceptors in group II were selectively affected by chlorethylclonidine, resulting in an irreversible attenuation of noradrenaline responses in the dog carotid artery and a persistent contraction in the rat thoracic aorta. 6. Nifedipine either produced no effect or a slight inhibition of alpha l-adrenoceptor-mediated contractions in all the blood vessels; these effects were not correlated to the above groups. 7. These results suggest that alpha,-adrenoceptors of blood vessels can be divided into three subtypes (designated as alpha 1H, alpha4L and alpha 1N) by antagonist affinity and their susceptibility to chloroethylclonidine but not to nifedipine: the characteristics of each subtype are summarized in Table 3. Subtypes alpha lH, alpha 1L and alpha lN may be predominantly involved in the contractile responses to noradrenaline or phenylephrine of the blood vessels in groups II, III and I, respectively.
La présente étude visait à examiner et comparer les effets antagonistes de l’atipamezole, la yohimbine et le prazosin sur la diurèse induite par la xylazine chez des chats cliniquement normaux. Cinq chats furent utilisés de manière répétée dans chacun des neuf groupes. Un groupe n’était pas médicamenté. Les chats dans les autres groupes reçurent de la xylazine par voie intramusculaire à un dosage de 2 mg/kg de poids corporel (PC), et de la saline (comme témoin); 160 μg/kg PC de prazosin; ou 40, 160, ou 480 μg/kg PC d’atipamezole ou de yohimbine par voie intraveineuse 0,5 h plus tard. Des échantillons d’urine et de sang furent prélevés 10 fois sur une période de 8 h. On mesura le volume, le pH, et la gravité spécifique de l’urine; la concentration plasmatique d’arginine vasopressine (AVP); les valeurs de créatinine, d’osmolalité, et d’électrolytes dans l’urine et le plasma ont également été mesurées. Autant l’atipamezole que la yohimbine ont antagonisé la diurèse induite par la xylazine, mais pas le prazosin. L’effet antidiurétique de l’atipamezole était plus puissant que celui de la yohimbine mais n’était pas dose-dépendant, contrairement à l’effet de la yohimbine aux doses testées. Autant l’atipamezole que la yohimbine ont renversé les diminutions induites par la xylazine de la gravité spécifique et l’osmolalité de l’urine, et l’augmentation de la clairance de l’eau libre. Le taux de filtration glomérulaire, la clairance osmolaire, et les concentrations d’électrolytes plasmatiques n’étaient pas affectés de manière significative. L’antidiurèse de l’atipamezole ou la yohimbine n’était pas liée à la surface sous la courbe de la concentration d’AVP, bien que les doses les plus élevées d’atipamezole et de yohimbine augmentèrent initialement et de manière temporaire la concentration d’AVP plasmatique, suggérant ainsi que ceci pourrait influencer partiellement les effets antidiurétiques de ces deux agents. L’effet diurétique de la xylazine chez les chats peut être médié par des adrénorécepteurs-α2 mais pas par des adrénorécepteurs-α1. L’atipamezole et la yohimbine peuvent être utilisés comme agents antagonistes contre la diurèse induite par la xylazine chez des chats cliniquement normaux.(Traduit par Docteur Serge Messier).
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Drinking mate or chimarrão, a hot infusion of Ilex paraguariensis (ILEX) leaves, is a common habit in Southern South America that has a social and almost ritualistic role. It has been used as a stimulant beverage in South America and analgesic in regions of Argentina for treatment of headache and others painful inflammatory conditions such as arthritis and rheumatism.
The combination of alpha-blockade and calcium antagonism has not previously been studied and should be useful for resistant hypertensives who have not tolerated beta-blockade or ACE inhibitors. The combination of ACE inhibition and calcium antagonism has previously been shown to be additive; its use as a positive control in the present studies suggests that the use of an active drug for a run-in period may be a useful design for permitting the study of patients from whom all treatment cannot safely be withdrawn.
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1. The interaction between chloroethylclonidine (CEC) and noradrenaline (NA) has been examined at alpha-adrenoceptors mediating contractions of rat aorta. 2. In rat aorta, the competitive antagonist prazosin, over the concentration-range 0.01-10 microM, produced concentration-dependent shifts in the contractile potency of NA, so that there was no component of the NA contraction resistant to prazosin. 3. The irreversible alpha 1-adrenoceptor antagonists, phenoxybenzamine (PBZ) (1-10 microM) and benextramine (10 microM) produced shifts in potency of NA and reduced the maximum response in a concentration-dependent manner. 4. The irreversible alpha 1-adrenoceptor antagonist, CEC (100 microM), produced a non-parallel shift in the NA concentration-response curve so that low concentrations of NA produced relatively small contractions but relatively high concentrations produced further contractions, so that the maximum response was not significantly reduced. 5. The combination of CEC pretreatment and subsequent prazosin (0.1 microM) produced a parallel shift in the potency of NA. However, prazosin (10 microM) failed to produce any further effect on the response to high concentrations of NA following CEC pretreatment. Hence, a component of the contraction to NA in the presence of CEC was resistant to subsequent prazosin. Likewise, this component was resistant to a combination of prazosin (10 microM) and yohimbine (10 microM). 6. Receptor protection experiments were carried out in which tissues were exposed to NA (100 microM), yohimbine (10 microM) or prazosin (0.1 microM) prior to and during exposure to CEC. Receptor protection with NA, yohimbine or prazosin (0.1 microM), followed by washout prevented the shift in potency of NA produced by CEC. 7. Further experiments examined the effects of prazosin (10 microM) on responses to NA following receptor protection with NA (100 microM), yohimbine (10 microM), prazosin (10 microM), or xylazine (100 microM). In receptor protection studies with NA, subsequent prazosin (10 microM) produced a shift in response to NA following CEC which was not signficantly different from the shift produced by prazosin alone in the absence of receptor protection. In receptor protection studies with prazosin, yohimbine or xylazine, subsequent prazosin (10 microM) produced shifts in the response to NA following CEC which were significantly less than the shift produced by prazosin alone in the absence of receptor protection.8. It is concluded that CEC has two actions in the rat aorta. Firstly, it behaves as an irreversible a,-adrenoceptor antagonist, reducing the response to low concentrations of NA (up to 10 microM). However,after exposure to CEC, concentrations of NA of 10 microM and above produced contractions resistant toprazosin. This resistant component was still present following receptor protection with alpha1,- or alpha2-adrenoceptor antagonists, but absent following receptor protection with NA. Hence, the latter response may represent an irreversible agonist interaction between CEC, NA and alpha-adrenoceptors which cannot be affected by subsequent competitive antagonism, but which can be prevented by receptor protection with the agonist NA prior to CEC.
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The peripheral mechanisms responsible for pressor response produced by microinjections of baclofen (GABA(B) agonist) into the nucleus tractus solitarii (NTS) of conscious rats were studied. Bilateral microinjections of baclofen (10-1,000 pmol/100 nl) produced a dose-related increase in mean arterial pressure (MAP) and heart rate. The maximal response was observed after 15 min. Intravenous injection of prazosin decreased MAP to control levels. Subsequent treatment with Manning compound (vasopressin receptor antagonist; iv) produced an additional decrease in MAP. In a different group of rats, vasopressin antagonist was injected first and MAP was significantly decreased; however, it remained elevated compared with prebaclofen injection levels. Subsequent treatment with prazosin abolished the baclofen-induced pressor response. Reductions in baclofen-induced pressor response with prazosin treatment were followed by a reflex tachycardia in animals that received a 100 pmol/100 nl dose of baclofen. The tachycardia was not observed with a dose of 1,000 pmol/100 nl. The pressor response induced by microinjection of baclofen into the NTS of conscious rats may be produced by both increases in sympathetic tonus and vasopressin release.
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The [3H]-verapamil binding activity of rat cardiac sarcolemmal fragments was studied, using membranes harvested from non-perfused, aerobically-perfused and ischaemic hearts. Glass-fibre filters were found to contain specific, high affinity--(KD 38 +/- 3.1 nM) [3H]-verapamil binding sites--making them unsuitable for use in [3H]-verapamil binding studies. Incubation of membranes from non-perfused hearts in a medium containing 150 mM NaCl, 1 mM CaCl2 and 50 mM Tris revealed two populations of [3H]-verapamil binding sites. When centrifugation instead of filtration was used to separate bound and free [3H]-verapamil, high affinity sites with a KD of 0.57 +/- 0.19 microM and a Bmax of 38 +/- 5.2 pmol mg-1 protein, and low affinity sites with a KD of 78 +/- 27.5 microM and a Bmax of 2.9 +/- 1.3 nmol mg-1 protein were detected. However, only low affinity binding sites could be detected in membranes which had been incubated in a cation-free medium containing 50 mM Tris. [3H]-verapamil binding to the low and high affinity sites was saturable, reversible, stereospecific and displaceable by D600 greater than diltiazem greater than Ca2+ but not by nifedipine, nitrendipine, nisoldipine or prazosin. The two populations of binding sites survived aerobic perfusion and 60 min ischaemia at 37 degrees C. Ischaemia reduced the Bmax and KD but selectivity was maintained.
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Hypertension is an underlying risk factor for cardiovascular disease. Despite this, its pathogenesis remains unknown in most cases. Recently, the transient receptor potential (TRP) channel family was associated with the development of several cardiovascular diseases linked to hypertension. The melastatin TRP channels TRPM4 and TRPM5 have distinct properties within the TRP channel family: they form nonselective cation channels activated by intracellular calcium ions. Here we report the identification of TRPM4 proteins in endothelial cells, heart, kidney, and chromaffin cells from the adrenal gland, suggesting that they have a role in the cardiovascular system. Consistent with this hypothesis, Trpm4 gene deletion in mice altered long-term regulation of blood pressure toward hypertensive levels. No changes in locomotor activity, renin-angiotensin system function, electrolyte and fluid balance, vascular contractility, and cardiac contractility under basal conditions were observed. By contrast, inhibition of ganglionic transmission with either hexamethonium or prazosin abolished the difference in blood pressure between Trpm4-/- and wild-type mice. Strikingly, plasma epinephrine concentration as well as urinary excretion of catecholamine metabolites were substantially elevated in Trpm4-/- mice. In freshly isolated chromaffin cells, lack of TRPM4 was shown to cause markedly more acetylcholine-induced exocytotic release events, while neither cytosolic calcium concentration, size, nor density of vesicles were different. We therefore conclude that TRPM4 proteins limit catecholamine release from chromaffin cells and that this contributes to increased sympathetic tone and hypertension.
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Placebo administration did not affect any hemodynamic values. Terlipressin administration, on the other hand, resulted in expected changes on the hepatic venous pressure gradient, hepatic blood flow, and systemic hemodynamics. In contrast, prazosin significantly decreased hepatic venous pressure gradient with an increased hepatic blood flow and intrinsic hepatic clearance. After terlipressin administration, a further decrease in hepatic venous pressure gradient was observed with preservation of hepatic blood flow and intrinsic hepatic clearance. The magnitude of decrease in hepatic venous pressure gradient was more profound in patients receiving prazosin plus terlipressin than in those receiving terlipressin alone. However, the magnitude of changes in systemic hemodynamics was no different between the two groups of patients.
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Medical treatment of distal ureteral stones with doxazosin has similar stone passage rate, expulsion time, and safety in women compared with men.
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In this in vitro study on the human umbilical artery, the effects of N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin, prazosin, yohimbine and propranolol on the responses induced by bupivacaine and ropivacaine were investigated. Arteries isolated from umbilical cords from women who did not exhibit systemic diseases, who were not on medication and who had normal full-term deliveries, were cut into spiral strips 12 x 3 mm. Strips were mounted in organ baths at 37 degrees C continuously gassed with 5% CO(2) in oxygen. The responses to the drugs were recorded isometrically on a polygraph. In the bupivacaine study, when we administered cumulative concentrations of bupivacaine (10(-9) - 10(-4) M; n = 6) on basal tonus, there was no relaxation or contraction response on the tissue. Strips were precontracted with serotonin (10(-6)M 5-HT) then bupivacaine (10(-9) - 10(-4) M) was directly administered cumulatively. In the ropivacaine group, when cumulative concentrations of ropivacaine (10(-9) - 10(-4) M; n = 6) were administered on the tissue, preconstricted with 5-HT, ropivacaine did not alter the contraction response. Ropivacaine (10(-9) - 10(-4) M) was directly administered to the bath. Though bupivacaine produced relaxation, ropivacaine produced contraction (P < 0.05). Indomethacin, prazosin, yohimbine and propranolol did not significantly alter these responses. In addition, it was demonstrated that L-NAME did not affect the relaxation responses induced by bupivacaine. Thus adrenergic receptors, nitric oxide syntenaze and prostaglandins do not appear to affect the responses induced by these two local anesthetics.
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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.
In this study, the mechanism of action of dexfenfluramine (DEXF) at the hepatic level was investigated. The drug is shown to bind to the alpha 1-adrenergic receptor and to increase intracellular calcium in isolated rat hepatocytes, thereby activating phosphorylase via a calcium-dependent mechanism. Moreover, phosphorylase activation by DEXF was inhibited by different agents that interfere with the alpha 1-adrenergic signalling system: prazosin, phorbol 12 alpha-myristate 13 beta-acetate (PMA), and DEXF itself. We also show that phosphorylase activation induced by catecholamines and analogues (epinephrine, phenylephrine), whose actions are mediated by a calcium-dependent mechanism, was counteracted by the drug in the submillimolar range (0.1-1 mM). The activation of glycogenolysis by the drug is accompanied by a stimulation of the glycolytic flux (54% increase in lactate plus pyruvate accumulation), consistent with an increase in fructose-2,6-bisphosphate (F-2,6-BP) levels (36%). These results indicate that the interaction of DEXF with the alpha 1-adrenergic receptor channels glucose 6-phosphate derived from glycogen away from glucose production into the glycolytic pathway.
1. We have characterized alpha 1-adrenoceptor in the conduction systems of the rat heart by quantitative autoradiography. 2. Consecutive 20 micron thick sections from a single rat heart containing the sinoatrial (SA) node and atrioventricular (AV) node were incubated with increasing concentrations of [3H]-prazosin with or without 10 microM phentolamine. After exposure to 3H-Ultrofilm, optical densities corresponding to the SA node and AV node were determined by computerized densitometry after comparison with 3H standards. 3. The SA node and AV node were stained heavily for cholinesterase and they contained a higher concentration of alpha 1-adrenoceptors than the adjacent myocardium without a significant change in the affinity. 4. These results support the hypothesis that alpha 1-adrenoceptors may play an important role not only in inotropism but also in chronotropism of rat hearts.