Isoprenaline is known to produce vascular relaxation through activation of beta-adrenoceptors. In recent years, beta-adrenoceptor-activated vascular relaxation has been the focus of pharmacological study in terms of both the receptor subtypes and the intracellular signaling mechanisms which trigger smooth muscle mechanical functions. In addition, the possible contribution of the endothelium to beta-adrenoceptor-activated relaxation of vascular beds has provoked considerable discussion, with consensus still to be established. In the present study, we examined the effects of isoprenaline on isolated mouse aortic smooth muscles to determine whether the presence of the endothelium plays a substantial role in the relaxation it produces. A possible role for nitric oxide (NO) as a primary endothelium-derived factor released in response to isoprenaline was also elucidated pharmaco-mechanically. In isolated thoracic and abdominal aortae pre-contracted with phenylephrine (3 x 10(-7)-10(-6) M), isoprenaline elicited relaxation in a concentration-dependent fashion (10(-9)-10(-5) M). In endothelium-denuded preparations, isoprenaline-elicited relaxation was reduced to 40-50% of the response obtained in endothelium-intact preparations. In the preparations treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 3 x 10(-4) M; an NO synthase inhibitor) or 1H-[1,2,4]-oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ, 10(-5) M; a soluble guanylyl cyclase inhibitor), isoprenaline-elicited relaxation was attenuated almost to the same degree as the response in endothelium-denuded preparations. The degree of endothelium-dependency in isoprenaline-elicited relaxation was largely diminished when treated with propranolol (3 x 10(-6) M). The present findings indicate that isoprenaline substantially relaxes the mouse aorta with both endothelium-dependent and -independent mechanisms. The endothelium-dependent component seems to correspond to about 50% of the isoprenaline-elicited relaxation, and is almost entirely due to endothelium-derived NO. Activation of propranolol (3 x 10(-6) M)-inhibitable beta-adrenoceptors seems to be primarily responsible for the NO-mediated endothelium-dependent pathway in isoprenaline-elicited relaxant response of mouse aorta.
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Rotating the rats caused a significant decrease in gastric emptying as compared to the non-rotated group. Pretreatment with scopolamine (5 mg/kg, ip) did not reverse the delay in gastric emptying, while it per se caused inhibition of gastric emptying in the non-rotated group. Similarly other drugs mepyramine, cisapride, and granisetron did not have any effect on delay in gastric emptying caused by rotation. However beta blocker propranolol could partially but significantly reverse the decrease in gastric emptying.
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Rebound growth occurred in 25% of patients, requiring modification of systemic therapy in 15%. Predictive factors for rebound growth included age of discontinuation, deep IH component, and female gender. Patients with these predictive factors may require a prolonged course of therapy.
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A variety of approaches have been used to alleviate symptoms in postural tachycardia syndrome (POTS). Drugs reported to be of benefit include midodrine, propranolol, clonidine, and phenobarbital. Other measures used include volume expansion and physical countermaneuvers. These treatments may influence pathophysiologic mechanisms of POTS such as alpha-receptor dysfunction, beta-receptor supersensitivity, venous pooling, and brainstem center dysfunction. The authors prospectively studied hemodynamic indices and symptom scores in patients with POTS who were acutely treated with a variety of interventions. Twenty-one subjects who met the criteria for POTS were studied (20 women, 1 man; mean age, 28.7 +/- 6.8 y; age range, 14-39 y). Patients were studied with a 5-minute head-up tilt protocol, ECG monitoring, and noninvasive beat-to-beat blood pressure monitoring, all before and after the administration of an intervention (intravenous saline, midodrine, propranolol, clonidine, or phenobarbital). The hemodynamic indices studied were heart rate (ECG) and systolic, mean, and diastolic blood pressure. Patients used a balanced verbal scale to record any change in their symptoms between the tilts. Symptom scores improved significantly after the patients received midodrine and saline. Midodrine and propranolol reduced the resting heart rate response to tilt (p <0.005) and the immediate and 5-minute heart rate responses to tilt (p <0.002). Clonidine accentuated the immediate decrease in blood pressure on tilt up (p <0.05). It was concluded that midodrine and intravenous saline are effective in decreasing symptoms on tilt in patients with POTS when given acutely. Effects of treatments on heart rate and blood pressure responses generally reflected the known pharmacologic mechanisms of the agents.
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The manuscript was sent to 262 reviewers; 203 (78%) reviews were returned. One-hundred ninety-nine reviewers recommended a disposition for the manuscript: 15 recommended acceptance, 117 rejection, and 67 revision. The 15 who recommended acceptance identified 17.3% (95% confidence interval [CI] 11.3% to 23.4%) of the major and 11.8% (CI 7.3% to 16.3%) of the minor errors. The 117 who recommended rejection identified 39.1 % (CI 36.3% to 41.9%) of the major and 25.2% (CI 23.0% to 27.4%) of the minor errors. The 67 who recommended revision identified 29.6% (CI 26.1% to 33.1%) of the major and 22.0% (CI 19.3% to 24.8%) of the minor errors. The number of errors identified differed significantly across recommended disposition. Sixty-eight percent of the reviewers did not realize that the conclusions of the work were not supported by the results.
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Ginger is a world known food plant which is equally reputed for its medicinal properties. We report here the hypotensive, endothelium-dependent and independent vasodilator and cardio-suppressant and stimulant effects of its aqueous extract (Zo.Cr). Zo.Cr, which tested positive for saponins, flavonoids, amines, alkaloids and terpenoids, induced a dose-dependent (3.0-10.0 mg/kg) fall in the arterial blood pressure (BP) of anaesthetized rats which was partially blocked by atropine (1 mg/kg). In isolated endothelium-intact rat aorta, Zo.Cr (0.01-5.0 mg/ml) relaxed the phenylephrine (1 microM)-induced contractions, effect partially blocked by atropine (1 microM). Zo.Cr inhibited the K+ (80 mM)-induced contractions and also shifted the Ca++ dose-response curves to the right, similar to verapamil, indicating Ca++ antagonist activity. An atropine-resistant and l-NAME-sensitive vasodilator activity was also noted from ginger phenolic constituents 6-, 8- and 10-gingerol, while 6-shogaol showed a mild vasodilator effect. In guinea-pig atria, Zo.Cr (0.1-5.0 mg/ml) inhibited the force and rate of atrial contractions. Pretreatment with atropine blocked the inhibitory effect and a stimulatory effect was unmasked which was resistant to propranolol and verapamil but sensitive to ryanodine, blocker of Ca++ release from intracellular stores. Later at doses >or=1.0 mg/ml, the extract completely suppressed the atrial tissue, effect resistant to glibenclamide, pyrilamine, aminophylline and L-NAME. These data indicate that the aqueous ginger extract lowers BP through a dual inhibitory effect mediated via stimulation of muscarinic receptors and blockade of Ca++ channels and this study provides sound mechanistic basis for the use of ginger in hypertension and palpitations.
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Based on these results it was concluded that secretion of stimulated mixed saliva, glucose, as well as sodium, potassium and calcium ions is significantly reduced in autonomic neuropathy. These findings may be associated with lesions to parasympathetic nerve fibers caused by long-lasting diabetes.
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Both facilitatory and inhibitory effects of the sympathetic nervous system (SNS) on experimental arthritis have been reported. It is unknown whether such bidirectional effects are inherent to all experimental arthritis models and/or whether critical time windows exist for influences of the SNS on inflammation.
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Infantile hemangioma (IH) clearance may be slow or incomplete in response to pulsed dye laser (PDL) or propranolol alone.
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Expression of heat shock proteins (hsp) is a homeostatic mechanism induced in both prokaryotic and eukaryotic cells in response to metabolic and environmental insults. A growing body of evidence suggests that in mammals, the hsp response is integrated with physiological responses through neuroendocrine signaling. In the present study, we have examined the effect of noradrenaline (NA) on the hsp70 response in mollusc immune cells. Oyster and abalone hemocytes transfected with a gene construct containing a gastropod hsp70 gene promoter linked to the luciferase reporter-gene were exposed to physiological concentrations of NA, or to various alpha- and beta-adrenoceptor agonists and antagonists. Results show that NA and alpha-adrenergic stimulations induced the expression of luciferase in transfected mollusc immunocytes. Furthermore, exposure of hemocytes to NA or to the alpha-adrenoceptor agonist phenylephrine (PE) resulted in the expression of the inducible isoform of the hsp70 protein. Pertussis toxin (PTX), the phospholipase C (PLC) inhibitor U73122, the protein kinase C (PKC) inhibitor calphostin C, the Ca(2+)-dependent PKC inhibitor Gö 6976 and the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002 blocked the PE-mediated induction of the hsp70 gene promoter. These results suggest that alpha-adrenergic signaling induces the transcriptionnal upregulation of hsp70 in mollusc hemocytes through a PTX-sensitive G-protein, PLC, Ca(2+)-dependent PKC and PI 3-kinase. Thus, a functional link exists between neuroendocrine signaling and the hsp70 response in mollusc immune cells.
Perfusion studies were performed 6 weeks after BDL when hepatic cirrhosis was induced. Three series of experiments were performed in BDL rats: (i) the Nepi (10(-10) mol/L-10(-5) mol/L) vasoconstrictory responses with (n = 6) and without (n = 5) alpha1- (phentolamine, 5 x 10(-6) mol/L) or beta- (propranolol, 10(-5) mol/L) receptor antagonist (n = 6 and 5, respectively); (ii) the Ach (10(-8) mol/L-10(-5) mol/L) vasodilatory responses in Nepi- preconstricted portal-systemic collaterals in the absence (n = 7) or presence (n = 8) of N(pi)- L-nitro-arginine (NNA, 10(-4) mol/L); and (iii) the effect of indomethacin (10(-5) mol/L; n = 6) on Nepi responses. The collateral vascular responses were evaluated by the in situ collateral perfusion.
To determine the effect of low-dose propranolol on maximal exercise capacity in patients with postural tachycardia syndrome (POTS).
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Graves' disease maybe an extrahepatic manifestation of acute HBV infection. Antiviral therapy is likely to be beneficial for this condition as without severe thyrotoxicosis.
To evaluate the first-pass hydrolysis of O-isovaleryl-propranolol (isovaleryl-PL), which was used as a model ester-compound, rat intestinal jejunum and blood vessels were perfused simultaneously. The membrane permeability of isovaleryl-PL was greater than that of PL because it was more lipophilic. Isovaleryl-PL was almost completely hydrolyzed to PL and isovaleric acid (IVA) in epithelial cells at a rate limited by its uptake. Based on pH partitioning, PL and IVA were transported into both vascular (pH 7.4) and luminal sides (pH 6.5). Therefore, when isovaleryl-PL was perfused into the jejunal lumen, more than 90% permeated into the blood vessel as PL. In addition, PL appeared in the lumen at a rate 6-fold greater than that in blood vessels. When isovaleryl-PL was perfused, its disappearance (50.5+/-1.95 nmol/min) was the sum of the absorption and secretion rates of PL. In contrast, IVA was transported into blood vessels rather than the jejunal lumen. In addition, the calculated degradation clearance from in vitro hydrolysis (Km 13.7+/-1.71 microM, Vmax 29.1+/-3.81 nmol/min/mg protein) was 3.42 ml/min/10 cm jejunum, which was 24-fold greater than the observed degradation clearance (CLdeg) (0.14+/-0.02 ml/min/10 cm jejunum). These findings indicate that in addition to the liver, the intestine markedly contributes to first-pass hydrolysis.
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Subjects with known LQT1 (n = 5) and LQT2 (n = 6) mutations but baseline QTc < or = 450 ms and age- and gender-matched controls (n = 22) received intravenous erythromycin (an I(Kr) blocker). RR, QRS, QT, and Tpe intervals were measured at baseline and after drug infusion.
Propranolol-treated mice demonstrated a 50% reduction in laser-induced CNV. Treatment with norepinephrine bitartrate stimulated Vegf messenger RNA expression and protein secretion in ChECs and RPE cells. This effect was blocked by β2-adrenoreceptor antagonism and mimicked by β2-adrenoreceptor agonists.
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The suppressive effect of (R)-albuterol on neural ICAM-1 expression may be an additional mechanism for decreasing bronchoconstriction, since it would decrease eosinophil recruitment to the airway nerves.
Mouse alveolar macrophages were stimulated in vitro with NTHi in the presence or absence of the beta2 receptor agonists salmeterol or salbutamol. In addition, mice received salmeterol or salbutamol by inhalation and were intranasally infected with NTHi. End points were pulmonary inflammation and bacterial loads.
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Infantile haemangiomas enter a rapid proliferative phase within months of birth, before slowly involuting. Those with the potential for disfigurement or morbidity require intervention. Propranolol has emerged as an effective new treatment modality, with the potential to become the first-line treatment of choice.
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Between March, 1993, and March, 1996, 126 patients with variceal bleeding were randomly assigned either transjugular shunt (n = 61) or endoscopic treatment (n = 65). Patients were followed up for a median of 14 (IQR 8-25) months and 13 (8-25) months, respectively. In 31 (51%) of the shunted patients, simultaneous transjugular-variceal embolisation was done at the time of shunt placement. Endoscopic treatment consisted of sclerotherapy and/or banding ligation and was combined with propranolol medication.
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5-hydroxytryptamine (5-HT) is a potent vasoconstrictor of equine digital arteries and veins which may play a role in the ischaemic disease, laminitis. The present investigation compared the properties of 5-HT1B/1D receptors in arteries with those in veins using isolated rings of equine digital blood vessels. The 5-HT1B/1D receptor-selective agonists, anpirtoline and sumatriptan were 17.9 and 10 times more potent and produced 4.1 and 5.6 times greater maximum contractions, respectively, in veins when compared to arteries. Other agonists tested were of equal potency and produced the same maximum responses in veins and arteries. Propranolol competitively inhibited 5-HT1B/1D receptor mediated responses in arteries, with a pKB of 6.7, but had no significant effects on responses in veins at 1 microM. Metergoline competitively inhibited 5-HT1B/1D receptor mediated responses in veins, with a pKB of 8.1, but had no significant effect in arteries at 0.1 microM. These data suggest that 5-HT1B/1D receptors mediating vasoconstriction in equine digital arteries are pharmacologically different to those found in digital veins.
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(1) Significant positive chronotropic response of sinus node to the stimulation by NO donor was observed in both patients: with and without electrophysiological signs of SSS. (2) The positive chronotropic response of sinus node to NTG bolus was observed despite of type of SSS.
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Treatment with prazosin + propranolol, or a combination of other centrally active α1 - and β-adrenergic receptor antagonists, may assist in preventing alcohol relapse in some individuals.
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Endogenous nitric oxide production was determined by measuring total plasma nitrite/nitrate (Griess method), and levels of soluble tumor necrosis factor receptors type 1 and type 2 (TNF-R1 and TNF-R2, respectively) were measured by commercially available enzyme-linked immunosorbent assay.
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Double-layered matrix tablets prepared from shellac wax-lutrol were fabricated using a molding technique, and the release of hydrochlorothiazide and propranolol HCl from the inner tablet or outer layer was studied. The simultaneous determination of dual drug release was measured with first derivative UV spectrophotometry. The tablet containing shellac wax as the outer tablet and lutrol as the inner tablet showed more appropriate drug release and the size of the inner layer influenced the rate of drug release. In addition, the aqueous solubility of the drug and the components of the inner tablet or outer layer affected the drug release behavior. Most of the double-layered tablets exhibited the drug-release pattern which fitted well with zero-order kinetic due to the restriction of the release surface. Biphasic drug release pattern was found in the tablet of which the outer layer rapidly eroded. The drug dissolution data from drug-loaded-outer layer could predict the dissolution time for the outer layer of drug-loaded inner part of double-layered matrix tablet. Incorporation of lutrol increased the drug release from shellac wax matrix, and the zero-order release was attained by fabricating it into a double-layered tablet.
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We investigated the response of refractory periods and blood flow to blockade of alpha 1- and beta-adrenoceptors alone, or in combination on endocardium and epicardium, during myocardial ischemia. Dogs were anesthetized with alpha-chloralose and divided into bunazosin (an alpha 1-blocking agent)-treated (0.1-0.2 mg/kg, i.v., n = 14), propranolol-treated (0.2 mg/kg, i.v., n = 12), and vehicle-control (n = 10) groups. The diagonal branches of the left anterior descending artery were ligated. The refractory period (ERP) and blood flow (RMBF) were determined by an S1-S2 extrastimulus method and a nonradioactive microsphere technique, respectively. The duration of regional electrograms (DRE) was measured in the endocardial and epicardial sites. Bunazosin alone reversed the ischemia-related shortening of ERPs at both the endocardial and epicardial sites, with a greater effect seen epicardially (P < .05). Subsequent administration of propranolol further prolonged ERPs in both sites, although the effect was greater in the epicardial surface (P < .05). Bunazosin reduced RMBF to a greater degree at the endocardial site than at the epicardial site in the ischemic zone (P < .01 and P < .05, respectively), but the magnitude of the reduction in RMBF and the difference in RMBF between sites were similar to the control group (P < .01). Propranolol alone and subsequent administration of bunazosin prolonged the ERP more at the epicardial site (P < .01) than at the endocardial sites in the ischemic zone. Propranolol produced no significant difference in RMBF between both sites. DREs in animals treated with bunazosin and propranolol alone, or in combination, were similar to those in animals treated with vehicle. These results suggest that differences in ERPs between endocardium and epicardium with blockade of alpha 1- and/or beta-adrenoceptor are not due to concomitant alterations in RMBF, but to differences in electrophysiological properties of the endocardial and epicardial cells during the acute phase of myocardial ischemia.
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We related the dissolution profiles with phase behavior and viscosity of the different liquid crystalline phases. Diolein has been added aiming to stabilize the cubic phases and thus preventing formation of less viscous (lamellar) phases.