Inotropic and sympathetic responses to the intracoronary infusion of a beta2-receptor agonist: a human in vivo study.
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BACKGROUND: On the basis of the presence of beta2-receptors within the sympathetic nervous system, beta2-stimulation may increase cardiac sympathetic outflow. We addressed the hypothesis that sympathoexcitatory beta2-receptors are present in the human left ventricle. METHODS AND RESULTS: The beta2-agonist salbutamol was infused into the left coronary artery in 3 groups of patients: group 1 (n=9, no beta-blocker therapy), group 2 (n=7, beta1-selective blockade with atenolol), and group 3 (n=6, nonselective beta-blockade with nadolol). Left ventricular +dP/dt in response to increasing concentrations of salbutamol was measured in all groups, and cardiac norepinephrine spillover was measured in group 1. There were no systemic hemodynamic changes in any group. Salbutamol resulted in a 44+/-6% increase in +dP/dt in group 1, a 25+/-6% increase in group 2 (P<0.05 versus group 1), and no increase in group 3. Salbutamol also resulted in a 124+/-37% increase in cardiac norepinephrine spillover in group 1 (P<0.05). CONCLUSIONS: Evidence that salbutamol increased norepinephrine release from cardiac sympathetic nerves was provided by the observations that atenolol suppressed the salbutamol inotropic response, demonstrating that this response was mediated in part by beta1-receptors and that salbutamol also resulted in an increase in cardiac norepinephrine spillover. This result provides in vivo evidence, in humans, for the role of sympathoexcitatory cardiac beta2-receptors. (+info)
Modulation of effect of dietary salt on prehepatic first-pass metabolism: effects of beta-blockade and intravenous salt loading.
(2/96)
We previously demonstrated that increased dietary salt markedly decreases plasma quinidine concentrations shortly after p.o. dosing, without an effect on the drug's terminal elimination half-life or concentrations after i.v. administration. These findings suggest an effect of dietary salt on intestinal metabolism or transport of the drug. Because one effect of salt loading is sympathetic inhibition, we examined the effect of beta-adrenoceptor blockade on salt-related changes in quinidine disposition. Furthermore, we examined whether the action of salt is local or systemic by determining the effect of salt loading by the i.v. route. To assess the effect of beta-blockade, quinidine disposition was studied in eight normal volunteers after a single p.o. dose of quinidine; data were obtained after 1 week on a high-salt diet (400 mEq/day) and 1 week on a low-salt diet (10 mEq/day) during chronic nadolol and compared with those previously obtained in the same subjects without the beta-blocker. beta-Blockade had no effect on oral clearance during the high-salt diet [0.28 +/- 0.1 (quinidine + nadolol) versus 0.30 +/- 0.2 liters/h/kg (quinidine alone)] but increased clearance on the low-salt diet from 0.23 +/- 0.1 to 0.29 +/- 0.1 liters/h/kg (p <. 05). For the i.v. salt study, the disposition of single p.o. and single i.v. doses of quinidine was determined on two occasions in eight subjects: once during a low-salt diet (10 mEq/day) and once during the same diet, supplemented by 400 mEq/day NaCl i.v. for 8 days. In contrast to our findings after p.o. salt loading, i.v. salt loading did not alter the pharmacokinetics of p.o. quinidine. Taken together, these data implicate a local alteration of drug-metabolizing activity and/or drug transport in the intestinal mucosa as the major effect of dietary salt on the disposition of p.o. quinidine and further suggest that beta-adrenergic activation by a low-salt diet is one component of a signaling pathway whereby intestinal drug disposition is suppressed, resulting in increased oral bioavailability. (+info)
Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta.
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1. The relaxant effects of isoprenaline may result from activation of another beta-adrenoceptor subtype in addition to beta1 and beta2. This study evaluated the role of a third beta-adrenoceptor subtype, beta3, in beta-adrenoceptor-induced relaxation of rat thoracic aorta by isoprenaline. 2. Isoprenaline produced a concentration-dependent relaxation of phenylephrine pre-contracted rings of the thoracic aorta (pD2=7.46+/-0.15; Emax=85.9+/-3.4%), which was partially attenuated by endothelium removal (Emax=66.5+/-6.3%) and administration of the nitric oxide (NO) synthase inhibitor, L-NG-monomethyl arginine (L-NMMA) (Emax=61.3+/-7.9%). 3. In the presence of nadolol, a beta1- and beta2-adrenoceptor antagonist, isoprenaline-induced relaxation persisted (Emax=55.6+/-5.3%), but occurred at higher concentrations (pD2=6.71+/-0.10) than in the absence of nadolol and lasted longer. 4. Similar relaxant effects were obtained with two beta3-adrenoceptor agonists: SR 58611 (a preferential beta3-adrenoceptor agonist), and CGP 12177 (a partial beta3-adrenoceptor with beta1- and beta2-adrenoceptor antagonistic properties). SR 58611 caused concentration-dependent relaxation (pD2=5.24+/-0.07; Emax=59.5+/-3.7%), which was not modified by pre-treatment with nadolol but antagonized by SR 59230A, a beta3-adrenoceptor antagonist. The relaxation induced by SR 58611 was associated with a 1.7 fold increase in tissue cyclic GMP content. 5 Both relaxation and the cyclic GMP increase induced by SR 58611 were greatly reduced by endothelium removal and in the presence of L-NMMA. 6 We conclude that in the rat thoracic aorta, beta3-adrenoceptors are mainly located on endothelial cells, and act in conjuction with beta1- and beta2-adrenoceptors to mediate relaxation through activation of an NO synthase pathway and subsequent increase in cyclic GMP levels. (+info)
Long-term follow-up of patients with long-QT syndrome treated with beta-blockers and continuous pacing.
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BACKGROUND: The long-QT syndrome is associated with sudden cardiac death. Combination of beta-blocker and pacing therapy has been proposed for treatment of drug-resistant patients. The purpose of this study was to summarize our long-term experience with combined therapy in patients with long-QT syndrome. METHODS AND RESULTS: A total of 37 patients with idiopathic long-QT syndrome were treated with combined therapy consisting of continuous cardiac pacing and maximally tolerated beta-blocker therapy and followed up for 6.3+/-4. 6 years (mean+/-SD). The group consisted of 32 female and 5 male patients with a mean age of 31.6 years. The mean paced rate was 82+/-7 bpm (range, 60 to 100 bpm). On follow-up, recurrent symptoms caused by pacemaker malfunction were documented in 3 patients. Four patients died during the follow-up period: 2 adolescents stopped beta-blocker therapy, 1 patient died suddenly while treated with combined therapy, and 1 patient died of unrelated causes. In addition, 3 patients had resuscitated cardiac arrest while on combined therapy, and 1 patient had repeated, appropriate implantable cardioverter-defibrillator discharges on follow-up. CONCLUSIONS: Because 28 of 37 patients remain without symptoms with beta-blocker therapy and continuous pacing, combined therapy appears to provide reasonable, long-term control for this high-risk group. However, the incidence of sudden death and aborted sudden death (24% in all patients and 17% in compliant patients) strongly suggests the use of a "back-up" defibrillator, particularly in noncompliant adolescent patients. Implantable cardioverter-defibrillator therapy, however, may be associated with recurrent shocks in susceptible patients. (+info)
Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome.
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BACKGROUND: beta-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of beta-blockers in this disorder have not been evaluated. METHODS AND RESULTS: The study population comprised 869 LQTS patients treated with beta-blockers. Effectiveness of beta-blockers was analyzed during matched periods before and after starting beta-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed beta-blockers. After initiation of beta-blockers, there was a significant (P<0.001) reduction in the rate of cardiac events in probands (0.97+/-1.42 to 0.31+/-0.86 events per year) and in affected family members (0. 26+/-0.84 to 0.15+/-0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before beta-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during beta-blocker therapy compared with asymptomatic patients; 32% of these symptomatic patients will have another cardiac event within 5 years while on prescribed beta-blockers. Patients with a history of aborted cardiac arrest before starting beta-blockers (n=113) had a hazard ratio of 12.9 (95% CI, 4.7 to 35.5) for aborted cardiac arrest or death while on prescribed beta-blockers compared with asymptomatic patients; 14% of these patients will have another arrest (aborted or fatal) within 5 years on beta-blockers. CONCLUSIONS: beta-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed beta-blockers, particularly in those who were symptomatic before starting this therapy. (+info)
The cardiovascular responses of the red-eared slider (Trachemys scripta) acclimated to either 22 or 5 degrees C. II. Effects of anoxia on adrenergic and cholinergic control.
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Cardiovascular control in cold-acclimated freshwater turtles during chronic anoxic exposure is not well understood. We tested the hypothesis that the observed bradycardia in Trachemys scripta results from increased cholinergic inhibitory tone and reduced sympathetic activity. Cardiovascular status was measured in vivo in turtles acclimated to either 22 degrees C or 5 degrees C and either acutely exposed (6 h) to anoxia at 22 degrees C or chronically exposed (22 days) to anoxia at 5 degrees C. In 22 degrees C-acclimated turtles, injection of the cholinergic antagonist atropine induced a significant tachycardia under both normoxic and anoxic conditions. However, in 5 degrees C-acclimated turtles, atropine injection had little effect on heart rate. Therefore, cholinergic control of heart rate was suppressed during cold acclimation; instead, temperature effects are more important in bringing about bradycardia, while the intrinsic effects of anoxia and acidosis are probably important during chronic anoxia. Injection of adrenaline caused a pressor response through increased systemic resistance at both acclimation temperatures. This response was blunted by acute and chronic anoxic exposure, suggesting that systemic vasomotor control was altered independently of acclimation temperature. This anoxic blunting may be related in part to the anoxia-induced increase in systemic resistance. Injection of nadolol after atropine decreased systemic cardiac output. The tonic beta-adrenergic cardiac stimulation was attenuated by acute and chronic anoxic exposure. Some of this attenuation of beta-adrenergic control could be attributed to the 39-40 % reduction in cell surface beta-adrenoreceptor density in the ventricles of these turtles that accompanied acute and chronic anoxic exposure. In conclusion and contrary to our original hypothesis, cholinergic and adrenergic control of the cardiovascular system in turtles was attenuated under cold anoxic conditions, perhaps assisting in the depressed physiological state of these animals. (+info)
Catecholaminergic polymorphic ventricular tachycardia. An important diagnosis in children with syncope and normal heart.
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Syncope in children is primarily related to vagal hyperreactivity, but ventricular tachycardia (VT) way rarely be seen. Catecholaminergic polymorphic VT is a rare entity that can occur in children without heart disease and with a normal QT interval, which may cause syncope and sudden cardiac death. In this report, we describe the clinical features, treatment, and clinical follow-up of three children with syncope associated with physical effort or emotion and catecholaminergic polymorphic VT. Symptoms were controlled with beta-blockers, but one patient died suddenly in the fourth year of follow-up. Despite the rare occurrence, catecholaminergic polymorphic VT is an important cause of syncope and sudden death in children with no identified heart disease and normal QT interval. (+info)
Comparison of the effects of nadolol and bisoprolol on the isoprenaline-evoked dilatation of the dorsal hand vein in man.
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AIMS: We attempted to explore the possible differential involvement of beta-adrenoceptor subtypes in the dilator response of the human dorsal hand vein to isoprenaline by examining the ability of bisoprolol, a selective beta1-adrenoceptor antagonist, and nadolol, a nonselective beta1/beta2-adrenoceptor antagonist, to antagonize the response. METHODS: Twelve healthy male volunteers participated in four weekly sessions. In the preliminary session a dose-response curve to the vasoconstrictor effect of phenylephrine was constructed and the dose producing 50-75% maximal response was determined for each individual. In each of the remaining three (treatment) sessions, nadolol (40 mg), bisoprolol (5 mg) or placebo was ingested, and isoprenaline hydrochloride (3.33-1000 ng min(-1)) was infused locally into the dorsal hand vein along with a constant dose of phenylephrine hydrochloride (to preconstrict the vein) 2 h after the ingestion of the drugs. Changes in vein diameter were monitored with the dorsal hand vein compliance technique. Subjects were allocated to treatment session according to a double-blind balanced cross-over design. Systolic and diastolic blood pressure, and heart rate were also measured. RESULTS: Isoprenaline produced dose-dependent venodilatation which was antagonized by nadolol but remained unaffected by bisoprolol (ANOVA with repeated measures: P < 0.025; Dunnett's test: placebo vs nadolol, P < 0.01; placebo vs bisoprolol, P = NS). Mean log ED50 (ng min-1) was significantly increased in the presence of nadolol and remained unchanged in the presence of bisoprolol (ANOVA, P < 0.025; Dunnett's test: placebo vs nadolol, P < 0.005; placebo vs bisoprolol, P = NS; differences between mean log ED50 [95% CI]: placebo vs bisoprolol -0.11 [-0.38, 0.16], placebo vs nadolol 0.32[0.09, 0.72], bisoprolol vs nadolol -0.43 [-0.71, -0.15]). Mean Emax did not differ in the three treatment conditions. CONCLUSIONS: The failure of bisoprolol to attenuate isoprenaline-evoked venodilatation in the human dorsal hand vein argues against the involvement of a beta1-adrenoceptor-mediated component in the isoprenaline-evoked venodilatory responses. The possibility cannot be excluded that the consequences of beta1-adrenoceptor blockade by bisoprolol might have been obscured by a possible venodilator effect of bisoprolol. (+info)