Reversal of severe pulmonary hypertension with beta blockade in a patient with end stage left ventricular failure.
(9/4656)
A 52 year old man with severe chronic left ventricular failure (New York Heart Association class IV) was considered unsuitable for cardiac transplantation because of high and irreversible pulmonary vascular resistance (PVR). In an attempt to produce symptomatic improvement, metoprolol was cautiously introduced, initially at 6.25 mg twice daily. This was slowly increased to 50 mg twice daily over a two month period and continued thereafter. After four months of treatment the patient's symptoms had improved dramatically. His exercise tolerance had increased and diuretic requirements reduced to frusemide 160 mg/day only. Assessment of right heart pressures was repeated and, other than a drop in resting heart rate, there was little change in his pulmonary artery pressure or PVR. His right heart pressures were reassessed showing a pronounced reduction in pulmonary artery pressure and a significant reduction in PVR, which fell further with inhaled oxygen and sublingual nitrates. He was then accepted onto the active waiting list for cardiac transplantation. A possible mechanism of action was investigated by assessing responses to beta agonists during treatment. Not only was there pronounced improvement in PVR but it was also demonstrated that beta receptor subtype cross-regulation may have contributed to the mechanism of benefit. (+info)
Stroke volume decline during prolonged exercise is influenced by the increase in heart rate.
(10/4656)
This study determined whether the decline in stroke volume (SV) during prolonged exercise is related to an increase in heart rate (HR) and/or an increase in cutaneous blood flow (CBF). Seven active men cycled for 60 min at approximately 57% peak O2 uptake in a neutral environment (i.e., 27 degrees C, <40% relative humidity). They received a placebo control (CON) or a small oral dose (i.e., approximately 7 mg) of the beta1-adrenoceptor blocker atenolol (BB) at the onset of exercise. At 15 min, HR and SV were similar during CON and BB. From 15 to 55 min during CON, a 13% decline in SV was associated with an 11% increase in HR and not with an increase in CBF. CBF increased mainly from 5 to 15 min and remained stable from 20 to 60 min of exercise in both treatments. However, from 15 to 55 min during BB, when the increase in HR was prevented by atenolol, the decline in SV was also prevented, despite a normal CBF response (i.e., similar to CON). Cardiac output was similar in both treatments and stable throughout the exercise bouts. We conclude that during prolonged exercise in a neutral environment the decline in SV is related to the increase in HR and is not affected by CBF. (+info)
Wavelet transform to quantify heart rate variability and to assess its instantaneous changes.
(11/4656)
Heart rate variability is a recognized parameter for assessing autonomous nervous system activity. Fourier transform, the most commonly used method to analyze variability, does not offer an easy assessment of its dynamics because of limitations inherent in its stationary hypothesis. Conversely, wavelet transform allows analysis of nonstationary signals. We compared the respective yields of Fourier and wavelet transforms in analyzing heart rate variability during dynamic changes in autonomous nervous system balance induced by atropine and propranolol. Fourier and wavelet transforms were applied to sequences of heart rate intervals in six subjects receiving increasing doses of atropine and propranolol. At the lowest doses of atropine administered, heart rate variability increased, followed by a progressive decrease with higher doses. With the first dose of propranolol, there was a significant increase in heart rate variability, which progressively disappeared after the last dose. Wavelet transform gave significantly better quantitative analysis of heart rate variability than did Fourier transform during autonomous nervous system adaptations induced by both agents and provided novel temporally localized information. (+info)
beta2-adrenergic receptor-selective agonist clenbuterol prevents Fas-induced liver apoptosis and death in mice.
(12/4656)
Stimulation of the cAMP-signaling pathway modulates apoptosis in several cell types and inhibits Jo2-mediated apoptosis in cultured rat hepatocytes. No information is yet available as to whether the hepatic beta2-adrenergic receptor (AR) expression level, including beta2-AR-dependent adenylyl cyclase activation, modulates hepatocyte sensitivity to apoptosis in vivo or whether this sensitivity can be modified by beta2-AR ligands. We have examined this using C57BL/6 mice, in which hepatic beta2-AR densities are low, and transgenic F28 mice, which overexpress beta2-ARs and have elevated basal liver adenylyl cyclase activity. The F28 mice were resistant to Jo2-induced liver apoptosis and death. The beta-AR antagonist propranolol sensitized the F28 livers to Jo2. In normal mice clenbuterol, a beta2-AR-specific agonist, considerably reduced Jo2-induced liver apoptosis and death; salbutamol, another beta2-AR-selective agonist, also reduced Jo2-induced apoptosis and retarded death but with less efficacy than clenbuterol; and propranolol blocked the protective effect of clenbuterol. This indicates that the expression level of functional beta2-ARs modulates Fas-regulated liver apoptosis and that this apoptosis can be inhibited in vivo by giving beta2-AR agonists. This may well form the basis for a new therapeutic approach to diseases involving abnormal apoptosis. (+info)
Effects of beta2-adrenergic stimulation on single-channel gating of rat cardiac L-type Ca2+ channels.
(13/4656)
Cardiac L-type Ca2+ channels can be stimulated by activation of beta2-adrenoceptors. We intended to determine how the gating behavior at the single-channel level (cell-attached configuration) is affected after selective stimulation of beta2-adrenoceptors. Rat cardiomyocytes were exposed to zinterol, a beta2-agonist (n = 7), isoproterenol (n = 6), a nonselective agonist, 8-bromo-cAMP (n = 6), and a combination of isoproterenol and ICI-118551 (n = 8), a selective beta2-receptor antagonist, or isoproterenol and CGP-20712A, a beta1-selective antagonist (n = 7). In all groups the ensemble-average current and the availability of the channels to open on depolarization were increased in a similar fashion. In addition, the open probability (Po) within active sweeps was elevated. However, zinterol exerted this effect in a unique manner. It elevated Po not by shortening closed times but solely by reducing active sweeps with very low Po and a short burst duration. All zinterol effects were abolished by ICI-118551 (n = 5) and mimicked by isoproterenol plus CGP-20712A (n = 7). We conclude that beta2-adrenoceptor activation of L-type channels differs qualitatively from the classical cAMP-dependent mechanism. (+info)
Endothelin antagonists block alpha1-adrenergic constriction of coronary arterioles.
(14/4656)
We have previously observed that intracoronary administration of the alpha1-adrenergic agonist phenylephrine (PE) over a period of minutes induced both an immediate and long-lasting (2 h) vasoconstriction of epicardial coronary arterioles. Because it is unlikely that alpha1-adrenergic constriction would persist for hours after removal of the agonist, this observation supports the view that another constrictor(s) is released during alpha1-adrenergic activation and induces the prolonged vasoconstriction. Therefore, we hypothesized that the prolonged microvascular constriction after PE is due to the production of endothelin (ET). We focused on ET not only because this peptide produces potent vasoconstriction but also because its vasoconstrictor action is characterized by a long duration. To test this hypothesis, the diameters of coronary arterioles (<222 micrometers) in the beating heart of pentobarbital-anesthetized dogs with stroboscopic intravital microscopy were measured during a 15-min intracoronary infusion of PE (1 microgram. kg-1 . min-1) and at 15-min intervals for a total of 120 min. All experiments were performed in the presence of beta-adrenergic blockade with propranolol. At 120 min, arterioles in the PE group were constricted (-23 +/- 9% change in diameter vs. baseline). Pretreatment with the ET-converting enzyme inhibitor phosphoramidon or the ETA-receptor antagonist FR-139317 prevented the PE-induced constriction at 120 min (-1 +/- 3 and -6 +/- 3%, respectively, P < 0.01 vs. PE). Pretreatment with the selective alpha1-adrenergic antagonist prazosin (Prz) also prevented the sustained constriction (0 +/- 2%, P < 0.01 vs. PE) but Prz given 60 min after PE infusion did not (-13 +/- 3%). In the aggregate, these results show that vasoconstriction of epicardial coronary arterioles via alpha1-adrenergic activation is blocked by an ET antagonist and an inhibitor of its production. From these data, we conclude that alpha1-adrenergic activation promotes the production and/or release of ET, which produces or facilitates microvascular constriction of epicardial canine coronary arterioles. (+info)
Facilitatory beta2-adrenoceptors on cholinergic and adrenergic nerve endings of the guinea pig trachea.
(15/4656)
Using electrical field stimulation of epithelium-denuded intact guinea pig tracheal tube preparations, we studied the presence and role of prejunctional beta2-adrenoceptors by measuring evoked endogenous acetylcholine (ACh) and norepinephrine (NE) release directly. Analysis of ACh and NE was through two HPLC systems with electrochemical detection. Electrical field stimulation (150 mA, 0.8 ms, 16 Hz, 5 min, biphasic pulses) released 29.1 +/- 2.5 pmol ACh/g tissue and 70.2 +/- 6.2 pmol NE/g tissue. Preincubation for 15 min with the selective beta2-adrenoceptor agonist fenoterol (1 microM) increased both ACh and NE overflow to 178 +/- 28 (P < 0.01) and 165 +/- 12% (P < 0.01), respectively, of control values, increases that were abolished completely by the selective beta2-adrenoceptor antagonist ICI-118551 (1 microM). Further experiments with increasing fenoterol concentrations (0.1-100 microM) and different preincubation periods (1, 5, and 15 min) showed a strong and concentration-dependent facilitation of NE release, with maximum response levels decreasing (from nearly 5-fold to only 2.5-fold of control value) with increasing agonist contact time. In contrast, sensitivity of facilitatory beta2-adrenoceptors on cholinergic nerves to fenoterol gradually increased when the incubation period was prolonged; in addition, a bell-shaped concentration-response relationship was found at 15 min of preincubation. Fenoterol concentration-response relationships (15-min agonist preincubation) in the presence of atropine and yohimbine (1 microM each) were similar in the case of NE release, but in the case of ACh release, the bell shape was lost. The results indicate a differential capacity and response time profile of facilitatory prejunctional beta2-adrenoceptors on adrenergic and cholinergic nerve terminals in the guinea pig trachea and suggest that the receptors on adrenergic nerves are more susceptible to desensitization. (+info)
beta2-adrenoceptor agonists reduce the decline of rat diaphragm twitch force during severe hypoxia.
(16/4656)
The aim of the present study was to investigate the in vitro effects of the short-acting beta2-adrenoceptor agonist salbutamol and the long-acting beta2-adrenoceptor agonist salmeterol on hypoxia-induced rat diaphragm force reduction. In vitro diaphragm twitch force (Pt) and maximal tetanic force (Po) of isolated diaphragm muscle strips were measured for 90 min during hyperoxia (tissue bath PO2 83.8 +/- 0.9 kPa and PCO2 3.9 +/- 0.1 kPa) or severe hypoxia (PO2 7.1 +/- 0.3 kPa and PCO2 3.9 +/- 0.1 kPa) in the presence and absence of 1 microM salbutamol or 1 microM salmeterol. During hyperoxia, salbutamol and salmeterol did not significantly alter the time-related decreases in Pt and Po (to approximately 50% of initial values). Salbutamol had no effects on Po or the Pt-to-Po ratio. Salmeterol treatment significantly reduced Po and increased the Pt-to-Po ratio during hyperoxia (P < 0.05 compared with control value). Hypoxia resulted in a severe decrease in Pt (to approximately 30% of initial value) and Po after 90 min. Both salbutamol and salmeterol significantly reduced the decline in Pt during hypoxia (P < 0.05). The reduction in Po was not prevented. Salbutamol increased Pt rapidly but transiently. Salmeterol had a delayed onset of effect and a longer duration of action. Addition of 1 microM propranolol (a nonselective beta-adrenoceptor antagonist) did not alter Pt, Po, or the Pt-to-Po ratio during hypoxia but completely blocked the inotropic effects of salbutamol and salmeterol, indicating that these effects are dependent on beta2-adrenoceptor agonist-related processes. (+info)