Effects of α1‐Blockers for Lower Urinary Tract Symptoms and Sleep Disorders in Patients with Benign Prostatic Hyperplasia

Objectives: We evaluated the association of lower urinary tract symptoms (LUTS) and sleep disorders (SD) in patients with benign prostatic hyperplasia (BPH). We also examined improvement of SD following the α1‐blocker therapy for LUTS. Methods: Sixty‐eight male patients were enrolled in the study, consisting of 38 cases with LUTS and BPH (BPH group), and 30 men without significant LUTS or BPH (non‐BPH group). The degree of LUTS and SD was evaluated by the International Prostate Symptom Score and the Pittsburg Sleep Quality Index (PSQI), respectively. The patients of BPH group then were treated with α1‐blocker for 4 weeks, and were re‐examined by all the questionnaires to evaluate the therapeutic efficacies. Results: The correlation analyses showed a significant association of LUTS with SD in BPH group (r = 0.4995, P = 0.0068). Twenty cases (52.6%) in BPH group showed 5.5 or more PSQI scores. Following 4 weeks of α1‐blocker administration, the average PSQI decreased significantly from 6.3 to 4.8 points (P < 0.001). Significant improvement was observed in domains of “sleep quality” and “sleep disturbances” among PSQI (P = 0.0215 and 0.0391, respectively). Moreover, significant association between α1‐blocker induced improvements of nocturia and SD was identified in patients with 5.5 or more PSQI score at baseline (r = 0.445, P = 0.0334). Conclusion: These results suggested that SD is associated with LUTS among BPH patients and therapeutic effects of α1‐blockers on LUTS lead to improvements of SD.     

Conversion to Silodosin in Men on Conventional α1‐Blockers for Symptomatic Benign Prostatic Hyperplasia

Objectives: α₁‐blockers have commonly been used as first‐line medical therapy for symptomatic benign prostatic hyperplasia (BPH). Recently, a highly selective α_1A‐adrenoceptor antagonist, silodosin, was developed in Japan. We examined the efficacy and safety of conversion from conventional α₁‐blockers to silodosin in men with BPH. Methods: Conversion to silodosin was proposed to consecutive patients on conventional α₁‐blockers for symptomatic BPH for at least 6 months. The effects of conversion were examined by the International Prostate Symptom Score, quality of life index, overactive bladder symptom score, peak flow rate, residual urine volume, and adverse events at 12 weeks. The efficacy of silodosin was also evaluated by patients' impression. Results: Eighty‐one men underwent conversion, for the most part because of dissatisfaction with the efficacy of their current treatment in improving nocturia or weak stream. The International Prostate Symptom Score total score significantly improved from 12.7 ± 5.9 at baseline to 10.6 ± 5.4 at 4 weeks (P < 0.001) and 10.9 ± 5.8 at 12 weeks (P < 0.01). The progress was mostly due to improvement in voiding symptoms, although reduction of storage symptoms was also significant. The quality of life index also significantly decreased with conversion to silodosin. Efficacy as judged by patients' impression was 76% (37/49) at 12 weeks of treatment. None of the overactive bladder symptom score, peak flow rate, and residual urine volume exhibited significant change. No serious adverse events were observed during the study period. Conclusion: Conversion to silodosin may be beneficial in men who are dissatisfied with conventional α₁‐blockers for BPH, and be particularly useful in improving voiding symptoms.     

Potential Use of β3‐Adrenoceptor Antagonists in Heart Failure Therapy

Recently, a functional, negatively inotropic, β₃‐adrenoceptor was characterized in the human heart. Several studies now suggest that this receptor might play an important role in the pathophysiology of heart failure, by counterbalancing the effects of a β₁ and β₂‐stimulation. Therefore, this review summarizes the rationale and effects of β‐adrenergic blockade in chronic heart failure and specifically addresses the question of the potential use of β₃‐adrenoceptor antagonists in the treatment of heart failure and other pathophysiological conditions associated with a decreased cardiac contractility.     

Metabolic Syndrome Enhances Prostate Contractility and In Vitro Phenylephrine‐induced α1‐Adrenoceptor Protein Expression in the Fructose‐fed Rat

Objectives: To study the effects of metabolic syndrome on prostate α‐adrenergic contractile function using fructose‐fed rats (FR). Methods: Age‐matched male Wistar rats were divided into two groups: group I, normal control rats; and group II, 9‐week FR. Animal body weight, blood pressure and serum metabolic parameters were monitored. The prostate was removed 9 weeks after induction of metabolic syndrome in the FR. The contractile responses of prostatic strips to phenylephrine (10^?7 to 10^?6 M) and KCl (50 mM) were tested. Prostate α₁‐adrenoceptor (α₁‐AR) protein expression was studied by Western blotting analysis with a polyclonal antiserum. Results: At week 9, the FR showed significant increases in body weight, blood pressure, plasma glucose, insulin and triglyceride levels. The FR prostate weight was significantly higher than that of the controls (610.5 ± 13.2 vs 422.3 ± 7.7 mg, P < 0.05 for n = 8). FR prostate contractile responses to phenylephrine and KCl were both significantly increased. Interestingly, prostate α₁‐AR protein expression level was lower in the FR. However, after in vitro 10^?6 M phenylephrine stimulation, FR prostate α₁‐AR protein expression was significantly increased. Conclusion: Metabolic syndrome in FR significantly increases prostate contractile responses to KCl and α‐adrenergic stimulation. Paradoxically, FR prostate α₁‐AR protein expression is decreased, but significantly enhanced after in vitro phenylephrine stimulation.     

β‐Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta‐analysis

Introduction: Bacterial infections have been hypothetized to be a trigger of variceal bleeding in cirrhotic patients and β‐blockers may have a protective effect by decreasing bacterial translocation, reducing portal pressure. The aim of our study was to evaluate the possible role of β‐blockers in preventing spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis and ascites. Materials and Methods: Extensive search of the literature including randomized controlled trial (RCT) and non‐RCT of primary and secondary prophylaxis for variceal bleeding in cirrhotics using β‐blockers were evaluated. We performed a meta‐analysis using the occurrence of SBP as endpoint in all the studies, using the random effect model. Results: Three RCT and three retrospective studies in which β‐blockers were evaluated against no treatment for the prevention of SBP in ascitic cirrhotics were included. There was a statistically significant difference of 12.1%, P<0.001 in favour of propranolol in preventing SBP, which was confirmed by sensitivity analysis evaluating only RCTs (7.8% difference). The effect was still present when haemodynamic responders were compared with non‐responders. Conclusions: This analysis suggests a role of β‐blockers in preventing SBP in ascitic cirrhotics, independent of haemodynamic response. Further formal RCTs are needed to confirm this finding.     

Differential Hemodynamic Effects of β-Adrenoceptor Blockers,Ca Antagonists and Combined α-β-Receptor Blockade in Ischemic Heart Disease

ABSTRACT. The hemodynamic responses to 3 different therapeutical regimens: β-adrenoceptor blockade, calcium inflow inhibition and combined α-β-blockade were evaluated in 3 matched randomized groups of patients with ischemic heart disease and typical exercise-induced angina. The groups consisted of 22, 16 and 15 men, mean age 55–59 years. They were studied at rest and during ischemia-inducing exercise, before and after single oral doses of 100 mg metoprolol, 10 mg nifedipine and 200 mg labetalol. Pressures in the brachial artery and the pulmonary circulation were recorded by means of percutaneously introduced catheters. Cardiac output was determined according to the Fick principle. Metoprolol reduced mean arterial pressures, heart rate and cardiac output. Systemic vascular resistance and left ventricular filling pressure increased. Nifedipine resulted under all conditions in a distinct reduction of systemic vascular resistance and arterial pressures and a slight increase in heart rate and cardiac output. Left ventricular filling pressure was significantly lowered, the more the higher the initial level. The effect of labetalol was similar to that of nifedipine; however, cardiac output was unchanged and heart rate was slightly reduced. Left ventricular filling pressure was significantly lower. It is apparent that suppression of adrenergic stimulation by β-receptor blockade alone may have adverse hemodynamic effects in ischemic heart disease and prompt further functional deterioration. Conversely, both calcium and combined α-β-receptor blockade tend to improve left ventricular function by lowering both left ventricular preload and total systemic vascular resistance. The results strongly suggest that in patients in whom β-receptor blockers appear indicated, their adverse hemodynamic effects can be offset by concomitant α₁-receptor blockade or vasodilation without losing symptomatic efficacy. Combined α-β-receptor blockade has the advantage over calcium antagonists alone to prevent any increase in adrenergic activity and related hyperkinetic response.     

Ion Channel Mechanisms Related to Sudden Cardiac Death in Phenotype‐Negative Long‐QT Syndrome Genotype–Phenotype Correlations of the KCNQ1(S349W) Mutation

Phenotype‐Negative LQTS. Background: Data regarding possible ion channel mechanisms that predispose to ventricular tachyarrhythmias in patients with phenotype‐negative long‐QT syndrome (LQTS) are limited. Methods and Results: We carried out cellular expression studies for the S349W mutation in the KCNQ1 channel, which was identified in 15 patients from the International LQTS Registry who experienced a high rate of cardiac events despite lack of significant QTc prolongation. The clinical outcome of S349W mutation carriers was compared with that of QTc‐matched carriers of haploinsufficient missense (n = 30) and nonsense (n = 45) KCNQ1 mutations. The channels containing the mutant S349W subunit showed a mild reduction in current (<50%), in the haploinsuficient range, with an increase in maximal conductance compared with wild‐type channels. In contrast, expression of the S349W mutant subunit produced a pronounced effect on both the voltage dependence of activation and the time constant of activation, while haploinsuficient channels showed no effect on either parameter. The cumulative probability of cardiac events from birth through age 20 years was significantly higher among S349W mutation carriers (58%) as compared with carriers of QTc‐matched haploinsufficent missense (21%, P = 0.004) and nonsense (25%, P = 0.01) mutations. Conclusions: The S349W mutation in the KCNQ1 potassium channel exerts a relatively mild effect on the ion channel current, whereas an increase in conductance compensates for impaired voltage activation of the channel. The changes observed in voltage activation of the channel may underlie the mechanisms predisposing to arrhythmic risk among LQTS patients with a normal‐range QTc. (J Cardiovasc Electrophysiol, Vol. 22, pp. 193‐200, February 2011)     

Adrenergic Induction of Delayed Afterdepolarizations in Ventricular Myocardial Cells: β Induction and α Modulation

Adrenergic Afterdepolarizations in Ventricular Cells. Introduction: The purpose of these studies was to expose canine multicellular ventricular endocardial preparations and disaggregated myocytes to adrenergic agonists and antagonists, and to investigate the generation of delayed afterdepolarizations and triggered action potentials. Methods and Results: We used multicellular preparations and disaggregated myocytes from canine ventricles. The threshold concentration for induction of delayed afterdepolarizations in isolated myocytes for norepinephrine was between 1 × 10^?8 M and 5 × 10^?5 M, with 50% of the cells showing delayed afterdepolarizations at 4.3 × 10^?8 M. Higher concentrations of epinephrine are required with 50% of the cells responding to 8.3 × 10^?8 M. The threshold concentrations for induction of delayed afterdepolarizations in myocardial cells of multicellular preparations were an order of magnitude higher. Delayed afterdepolarizations could not be induced in Purkinje fibers with concentrations up to 10^?4 M with norepinephrine. Adrenergic delayed afterdepolarizations were inhibited promptly by reduction of pO₂ in superfusate that was equilibrated with N₂ (95%) in place of O₂. The amplitudes of adrenergic delayed afterdepolarizations and the propensity to triggered action potentials were inversely related to cycle length down to the shortest cycle length tested (330 msec). Adrenergic delayed afterdepolarizations were induced by isoproterenol but not by α-adrenergic agonists (methoxamine or phenylephrine). They were inhibited by a β antagonist (propranolol) but not by α antagonists (prazosin or yohimbine). Delayed afterdepolarizations induced by isoproterenol were inhibited by α agonists (methoxamine or phenylephrine). The α-adrenergic inhibitory effects on β-adrenergic delayed afterdepolarizations could be reversed by prazosin, but not by yohimbine. Conclusions: We conclude the natural catecholamines norepinephrine and epinephrine generate delayed afterdepolarizations in myocardial cells, but not in Purkinje cells, by activating β receptors, but activation of α₁ receptors inhibits adrenergic delayed afterdepolarizations. Individual myocytes exhibit widely varying sensitivities for induction of adrenergic delayed afterdepolarizations, but some cells respond to concentrations similar to those that may exist in vivo. Therefore, sympathetic activation in vivo may generate delayed afterdepolarizations, triggered action potentials, and arrhythmias.     

Pharmacological Mechanisms of Clinically Favorable Properties of a Selective β1‐Adrenoceptor Antagonist,Nebivolol

Nebivolol is a racemic mixture of d‐ and 1‐enantiomers. The drug is characterized by β₁‐adrenoceptor selectivity and long‐acting β₁‐blockade exerted predominantly by d‐enantiomer. Nebivolol is devoid of intrinsic sympathomimetic activity and has no relevant membrane stabilizing action. Antiproliferative properties of nebivolol were demonstrated in endothelial and smooth muscle cell cultures. Infusion of nebivolol causes a vasodilation in all vascular beds by endothelial‐dependent mechanism involving stimulation of β₃‐adrenoceptors as well as by endothelial‐independent mechanism. Nebivolol possesses not only direct vasodilator properties but also augments the action of endothelium‐dependent vasodilators. The antioxidant property of nebivolol can at least in part explain why treatment with this drug enhances eNOS activity and minimizes the reperfusion‐induced myocardial injury. The systemic effects of nebivolol in humans have an unusual hemodynamic profile. In contrast to traditional β‐adrenoceptor antagonists, nebivolol reduces preload and afterload due to systemic vasodilation and improves arterial distensibility. At 5 mg daily nebivolol effectively reduces systolic and diastolic blood pressure over a 24‐h period. During treatment with nebivolol arterial pressure follows the natural circadian rhythm. Trough‐to‐peak ratio for nebivolol is 0.9. It has been demonstrated in numerous placebo‐controlled studies that exercise tolerance is not reduced during nebivolol therapy. By chronic administration to patients with left ventricular dysfunction nebivolol increases myocardial contractility. Nebivolol produced no significant changes in lipid levels, insulin sensitivity or glucose tolerance. These findings make nebivolol a promising therapeutic tool for the treatment of arterial hypertension and chronic heart failure.     

α‐thalassaemia masked by β gene defects and a new polyadenylation site mutation on the α2‐globin gene

We report three examples of chronic anaemia involving complex combinations of α‐ and β‐globin gene defects. The first case had a potential Hb H disease caused by the classic SEA/RW deletions masked by Hb E [β26(B8)Glu→Lys] in the homozygous state. The second had an unusual Hb H disease caused by compound heterozygosity for two different α2 polyadenylation site mutations masked by a β‐thalassaemia heterozygosity. The third had an intermediate α‐thalassaemia with considerable anaemia caused by an as yet unknown polyadenylation site (AATAAA>AATAAC) mutation in combination with a common RW deletion masked by a common Hb C [β6(A3)Glu→Lys] heterozygosity. Diagnostic methods, genotype/phenotype correlations and the chance of overlooking these combinations during risk assessment in a multiethnic society are discussed.     

Chronotropic Incompentence and Functional Capacity in Chronic Heart Failure: No Role of β‐Blockers and β‐Blocker Dose

Aim : To assess the effect of chronotropic incompetence on functional capacity in chronic heart failure (CHF) patients, as evaluated as NYHA and peak oxygen consumption (pVO₂), focusing on the presence and dose of β‐blocker treatment. Methods : Nine hundred and sixty‐seven consecutive CHF patients were evaluated, 328 of whom were discarded because they failed to meet the study criteria. Of the 639 analyzed, 90 were not treated with β‐blockers whereas the other 549 were. The latter were further subdivided in high (n = 184) and low (n = 365) β‐blockers daily dose group in accordance with an arbitrary cut‐off of 25 mg for carvedilol and of 5 mg for bisoprolol. Failure to achieve 80% of the percentage of maximum age predicted peak heart rate (%Max PHR) or of HR reserve (%HRR) constituted chronotropic incompetence. Results : No differences were found in NYHA or pVO2 between patients with and without β‐blockers and, similarly, between high and low β‐blocker dose groups. Twenty and sixty‐nine percent of not β‐blocked patients showed chronotropic incompetence according to %Max PHR and %HRR, respectively, whereas this prevalence rose to 61% and 84% in those on β‐blocker therapy. Patients taking β‐blockers without chronotropic incompetence, as inferable from both %Max PHR and %HRR, showed higher NYHA and pVO2 regardless of drug dose, whereas, in not β‐blocked patients, only %HRR revealed a difference in functional capacity. At multivariable analysis, HR increase during exercise (ΔHR) was the variable most strongly associated to pVO2 (β: 0.572; SE: 0.008; P < 0.0001) and NYHA class (β: ?0.499; SE: 0.001; P < 0.0001). Conclusions : ΔHR is a powerful predictor of CHF severity regardless of the presence of β‐blocker therapy and of β‐blocker daily dose.     

Differential β-adrenoceptor expression induced by nerve growth factor infusion into the canine right and left stellate ganglia

BACKGROUND: Nerve growth factor (NGF) infusion into the right stellate ganglion (RSG) is antiarrhythmic, while NGF infusion into the left stellate ganglion (LSG) is proarrhythmic in dogs with myocardial infarction (MI) and complete atrioventricular block (CAVB). This functional asymmetry suggests differential neural remodeling. OBJECTIVES: To test the hypothesis that NGF infusion into the RSG and the LSG can lead to differential beta-adrenoceptor (beta-AR) expression in dogs with MI and CAVB. METHODS AND RESULTS: We performed immunostaining to quantify beta(1)-AR and beta(3)-AR immunoreactivity in six dogs with MI and CAVB, nine dogs with MI, CAVB, and NGF infusion to the LSG, six dogs with MI, CAVB, and NGF infusion to the RSG, and six normal dogs. There was significantly increased beta(3)-AR immunoreactivity in dogs with NGF infusion into the LSG and significantly decreased beta(3)-AR immunoreactivity in dogs with NGF infusion into the RSG compared with controls and with the MI and CAVB group. There were no significant differences in beta(1)-AR immunoreactivity among these four groups. To determine protein and mRNA expression of beta-ARs, we created MI and CAVB and infused NGF into the LSG in six additional dogs. The noninfarcted left ventricle free wall was harvested 1 week later. The protein level and receptor density of beta(3)-AR (but not beta(1)- or beta(2)-AR) significantly increased in these six dogs compared with normal controls. CONCLUSIONS: We conclude that NGF infusion into the RSG and the LSG in dogs with MI and CAVB induced differential beta(3)-AR expression in the left ventricular myocardium.     

Molecular scanning of the beta‐3‐adrenergic receptor gene in Pima Indians and Caucasians

Background

The beta‐3‐adrenergic receptor (β3AR) stimulates lipolysis and thermogenesis in adipocytes. The Trp64Arg β3AR variant is associated in some, but not all, studies with an earlier onset of Type 2 diabetes mellitus and features of the insulin resistance syndrome. Functional studies as to the role of the Trp64Arg variant have been inconclusive. Earlier studies screened the β3AR gene in only ten obese, diabetic Pima Indians. Potentially another yet to be identified polymorphism in the β3AR gene in linkage disequilibrium with the Trp64Arg polymorphism could explain the findings in the association and functional studies.

Methods

We scanned the β3AR gene in 20 diabetic Pima subjects and 20 Caucasian subjects using single stranded conformational polymorphism (SSCP) analysis. Variants were sequenced using dideoxy sequence analysis and further characterized using allele specific oligonucleotide hybridization (ASO) and RNA template specific‐polymerase chain reaction (RS‐PCR) assays.

Results

We found a guanine to thymidine substitution in the first intron, 14 bases from the splice donor site in both groups. In virtually all subjects, only two haplotypes were detected, Trp64/g1856 and Arg64/t1856, indicating that the g1856t polymorphism is in linkage disequilibrium with the Trp64Arg polymorphism. The g1856t substitution introduces a new consensus splice donor site which, if used, would encode a truncated protein. RNA levels of the two β3AR alleles were approximately equal in omental adipose tissue of heterozygotes. No aberrantly spliced β3AR mRNA was detected, indicating that the new consensus splice donor site is not used in vivo.

Conclusion

The g1856t polymorphism is in linkage disequilibrium with the Trp64Arg variant, but does not appear to have a functional role. Copyright © 1999 John Wiley & Sons, Ltd.

     

Bunazosin,a Selective α1 ‐Adrenoceptor Antagonist,as an Anti‐glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage

Bunazosin hydrochloride is a potent and selective α₁‐adrenoceptor antagonist that has been clinically used both as a systemic antihypertensive as well as an ocular hypotensive drug. In a number of studies, we have examined some effects of bunazosin hydrochloride that might indicate its potential as an anti‐glaucoma drug. In normal rabbit eyes, topically instilled bunazosin hydrochloride reached the posterior retina by local penetration at concentrations sufficient to attenuate the phenylephrine‐ or endothelin‐1 (ET‐1)‐induced constriction of retinal arteries. Furthermore, bunazosin hydrochloride improved the impairment of optic nerve head (ONH) blood flow, the prolongation of visual‐evoked potentials (VEP) implicit time, the enlargement of the optic disk cup, and the decrease in the number of retinal ganglion cell layer cells induced by repeated injections of ET‐1 in rabbits. Topically instilled bunazosin hydrochloride improved the reductions in ONH capillary blood flow and VEP amplitude induced in rabbit eyes by nitric oxide synthase inhibition. In rat primary retinal cultures, bunazosin hydrochloride reduced glutamate‐induced neuronal cell death, presumably through a Na⁺ channel blocking effect. In healthy humans, topically instilled bunazosin hydrochloride reportedly increases blood velocity in the ONH, retina and choroid, without significantly altering either blood pressure or heart rate. These results indicate that bunazosin hydrochloride exerts both an improvement effect within the ocular circulation and a direct neuroprotective effect. Hence, bunazosin hydrochloride may be useful as a therapeutic drug against ischemic retinal diseases (such as glaucoma and retinal vascular occlusive diseases) that are associated with disturbances of the ocular circulation.