Non-selective Beta-adrenoceptor Blocker Research Articles

Nonselective beta-adrenoceptor blocker use and risk of Parkinson’s disease: from multiple real-world evidence

BackgroundPeople with hypertension have a higher risk of developing Parkinson’s disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the occurrence and development of PD with inconsistent results. With multisource data, we sought to determine whether specific antihypertensive classes elevated or reduced the risk for PD.MethodsWe used a mixed methods approach that combines 4 methodologies. First, we conducted a disproportionality analysis using the reports causing adverse events in the US Food and Drug Administration Adverse Events Reporting System (FAERS) to explore the effect of different classes of antihypertensive medications on the risk of PD; based on the findings from FAERS, a meta-analysis and a UK Biobank cohort analysis were used to further assess the association of drug use with PD; finally, we employed Mendelian randomization (MR) analysis to validate the causal relationship between the drug target and the occurrence of PD.ResultsIn the disproportionality analysis using the FAERS (N = 187,266), nonselective beta-adrenoceptor blockers (NBBs) were demonstrated to have a significant association with PD (reporting odds ratio (ROR) = 3.13; 95% CI 2.33–4.22). In the meta-analysis of 12 studies with 12,183,809 participants, PD risk was elevated in NBBs (RR, 1.64; 95% CI, 1.19–2.09) when stratified by subtypes of BBs. Among the 105,763 participants included in the cohort analysis using data from the UK Biobank, individuals who used NBBs had a significantly increased risk of PD compared to nonusers (HR, 1.47; 95% CI 1.04–2.06). The MR analysis revealed a significant association between higher expression of the β2 adrenergic receptor (ADRB2) gene, a drug target blocked by NBBs, and a reduced risk of PD (OR, 0.85; 95% CI 0.73–0.99).ConclusionsOur comprehensive study indicated that regular NBB use is associated with an increased risk of PD. In light of the detrimental effects of NBBs on PD, some people should choose alternative antihypertensive treatments.

Curcumin and α/β-Adrenergic Antagonists Cotreatment Reverse Liver Cirrhosis in Hamsters: Participation of Nrf-2 and NF-κB

Liver cirrhosis is the result of an uncontrolled fibrogenetic process, due to the activation and subsequent differentiation into myofibroblasts of the hepatic stellate cells (HSC). It is known that HSC express adrenoreceptors (AR), and the use of AR antagonists protects experimental animals from cirrhosis. However, several studies suggest that the toxicity generated by metabolism of these antagonists would hinder its use in cirrhotic patients. In addition, liver fibrosis may be associated with a decrease of the antioxidant response of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and the overregulation of the proinflammatory pathway of nuclear factor kappa B (NF-κB). Therefore, in the present work, the capacity of doxazosin (α1 antagonist), carvedilol (nonselective beta-adrenoceptor blocker with alpha 1-blocking properties), and curcumin (antioxidant and anti-inflammatory compound) to reverse liver cirrhosis and studying the possible modulation of Nrf-2 and NF-κB were evaluated. Hamsters received CCl4 for 20 weeks, and then treatments were immediately administered for 4 weeks more. The individual administration of doxazosin or carvedilol showed less ability to reverse cirrhosis in relation to concomitantly curcumin administration. However, the best effect was the combined effect of doxazosin, carvedilol, and curcumin, reversing liver fibrosis and decreasing the amount of collagen I (Sirius red stain) without affecting the morphology of hepatocytes (hematoxylin and eosin stain), showing normal hepatic function (glucose, albumin, AST, ALT, total bilirubin, and total proteins). In addition, carvedilol treatment and the combination of doxazosin with curcumin increased Nrf-2/NF-κB mRNA ratio and its protein expression in the inflammatory cells in the livers, possibly as another mechanism of hepatoprotection. Therefore, these results suggest for the first time that α/β adrenergic blockers with curcumin completely reverse hepatic damage, possibly as a result of adrenergic antagonism on HSC and conceivably by the increase of Nrf-2/NF-κB mRNA ratio.

Cost-effectiveness analysis of preventing esophageal variceal rebleeding in liver cirrhosis

Objective To compare cost-effectiveness between endoscopical esophageal variceal ligation (EVL) combined non-selective beta-receptor blocker strategies and covered-stents transjugular intrahepatic portosystemic shunt (cTIPS) in preventing esophageal variceal rebleeding in liver cirrhosis with portal hypertension. And to explore the threshold of cost-effectiveness in stents in China. Methods According to clinical practice and associated guidelines, a six state Markov-based decision analytic model was established with TreeAge Pro Suite 2014 to compare the cost-effectiveness between two interfering strategies after followed up for seven years. The parameters such as costs, life years (LY), quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER) were directed. Results The results of baseline research in the seven-year follow-up period indicated that the cost of endoscopical EVL combined non-selective beta-receptor blocker B was 7 444.25 United States dollar (USD)/each, and yielded 1.98 QALY. The expected cost of cTIPS was 13 151.69 USD/each and could have 2.34 QALY. In the 7th year, ICER was 16 001.74 USD. Based on willingness-to-pay (WTP) threshold of China (19 887.00 USD), cTIPS had better cost-effectiveness than endoscopical EVL combined non-selective beta-receptor blocker B. The price of covered stents less than 5 401.52 USD had cost-effectiveness. The results of single factor sensitivity analysis indicated that rebleeding probability of endoscopical EVL combined non-selective beta-receptor blocker B group was the most influential factor in the result of model. The second important factor was the cost of cTIPS. The probabilistic sensitivity analysis reported cTIPS to be the optimal strategy at WTP of 19 887.00 USD in 83% of the iterations. Conclusions Seven-year follow-up indicates that cTIPS may be a more cost-effective strategy than endoscopical EVL combined non-selective beta-receptor blocker B in preventing esophageal variceal rebleeding. The price of covered stents less than 5 401.52 USD which have cost-effectiveness in China. Key words: Portasystemic shunt, transjugular intrahepatic; Covered stents; Esophageal variceal ligation; Non-selective beta-blocker; Markov model; Cost-effectiveness analysis; Probability senstivity analysis

Pleiotropic Effects of the β-Adrenoceptor Blocker Carvedilol on Calcium Regulation during Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Carvedilol is a nonselective beta-adrenoceptor blocker with multiple pleiotropic actions. A recent clinical study suggested that carvedilol may be superior to other beta-adrenoceptor blockers in the treatment of heart failure. Despite numerous investigations, the underlying mechanisms of carvedilol on improving heart failure are yet to be fully established. The purpose of this study is to clarify the pleiotropic effect of carvedilol on cytosolic and mitochondrial calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes. Carvedilol (10 microM), but not metoprolol (10 microM), reduced H2O2 (100 microM)-induced apoptosis in neonatal rat cardiomyocytes. During the process, changes in cytosolic calcium concentration ([Ca2+]i) and mitochondrial calcium concentration ([Ca2+]m) and mitochondrial membrane potential (DeltaPsim) were measured by fluorescent probes [Fluo-3/acetoxymethyl ester (AM), Rhod-2/AM, and tetramethylrhodamine ethyl ester, respectively] and imaged by laser confocal microscopy. The results showed that H2O2 caused [Ca2]m overload first, followed by [Ca2+]i overload, leading to DeltaPsim dissipation and the induction of apoptosis. Carvedilol (10 microM) significantly delayed these processes and reduced apoptosis. These effects were not observed with other beta-adrenoceptor blockers (metoprolol, atenolol, and propranolol) or with a combination of the alpha (phentolamine)- and the beta-adrenoceptor blocker. The antioxidant N-acetyl-L-cysteine (NAC, 5 mM) and the combination of NAC and propranolol (10 microM) showed an effect similar to that of carvedilol. Therefore, the effect of carvedilol on H2O2-induced changes in [Ca2+]m, [Ca2+]i, and DeltaPsi(m) is independent of alpha- and beta-adrenoceptors but is probably dependent on the antioxidant effect.

Effect of adrenaline on transmesothelial resistance of isolated sheep pleura

The effect of adrenaline on the transmesothelial resistance (RTM) of sheep's visceral and parietal pleura was studied using the Ussing chamber technique. Basal transmesothelial resistance of visceral pleura was found to be 20.71 +/- 0.31 Omega cm2, whereas that of parietal pleura was found to be 19.53 +/- 0.34 Omega cm2. Immediately after the addition of adrenaline (10(-7) M) both apically and basolaterally on the visceral and parietal pleura, these values were significantly increased (P < 0.05). Addition of the nonselective beta-receptor blocker, propranolol (10(-5) M), suppressed this effect in both visceral and parietal pleura, while addition of the nonselective alpha-receptor blocker, phentolamine (10(-5) M), partly suppressed the above-mentioned increase in the parietal pleura. In conclusion, our results show that adrenaline has a rapid effect on both pleurae. This rapid effect is mediated by the stimulation of beta-adrenergic receptors in the case of visceral pleura, while in the case of parietal pleura this effect seems to be due to a stimulation of alpha- and beta-adrenergic receptors. On the visceral pleura the effect of adrenaline vanishes after some minutes and on the parietal this effect is more permanent than the visceral's one, suggesting differences in the distribution of the adrenergic receptors between the visceral and parietal pleura.

Successful management of cesarean section in a patient with Romano–Ward syndrome using landiolol, a selective and short-acting β1 receptor antagonist

Romano-Ward (R-W) syndrome is an autosomal dominant hereditary disorder and is characterized by a prolonged QT interval on the electrocardiogram (ECG), syncope, and sudden death. We report here a case of cesarian section in a patient with R-W syndrome whose QT prolongation was successfully managed with landiolol, a selective beta1 receptor blocker. A 25-year-old woman with R-W syndrome was scheduled for cesarean section. In the operating room, the patient's ECG showed tachycardia (102 beats x min(-1)) and marked QT prolongation (QTc = 0.56 s). After spinal anesthesia, the patient's heart rate (HR) increased to 130 beats/min accompanied by a slight decrease in arterial blood pressure to 97/57 mmHg and the QTc was prolonged to 0.57 s. Landiolol was continuously infused at a rate of 0.04 mg.kg(-1) x min(-1) and the HR gradually decreased to 80-90 beats x min(-1) accompanied by the normalization of QTc to 0.48 s. We thought that the use of landiolol was more rational and was preferable to a nonselective beta receptor blocker for a term-pregnant woman because blockade of the beta2 receptor might cause uterine contraction. After the use of landiolol, intraoperative and postoperative courses in both the patient and the baby were uneventful.

DRUGS AND SMOKING

Smoking is a well – known risk factor of many diseases. It influences the efficacy and safety of drug treatment by affecting the course of different physiological processes and modifying the metabolism of drugs. The number of researches showed decrease in efficacy of some cardiovascular drugs in smokers. Aim. To compare efficacy and safety of selective and non-selective beta–adrenoceptor blockers in smokers and nonsmokers with chronic ischemic disease. Material and Methods. Antianginal efficacy of drugs in patients of both groups was evaluated by burden tests on treadmill, effective doses of bisoprolol and propranolol were adjusted. Results. The result shows that smokers two times more often need prescription of double doses of drugs. Depressed antianginal activity of both beta-adrenoceptor blockers, especially of non-selective propranolol, in smokers was revealed. When evaluating the parameters of spirography, it was found that non-selective beta-adrenoceptor blocker propranol statistically significant decreases figures of bronchial passage, irrespective of the status of smoking. Moreover, with propranol treatment, bigger number of side effects is registered in both groups, demonstrating 30% more in smok???ers compared to nonsmokers. Conclusion. Smoking attenuates efficacy and safety of beta-blockers, especially these of non-selective ones.

Calcium dynamics in the failing heart: restoration by beta-adrenergic receptor blockade.

Changes in calcium (Ca2+) regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using beta-adrenergic receptor antagonists (beta-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of beta-blocker treatment on Ca2+ dynamics in the failing heart are unknown. To address this issue, tropomodulin-overexpressing transgenic (TOT) mice, which suffer from dilated cardiomyopathy, were treated with a nonselective beta-receptor blocker (5 mg. kg-1. day-1 propranolol) for 2 wk. Ca2+ dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared with untreated TOT mice. Frequency-dependent diastolic and Ca2+ transient amplitudes were returned to normal in propranolol-treated TOT mice and but not in untreated TOT mice. Ca2+ kinetic measurements of time to peak and time decay of the caffeine-induced Ca2+ transient to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), whereas Na+/Ca2+ exchanger (NCX) concentrations were increased 2.6-fold relative to nontransgenic samples. Propranolol treatment of TOT mice reversed the alterations in SERCA and NCX protein levels but not potassium channels. Although restoration of Ca2+ dynamics occurred within 2 wk of beta-blockade treatment, evidence of functional improvement in cardiac contractility assessed by echocardiography took 10 wk to materialize. These results demonstrate that beta-adrenergic blockade restores Ca2+ dynamics and normalizes expression of Ca2+-handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts.

Comitogenic effect of catecholamines on rat cardiac fibroblasts in culture.

We studied the ability of norepinephrine and of other catecholamines to affect the proliferation of cardiac fibroblasts isolated from adult rat hearts. Furthermore, we investigated the possible adrenergic receptor involved in this process. Norepinephrine (NE), phenylephrine (PE), isoproterenol (ISO), forskolin (FO), epidermal growth factor (EGF), platelet-derived growth factor AA (PDGF-AA) and specific inhibitors of the alpha(1)-, alpha(2)-, beta(1)- and beta(2)-adrenoceptors and of the protein kinase A (PKA) were applied to cardiac fibroblasts in culture. Cell number was measured by use of a Coulter Counter. Activation of the cAMP response element binding protein (CREB) was measured by Western blotting and subsequent use of a phospho-specific antibody. Activation of the p42- and the p44-mitogen activated protein kinase (p42/p44(MAPK)) was assessed by detection of phosphorylation shifts and by incorporation of 32P-labelled phosphate into myelin basic protein. Fibroblasts isolated from hearts of adult rats were grown in 10% serum-containing media which induced an increase in cell number by 94%. After 48 h, treatment with 10 microM NE caused an even greater increase in cell number by 222%, i.e. another 128% (comitogenic effect). In contrast, NE alone had no effect on the growth of serum-deprived cells. EGF and PDGF-AA did not replace serum as the basic mitogen. After addition of NE to proliferating cells under serum conditions, there was a rapid, time-dependent significant activation of the p42/p44(MAPK) and of CREB for up to 60 and 120 min, respectively. In both cases, the maximum of activation was reached after 5 min. Application of FO (0.1-20 microM) caused a strong activation of CREB, while no increase in the phosphorylation of the p42/p44(MAPK) was detected. Treatment with 20 microM FO led to an identical increase in cell number as application of NE. Specific blockade of PKA with RpcAMPS prevented the activation of CREB and also the comitogenic effect of FO as well as of NE. The alpha- and beta-adrenergic receptor blocker carvedilol (10 microM) normalized all NE-induced effects. Prazosin and yohimbine, inhibitors of alpha(1)- and alpha(2)-adrenoceptor activation, respectively, did not influence the NE-evoked increase in cell number. In contrast, the non-selective beta-adrenoceptor blocker propranolol (1 microM) completely suppressed the comitogenic effect of NE. A similar effect was obtained with the specific beta(2)-adrenoceptor blocker ICI 118,551 (5 microM), while the beta(1)-adrenoceptor blocker metoprolol did not influence the increase in cell number. NE elicits a comitogenic effect on cultured rat cardiac fibroblasts which is prevented by beta(2)-adrenergic blockade. The activation of CREB contributes to the increase in proliferation. The p42/p44(MAPK) which was also found to be activated by NE might as well be involved in the regulation of the comitogenic effect.

Differential effects of carvedilol on norepinephrine release in normoxic and ischemic heart.

Carvedilol is a beta-adrenoceptor antagonist with multiple actions, which may contribute to superior cardioprotection in heart failure and myocardial infarction. We hypothesized that carvedilol may modulate presynaptic norepinephrine release in the heart. Therefore, we compared the effects of carvedilol (racemate and both enantiomers) and beta1-selective as well as nonselective beta-adrenoceptor blockers on norepinephrine release in isolated perfused rat hearts under normoxic and brief ischemic conditions. Exocytotic release of endogenous norepinephrine was induced by paired electric field stimulations to compare the release before (S1) and after (S2) beta-adrenoceptor blocker application. Metoprolol, bisoprolol, and pindolol (0.1-10 microM) had essentially no effect on exocytotic norepinephrine release under normoxic and ischemic conditions. In contrast, carvedilol exerted a biphasic concentration-response curve (increase followed by suppression) on norepinephrine release. The increase in norepinephrine release was more pronounced with R-carvedilol than with S-carvedilol, indicating an effect independent from beta-receptor antagonism. During ischemia, the facilitatory effect of carvedilol on norepinephrine release was lost, resulting in a concentration-dependent suppression of the release. These results indicate that carvedilol in contrast to classic beta1-selective and -nonselective beta-adrenoceptor blockers has pronounced effects on cardiac norepinephrine release with a remarkable difference between normoxic and ischemic conditions. Whereas a facilitation of norepinephrine release prevailed in normoxia, we observed a suppression of the release in ischemia. It remains to be established whether this unique action of carvedilol on cardiac sympathetic neurotransmission is of clinical relevance.

Eugenodilol: a third-generation beta-adrenoceptor blocker, derived from eugenol, with alpha-adrenoceptor blocking and beta2-adrenoceptor agonist-associated vasorelaxant activities.

Eugenodilol, derived from natural eugenol, was first investigated with in vivo and in vitro models. In our in vivo study, eugenodilol (0.5, 1.0, and 1.5 mg/kg, i.v.) produced dose-dependent hypotensive and bradycardic responses in pentobarbital-anesthetized Wistar rats. Eugenodilol also inhibited the tachycardia and arterial pressor effects induced by (-)isoproterenol and phenylephrine, respectively. In our in vitro study, eugenodilol competitively antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects and tracheal-relaxation responses on isolated guinea pig tissues in a concentration-dependent manner. The apparent pA2 values were 7.88+/-0.12 for right atria, 7.52+/-0.05 for left atria, and 7.33+/-0.15 for trachea, indicating that eugenodilol was a nonselective beta-adrenoceptor blocker. In thoracic aorta experiments, the apparent pA2 values of alpha-adrenoceptor blockade were 7.05+/-0.25 and 6.87+/-0.08 for eugenodilol and labetalol, respectively. In addition, eugenodilol produced cumulative relaxation responses on isolated guinea pig tracheal strips. The effects were competitively antagonized by ICI 118,551 (10(-8)-10(-6) M), a relatively selective beta2-adrenoceptor antagonist. In the radioligand-binding assay, the Ki values of [3H]CGP-12177 binding to rat ventricle and lung membranes were 9.72 and 48.29 nM, respectively, and the value of [3H]prazosin binding to rat brain membrane was 38.72 nM. These results further confirmed the alpha/beta-adrenoceptors-blocking activities of eugenodilol reported in the functional studies. We conclude that eugenodilol is a novel third-generation beta-adrenoceptor blocker with ancillary blocking activity at alpha-adrenoceptors and weak sympathomimetic activity at beta2-adrenoceptors.

Effects of the beta-adrenoceptor blocker nipradilol on renal microcirculation in a rat model: A comparative study with propranolol

The objective of the present study was to compare the effects of the vasodilating nonselective beta-adrenoceptor blocker nipradilol on renal microvasculature with those occurring with propranolol, a typical nonselective beta-adrenoceptor blocker. Hydronephrosis was induced by ligation of the left ureter in seventeen 8-week-old stroke-prone, spontaneously hypertensive rats. The experiment was performed 2 months after the surgery. The hydronephrotic kidney was split longitudinally and spread out as a thin sheet, and the renal microvasculature was observed directly under a light microscope. Intravenous administration of nipradilol 200 μg/kg as a bolus caused a significant decrease in the systolic blood pressure (−36 mm Hg) at 5 minutes. The afferent arteriole was significantly dilated transiently (+13% in diameter) at 10 minutes. The changes in the efferent arteriole were not statistically significant. The glomerular blood flow was statistically significantly increased (+22%) at 10 minutes. Intravenous administration of propranolol 600 μg/kg did not cause statistically significant changes in the systolic blood pressure, the afferent arteriolar diameter, or the glomerular blood flow. The efferent arteriole showed a statistically significant constriction (−16% in diameter) at 20 minutes. In summary, nipradilol dilated the afferent arteriole and increased the glomerular blood flow despite a significant decrease in the systolic blood pressure. This vasodilating effect on the afferent arteriole was not observed with propranolol.

Effects of tilisolol, a nonselective beta-adrenergic blocker, on the membrane currents of isolated guinea pig ventricular myocytes.

The effects of tilisolol, a nonselective beta-adrenoceptor blocker, on transmembrane ionic currents were studied in single guinea pig ventricular myocytes by using the whole-cell voltage clamp technique. In the absence of beta-adrenergic stimulation, 10 microM tilisolol, a concentration higher than that used in the clinical therapeutic regimen, did not affect the L-type Ca2+ current (ICa), the inwardly rectifying K+ current (IK1), or the delayed rectifying K+ current (IK). In addition, it did not induce currents through the adenosine triphosphate (ATP)-sensitive K+ channels. However, under the nonselective beta-adrenergic stimulation with 1 microM isoproterenol, 1 microM tilisolol almost completely reversed the agonist-induced increase of IK. The increase of ICa by isoproterenol was blocked only by approximately 30% with tilisolol. We concluded that, at therapeutic concentrations (0.01-0.15 microM), tilisolol is a pure beta-adrenoceptor antagonist that has no direct effects on the transmembrane ionic currents of mammalian ventricular myocytes, such as ICa, IK1, or IK. Comparison of the dose-dependent effects of tilisolol on ICa and IK suggested that tilisolol may selectively inhibit catecholamine-induced increase of IK at the therapeutic concentrations. The virtually selective inhibition of IK, leaving ICa intact, may be favorable to prevent the catecholamine-induced arrhythmia without inhibiting contraction.

Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity

Hypertensive patients frequently show resistance to insulin-stimulated glucose uptake and hyperinsulinemia. Diuretics and beta-adrenoceptor blocking agents have been found to decrease insulin sensitivity, whereas alpha 1-blockers and angiotensin converting enzyme inhibitors seem to improve it. To compare the effects of a 3 months' antihypertensive treatment with carvedilol, a non-selective beta-adrenoceptor blocker with alpha 1-blocking properties, with the beta 1-selective receptor blocker metoprolol on insulin sensitivity in non-diabetic hypertensive patients. A multicenter double-blind randomized study. Seventy-two non-diabetic hypertensive patients were randomly assigned to treatment with either carvedilol or metoprolol. An isoglycemic, hyperinsulinemic glucose clamp was conducted before and after 12 weeks of treatment; the metabolic clearance rate for glucose was taken as an indicator of insulin sensitivity. The two groups did not differ in age, sex, body mass index, blood pressure or lipids, and treatment effectively lowered blood pressure. In both groups, insulin sensitivity was impaired at baseline. After metoprolol treatment, insulin sensitivity further decreased significantly by about 14%, whereas it increased after carvedilol. There was also a decrease in high-density lipoprotein and an increase in triglycerides levels in patients in the metoprolol-treated group, whereas these parameters remained unchanged in patients in the carvedilol-treated group. This study confirms previous findings of a reduction in insulin sensitivity after chronic metoprolol treatment. Carvedilol treatment, however, resulted in a small amelioration of insulin resistance and a better lipid profile [corrected]. We thus demonstrate that a beta-blocker with alpha 1-blocking properties has favorable effects on glucose metabolism, suggesting a potentially important role of peripheral blood flow in regulating glucose uptake. These findings imply that beta-blocker treatment, when combined with alpha 1-blocking activity has advantageous effects on insulin sensitivity and lipids and could therefore be suitable for patients with the metabolic syndrome.

Effects of carvedilol on atrial natriuretic peptide, catecholamines, and hemodynamics in hypertension at rest and during exercise.

Possible counterregulatory neurohumoral and hemodynamic responses to carvedilol (a new vasodilating nonselective beta-receptor blocker) were studied in 19 men with essential hypertension (age range, 34-59 years; mean age, 44 years). Intra-arterial pressure, cardiac output (Cardio-green), heart rate, and the vasoactive peptides norepinephrine, epinephrine, and atrial natriuretic peptide (ANP) were measured at rest supine and sitting and during 100-W bicycle exercise before and 2 h after administration of 25 mg carvedilol. The same protocol was followed after 9 months of chronic carvedilol treatment (mean dose, 52 mg/day). Carvedilol induced both acute and chronic reductions (at rest supine, 11%) in mean arterial pressure, due in part to reduction in cardiac output (5%) and in part to reduction in total peripheral resistance (5%). At rest supine, carvedilol induced a reduction in ANP (27%) that could be viewed as a counterregulatory response to decrease in cardiac output, preventing excessive blood pressure reduction. ANP decreased (18%) when the patient sat up from the supine position and increased (67%) during exercise, but no further change was seen after acute or chronic carvedilol treatment. With the patient in the sitting position, norepinephrine was 110% higher than at rest supine; during 100-W exercise, norepinephrine increased 368%. A further increase (38-86% in the three situations, respectively) was seen after the first dose of carvedilol. Epinephrine showed similar but less marked changes. Neither extracellular fluid volume nor plasma volume (isotope dilution techniques) changed significantly during the study, but the acute blood pressure response to carvedilol was directly related to changes in extracellular fluid volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute haemodynamic effects of carvedilol in essential hypertension at rest and during exercise

The acute haemodynamic effect of carvedilol, a new non-selective beta-receptor blocker with vasodilating effect, was examined at rest supine and sitting and during 100 W bicycle exercise in 18 patients (mean age 44 years) with essential hypertension. Intra-arterial blood pressure and heart rate were recorded continuously. Cardiac output was measured by dye dilution (Cardiogreen). Two h after the first oral dose (12.5-25 mg) of carvedilol, blood pressure was reduced in all patients sitting at rest, from 176/110 to 153/101 mmHg (P less than 0.001), associated with a reduction in cardiac index (16%; P less than 0.001) while total peripheral resistance remained unchanged or was slightly reduced. When sitting up after 2 h supine rest two patients had hypotensive reactions (excessive blood pressure drop; cold, pale, sweating skin) which disappeared after lying down with elevation of the legs and light physical exercise. The fall in cardiac index was due to reduction both in heart rate (8%, P less than 0.001) and stroke index (9%; P less than 0.01). During exercise the reduction in cardiac output was less (6%; P less than 0.05) while a clear reduction (6%; P less than 0.01) was seen in total peripheral resistance. This acute haemodynamic response is different from that seen immediately after conventional beta-blockers when total peripheral resistance always increases.

Skin irritation induced by topically applied timolol.

1. Erythema induced by topically applied timolol, a non-selective beta-adrenoceptor blocker, was assessed in six male volunteers. Intensity of erythema developed on the inner surface of the left forearm where timolol free base was applied for 10 h was measured by a visual score, laser doppler flowmeter and reflectance spectrophotometry. Plasma timolol concentrations collected from the left and right arms were also measured. 2. The mean values for blood volume and blood flow per unit volume of tissue both of which were assessed by a laser doppler flowmeter, haemoglobin index measured by reflectance spectrophotometry, and magnitude of erythema graded by a visual score significantly increased after the application of an acrylic co-polymer adhesive patch containing 20% (w/v) timolol free base. 3. Plasma timolol concentrations collected from the left antecubital vein were 2.4 to 10.7 times greater than those from the right arm and had significant correlations (rs = 0.55 to 0.76) with the parameters indicating the extent of erythema developed where a patch containing timolol was applied. 4. The inter-individual variation of timolol was attributed to that of the diffusivity of timolol through skin rather than that of the skin reactivity to topically applied timolol because the plasma timolol concentrations drawn from the left arm in the subjects who did not develop erythema were very low.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the antihypertensive and renal effects of tertatolol and nadolol in hypertensive patients with mild renal impairment

The antihypertensive and renal haemodynamic effects of 5 mg/day tertatolol (T), a new nonselective and long-acting beta-adrenoceptor blocker, and 80 mg/day nadolol (N) in hypertensive patients with mild renal impairment have been compared in a randomized double-blind trial. Before and after 30 days of active treatment glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by use of a simultaneous i.v. bolus of 99mTc-DTPA and 131I-hippuran. Both T and N significantly decreased blood pressure and heart rate, and induced an insignificant increase in GFR and ERPF. There were no differences between the effect of the treatments on blood pressure and heart rate. Despite the persistent fall in BP and HR, renal function was maintained during both T or N treatment, suggesting that both drugs may act by a direct intrarenal vasodilator mechanism.

Effect of CGP 17/582, a selective beta‐adrenoceptor antagonist, on the haemodynamic and hypokalaemic response to adrenaline.

1. CGP 17/582B is a new beta-adrenoceptor antagonist which on experimental studies appears to combine selective beta 1-adrenoceptor blockade with partial agonist activity (ISA). Assessing beta-adrenoceptor selectivity and the degree of partial agonist activity in vivo can be difficult. 2. In a double-blind placebo controlled crossover study we have compared the effect of oral pretreatment for 7 days with CGP (100 mg twice daily), with propranolol (non-selective beta-adrenoceptor blocker with no ISA) and metoprolol (selective beta-adrenoceptor blocker with no ISA) on resting heart rate and heart rate response to submaximal exercise on a bicycle ergometer to assess the degree of beta-adrenoceptor blockade and also the changes in blood pressure, heart rate and potassium during the intravenous infusion of (-)-adrenaline to determine the degree of beta 2-adrenoceptor blockade. 3. Subjects underwent submaximal exercise testing on the second and fifth day of each treatment period and on the seventh day received a 2 h infusion of (-)-adrenaline (0.06 microgram kg-1 min-1). Heart rate, blood pressure, plasma potassium and catecholamines were measured throughout the study period. 4. All three active treatments significantly reduced exercise induced tachycardia. The (-)-adrenaline infusion significantly reduced plasma noradrenaline levels following propranolol and metoprolol and to a lesser extent with placebo but were unaltered on CGP. Baseline heart rate was unaltered by CGP but was significantly reduced by metoprolol and propranolol. Adrenaline significantly reduced plasma potassium levels following placebo and CGP pretreatment but plasma potassium was unaltered by adrenaline with metoprolol and propranolol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonselective Beta-Receptor Blocker Effect on High Density Lipoprotein Cholesterol After Chronic Exercise

High density lipoprotein (HDL) cholesterol changes were followed in 45 men with coronary heart disease who underwent 12 weeks of monitored aerobic exercise. Twenty-five patients who were taking a nonselective beta-receptor blocking drug (Group 1) did not demonstrate a significant change in HDL cholesterol after exercise (mean difference 2.8 +/- 11.5 mg/dl), whereas patients who had not received a beta-blocking drug for greater than or equal to 3 months (Group 2) showed a significant increase (mean difference 8.4 +/- 5.5 mg/dl; p less than 0.05). However, for those patients in each group who had an initial HDL cholesterol level less than 35 mg/dl before exercise, there was a significant increase in HDL cholesterol levels (mean difference 8 +/- 6.9 mg/dl [p less than 0.02] and 11 +/- 3 mg/dl [p less than 0.001] for Group 1 and Group 2, respectively) and a significant decrease in the low density lipoprotein (LDL/HDL cholesterol ratio (mean difference -1.2 +/- 1.6 [p less than 0.05] and -0.9 +/- 0.57 [p less than 0.001], respectively). Patients in both groups who started exercise with an HDL cholesterol level greater than 35 mg/dl did not show a significant change after exercise. Patients in Groups 1 and 2 achieved similar levels of exercise training after 12 weeks and were closely matched in age, medications, alcohol intake and smoking. The results indicate that among high risk patients (with an abnormally low HDL cholesterol level) exercise training can induce an augmentation of HDL cholesterol in those receiving a beta-blocking drug similar to that of patients not receiving such a drug.