Effects Of Nadolol Research Articles

396. ‘Nadolol use in pregnancy and Small for Gestational Age (SGA) newborns at term: a case series’.

Introduction Nadolol, a hydrophilic, long-acting, non-selective beta-blocker, is commonly used to treat congenital long QT-syndrome (LQTS) in non-pregnant adults. Nadolol is efficacious in both primary and secondary prevention of cardiac events in non-pregnant adults with LQTS [1] . Recent evidences suggests Nadolol may be superior to other beta-blockers at preventing cardiac events in these patients and hence more women are continuing Nadolol during pregnancy. The current published data regarding Nadolol in pregnancy is limited to a single case and suggests that use during pregnancy may be associated with SGA of the fetus [2] . This case series will contribute to the literate on the possible effects of Nadolol on the fetus and assist with counselling women. Case series This case series describes three pregnancies in two mothers treated with Nadolol for LQTS during pregnancy. In all three cases, the newborns were SGA with birth weights below the 10th percentile at term using Fenton growth charts. The mothers were non-smokers and had no other significant medical history. Informed consent from both women was obtained prior to publication. Discussion This case series suggests a possible association between Nadolol use in pregnancy and SGA at term. Adding Nadolol to a cardiac registry may be helpful to further define its implications on pregnancy outcome.

Green Tea Ingestion Greatly Reduces Plasma Concentrations of Nadolol in Healthy Subjects

This study aimed to evaluate the effects of green tea on the pharmacokinetics and pharmacodynamics of the β-blocker nadolol. Ten healthy volunteers received a single oral dose of 30 mg nadolol with green tea or water after repeated consumption of green tea (700 ml/day) or water for 14 days. Catechin concentrations in green tea and plasma were determined. Green tea markedly decreased the maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC(0-48)) of nadolol by 85.3% and 85.0%, respectively (P < 0.01), without altering renal clearance of nadolol. The effects of nadolol on systolic blood pressure were significantly reduced by green tea. [(3)H]-Nadolol uptake assays in human embryonic kidney 293 cells stably expressing the organic anion-transporting polypeptides OATP1A2 and OATP2B1 revealed that nadolol is a substrate of OATP1A2 (Michaelis constant (K(m)) = 84.3 μmol/l) but not of OATP2B1. Moreover, green tea significantly inhibited OATP1A2-mediated nadolol uptake (half-maximal inhibitory concentration, IC(50) = 1.36%). These results suggest that green tea reduces plasma concentrations of nadolol possibly in part by inhibition of OATP1A2-mediated uptake of nadolol in the intestine.

Effect of nadolol, a beta-adrenoceptor blocking agent, on myocardial metabolism in the dog ischaemic heart.

The effect of nadolol at a dose of 1 mg kg-1, i.v. on the ischaemic myocardial metabolism has been examined in the dog. Ischaemia was induced by ligating the left anterior descending coronary artery for 3 min, and nadolol was injected 5 min before ligation. Ischaemia caused myocardial metabolic changes; it decreased energy charge potential and inhibited glycolytic flux through phosphofructokinase reaction. Pretreatment with nadolol lessened the decrease in energy charge potential and the inhibition of glycolytic flux being caused by ischaemia. Nadolol may have a beneficial effect on the ischaemic myocardium.

The effects of acute and chronic nadolol treatment on β2AR signaling in HEK293 cells.

Nadolol (NAD) is a β-adrenergic receptor blocker with inverse agonist activity at βARs. Previous studies in our laboratory showed that chronic treatment with NAD decreased airway resistance response (R (aw)) to the muscarinic agonist methacholine in a murine model of asthma while acute treatment with NAD increased R (aw) (Callaerts-Vegh et al., Proc Natl Acad Sci U S A 101:4948-4953, 2004). Chronic treatment with NAD also caused decreased airway inflammation and mucin content in a murine asthma model (Nguyen et al., Am J Respir Cell Mol Biol 38:256-262, 2008). In this study, we examined the effects of nadolol on β(2)AR levels and signaling components downstream of the β(2)AR using a line of HEK293 cells expressing human β(2)ARs. Chronic treatment with NAD increased β(2)AR protein levels and decreased receptor degradation, consistent with receptor stabilization by the inverse agonist. Basal cAMP levels decreased after 5min of treatment with NAD but increased after a 24-h treatment. A 5-min treatment with NAD decreased forskolin-stimulated phosphorylation at the β(2)AR PKA site Ser 262 while a 24-h treatment with NAD increased it. In contrast, chronic treatment with NAD had no effect on phosphorylation of the β(2)AR GRK site at Ser 355, 356. Chronic treatment with NAD upregulated cellular levels of G(α)s but had no effect on G(α)i. Chronic NAD treatment therefore increases cellular cAMP levels by mechanisms that include the upregulation of β(2)AR and G(α)s. This effect may explain in part the beneficial effects of chronic nadolol treatment on airway contractility.

Investigation of the inverse agonism effect of nadolol on the Gs signaling pathway

Nadolol is a nonselective beta‐adrenergic receptor (¦ÂAR) blocker with inverse agonist activity at ¦Â2‐ARs. Previous studies in human embryonic kidney 293 cells over‐expressing human ¦Â2AR showed an initial increase in the number of inactive state of receptors (R) after acute nadolol treatment, and an increase in the number of active state of receptors (R*) with decreased receptor degradation after chronic treatment. In this study, further experiments indicated that chronic treatment with isoproterenol significantly decreased cellular level of Gs while chronic nadolol treatment had no effect. In organ bath experiments using the tracheal rings from an asthmatic mouse model we investigated the effects of nadolol on other Gs‐coupled receptors. Nadolol treatment produced an enhanced relaxation response mediated by the prostacyclin receptor (IP) agonist cicaprost and prostaglandin E2 receptor (EP2) agonist CAY 10399, in addition to the ¦ÂAR agonist isoproterenol. In isolated airway smooth muscle cells, western blot data suggested chronic treatment with nadolol increased the levels of IP and EP2 receptors. These data suggest that nadolol enhances Gs signaling through the ¦Â2‐AR, IP and EP2 receptors and this enhancement of bronchorelaxant responses may contribute to the beneficial effects of chronic nadolol treatment in murine asthma model.

Effects of Nadolol and Its Combination With Atrial Pacing on Rate-Enhanced Ventricular Premature Complexes

Effects of Nadolol and Its Combination With Atrial Pacing on Rate-Enhanced Ventricular Premature Complexes

Effects of nadolol and its combination with atrial pacing on rate-enhanced ventricular premature complexes

Heart rate plays a prominent role in the genesis of tachycardia-enhanced VPCs because the administration of a β blocker reduces the arrhythmias, and atrial pacing restores them.

Holter-guided identification of premature ventricular contractions susceptible to suppression by β-blockers

To evaluate whether the identification of the different types of relations between premature ventricular contractions (PVCs) and the preceding sinus cycle length is capable of predicting the effect of β-blockers on the PVCs themselves, 55 patients (43 men, 12 women, mean age 52.6 ± 15.6 years) with different cardiac diseases, and >30 PVCs/hr characterized by stability and the same relation at two Holter monitoring periods were studied. The relation was tachycardia enhanced (the shorter the preceding cycle length, the higher the incidence of PVCs) in 23 patients (group 1); indifferent (no correlation between the preceding cycle length and PVC incidence) in 21 (group 2); and bradycardia enhanced (the longer the preceding cycle length, the higher the incidence of PVCs) in 11 (group 3). A third Holter monitoring was performed 6 days after nadolol administration (80 mg/day) to evaluate its effect on the three types of PVCs. In group 1, nadolol caused a reduction in the PVC incidence in all patients (−88%; p < 0.001). In group 2, it caused a reduction in the majority of patients (−60%; p < 0.05) but an increase in five. In group 3, it caused a reduction in only half of the patients (−45%) and a 91% increase in the remainder. The difference in the effect of nadolol in the three groups was highly significant ( χ 2 = 27.5; p < 0.0001). The relation between the incidence of PVCs and the preceding cycle length is a useful means of identifying subsets of patients with PVCs who will benefit from β-blockers.

Duplex doppler ultrasound evaluation of acute and chronic effects of nadolol on porto-hepatic and renal hemodyuamics in portal hypertensive patients

Duplex doppler ultrasound evaluation of acute and chronic effects of nadolol on porto-hepatic and renal hemodyuamics in portal hypertensive patients

The effect of nadolol on heart rate and the standard deviation of the RR intervals

The aim of this study was to evaluate the effect of nadolol in modifying the standard deviation of RR intervals (SDRR) and the coefficient of variance (CV) in 47 patients characterized by symptomatic, frequent (> 30 h-1) and reproducible premature ventricular contractions (PVCs). Sixteen patients had suffered a previous myocardial infarction (Group 1), 22 had various non-ischaemic cardiac diseases (Group 2) and nine had no heart disease (Group 3). All patients underwent two 24 h Holter recordings during the washout period, and a third Holter recording was taken 5 days after the administration of nadolol (80 mg.day-1). The RR cycle length (RR), SDRR and CV were evaluated for each 24 h period, as well as for six daytime (1000-1600h) and six night-time hours (0000-0600h). In all three groups, nadolol was highly effective in lengthening RR. However, the effect on SDRR was different in the three groups; 24-h SDRR tended to be reduced in all three groups (but the reduction was significant only in Group 1) due to a certain RR homogeneity. On the other hand, daytime SDRR tended to increase (but the increase was significant only in Group 3). CV is concomitantly affected by heart rate and SDRR, therefore it may be more sensitive in evaluating the effect of beta-blockers. The reduction in CV post-nadolol means that the bradycardia-induced effect is associated with an inadequate increase, or even a reduction in SDRR, whereas the absence of any CV changes (found only in Group 3) is the result of a concomitant increase in both RR cycle length and SDRR.(ABSTRACT TRUNCATED AT 250 WORDS)

Portal hemodynamic effects of nadolol and nadolol plus isosorbide-5-mononitrate in patients with portal hypertension: A study based on hepatic vein catheterization and duplex doppler ultrasonography

Portal hemodynamic effects of nadolol and nadolol plus isosorbide-5-mononitrate in patients with portal hypertension: A study based on hepatic vein catheterization and duplex doppler ultrasonography

Divergent effects of nadolol and propranolol in isolated perfused mesenteric arterial beds of normal and portal hypertensive rats

Divergent effects of nadolol and propranolol in isolated perfused mesenteric arterial beds of normal and portal hypertensive rats

Duplex doppler ultrasound evaluation of chronic effects of nadolol on porto-hepatic and renal hemodynamics in portal hypertensive patients

Duplex doppler ultrasound evaluation of chronic effects of nadolol on porto-hepatic and renal hemodynamics in portal hypertensive patients

Echo-Doppler evaluation of splanchnic and renal effects of nadolol (N) and isosorbide-5-mononitrate (I5M) in cirrhotics

Echo-Doppler evaluation of splanchnic and renal effects of nadolol (N) and isosorbide-5-mononitrate (I5M) in cirrhotics

Effect of Nadolol on Plasma Lipids in Hyperthyroidism

The effect of Nadolol treatment on lipid subfractions in a group of 23 hyperthyroid patients was assessed in a randomised double-blind placebo controlled trial lasting six weeks, carbimazole being given to both groups from weeks 2 to 6. Clinical and biochemical euthyroidism was seen in both groups at 6 weeks; no effect of nadolol on peripheral monodeiodination of T4 to T3 was observed. At time 0 there were significant negative correlations between total cholesterol and free T3 (r = 0.68), and free T4 (r = 0.54). In the Nadolol group there were significant rises between 0 and 6 weeks in total cholesterol (52.6%, P less than 0.01), LDL cholesterol (30.3%, P less than 0.01) and HDL cholesterol (18.2%, P less than 0.05). HDL cholesterol rose significantly in the placebo group (12.4%, P less than 0.05) but there were no significant increases in LDL cholesterol or total cholesterol. The rise in triglyceride during this period in the Nadolol group (64.7%, P less than 0.05) was significantly greater (P less than 0.05) than the rise in the placebo group (8.8%). Nadolol increases triglyceride more than placebo during the early management of hyperthyroidism.

Effect of nadolol on flushing reactions in rosacea

The effect of nadolol versus placebo on both flushing provoked in a laboratory setting and spontaneous flushing was studied in 15 patients with erythematous telangiectatic rosacea. The intensity of the flushing reactions was assessed in the laboratory by the cutaneous perfusion index method with laser-Doppler velocimetry. No effect of nadolol on the flushing reactions provoked in the laboratory was detected.

EFFECTS OF NADOLOL ON ARRHYTHMIAS DURING LAPAROSCOPY PERFORMED UNDER GENERAL ANAESTHESIA

Cardiac arrhythmias are a well recognized complication of anaesthesia for laparoscopy. The effect of nadolol, given by mouth 12 h before operation, was compared with placebo on arrhythmias in 86 females undergoing laparoscopy. All types of arrhythmia were documented; there was a 97% incidence in the placebo group, but in the nadolol group there was a smaller incidence of supraventricular tachycardia, ventricular ectopics and atrioventricular dissociation (P less than 0.01). There was no significant difference in the incidence of sinus bradycardia. Nadolol may be recommended as a safe agent to be given by mouth before laparoscopy to reduce the frequency of cardiac arrhythmias during anaesthesia.

Effects of nadolol on blood pressure, sleep efficiency, and sleep stages.

The effects of nadolol (20 and 80 mg) on blood pressure and sleep parameters were assessed in six patients with mild hypertension. A 32-night experimental protocol in the sleep laboratory was instituted consisting of four placebo-baseline nights followed by 4 weeks of drug administration. Both doses of nadolol had a clear-cut and consistent lowering effect on blood pressure throughout the night and during the day, with a greater reduction noted with the 80 mg dose. In fact, blood pressure values were reduced to normotensive levels. Neither dose had a disrupting effect on sleep, whereas the 80 mg dose improved sleep efficiency and also had a rapid eye movement-enhancing effect. This absence of sleep-disrupting effects is attributed to nadolol's low level of lipophilicity and lack of intrinsic sympathomimetic activity. The clinical significance of the lack of sleep disruption and possible improvement of sleep with nadolol is discussed in light of the well-recognized sleep disturbances produced by other beta-blockers.

Developmental changes in the effects of nadolol on adult and neonatal canine Purkinje fibers.

We used standard microelectrode techniques to determine developmental differences in the direct membrane and beta-blocking effects of nadolol on the electrophysiologic properties of adult and neonatal canine Purkinje fibers (PF). To study direct membrane effects, we superfused PF with nadolol 1 X 10(-8)-1 X 10(-4) M while stimulating them at a BCL of 800 ms. Nadolol less than 1 X 10(-5) M had no effect on the transmembrane potential in either age group. Nadolol, greater than or equal to 1 X 10(-5) M, increased action potential duration at 100% repolarization (APD100) in adult fibers and nadolol, 1 X 10(-4) M, decreased Vmax and APD at 50% repolarization (APD50) in neonatal fibers (p less than 0.05). The beta-blocking effects of nadolol were studied by examining the chronotropic response in automatic PF to cumulative doses of l-isoproterenol.HCl 3 X 10(-10)-3 X 10(-6) M, alone and then in the continued presence of nadolol 5 X 10(-8)-5 X 10(-6) M. Nadolol caused a concentration-dependent shift to the right of the concentration-response curve in both age groups. pA2 determinations in adult (7.88) and neonatal (7.57) PF indicated that there was no developmental difference in the affinity of nadolol for the beta-receptor (p greater than 0.05). Our results indicate that nadolol shows developmental changes in its direct membrane effects but not its beta-blocking effects. The latter characteristic differs from that of the more highly lipid-soluble beta-blocker, propranolol. This suggests that different beta-blocking molecules have differing abilities to block the beta-receptor at different ages that are influenced importantly by their lipid solubility.

A Comparison of Betaxolol and Nadolol on Renal Function in Essential Hypertension

Betaxolol, a beta 1-selective adrenergic antagonist, and nadolol, a nonselective beta-adrenergic antagonist are both potent long-acting antihypertensive drugs. The effects of betaxolol on renal function have not been reported. The effects of nadolol on renal function are controversial. The current randomized double-blind study was designed to compare the effects of betaxolol and nadolol on glomerular filtration rate, assessed by creatinine and inulin clearances, and renal hemodynamics, assessed by p-aminohippurate clearance. Following a 4-week placebo run-in period, 15 patients with essential hypertension were randomized to a mean dose of 22 mg betaxolol for 12 weeks, and 12 patients with essential hypertension were randomized to a mean dose of 103 mg nadolol for 12 weeks. Results indicate that neither drug produced a clinically relevant effect on renal function. These findings are consistent with previously reported observations with other beta-adrenergic blocking drugs. We conclude that neither of the beta-adrenergic antagonists, betaxolol or nadolol, convey a specific renal pharmacologic advantage; both are equally efficacious and safe in the treatment of mild-to-moderate essential hypertension.