The relationship of plasma levels of pindolol in hypertensive patients to effects on blood pressure, plasma renin and plasma noradrenaline levels

1. Fifteen, previously untreated, hypertensive patients were given 20 mg of pindolol, orally. The systolic and diastolic blood pressures fell significantly in 1 h; the effect was maximal 4 h after pindolol, and persisted for at least 8 h. 2. After oral administration of 20 mg of pindolol, its concentration in the plasma reached a peak in 2-3 h. At the end of 8 h, pindolol was not detectable in the plasma. 3. There was a significant relationship between the peak concentration of pindolol in plasma and the maximal change in blood pressure in fifteen previously untreated hypertensive patients. In a separate study of nine-nine hypertensive outpatients taking 15-80 mg of pindolol daily, the blood pressure responses corresponded generally to the concentration of pindolol in plasma 2-3 h after the morning dose. 4. There were no significant changes in plasma renin activity, plasma renin concentration or plasma noradrenaline concentration in the previously untreated patients taking 20 mg of pindolol. There was no relationship between initial plasma renin or noradrenaline levels and blood pressure responses to pindolol. Nor was there any significant relationship between the changes in plasma renin or noradrenaline levels and the changes in blood pressure.     

The effect of pindolol on plasma renin activity and blood pressure in hypertensive patients.

1 The effect of pindolol administered to twenty-six patients with hypertension of unknown origin was compared with respect to blood pressure and plasma renin activity change after increase of the dose over a period of 6 weeks. 2 There was no clear correlation between the fall of plasma renin activity, which in some patients was very marked, and the fall in blood pressure. Some patients with a fall in plasma renin activity did not drop their pressure. Conversely, some with a fall of pressure did not drop their plasma renin activity. 3 The addition of hydrochlorothiazide to the pindolol finally caused further lowering of the blood pressure in all but one patient and the plasma renin activity rose in all but two patinets. There was no clear correlation between change in plasma renin activity and the effect on blood pressure.     

Ventilatory effects of long-term treatment with pindolol and metoprolol in hypertensive patients with chronic obstructive lung disease.

Effects of long-term treatment with pindolol (10 mg twice daily) and metoprolol (100 mg twice daily) on lung function and blood pressure were investigated in eight patients with chronic obstructive lung disease and hypertension. After a placebo period, both beta-adrenoceptor blockers were administered double-blind and cross-over for 4 weeks. By assessing parameters of expiratory flow an attempt was made to distinguish between large and small airways function. Diastolic blood pressure decreased significantly during both pindolol and metoprolol (P less than 0.01). Except for a decrease in forced expiratory volume in 1 s (FEV1) during metoprolol treatment, there was no other change in expiratory flow parameters after placebo or both beta-adrenoceptor blockers. Inhalation of terbutaline induced a small improvement in large airways function after placebo and metoprolol, but not after pindolol; there was no effect of terbutaline on parameters of small airways function. If a beta-adrenoceptor blocker is necessary in patients with chronic obstructive lung disease, a beta 1-adrenoceptor selective blocker is preferred in combination with bronchodilator agents.     

Acute tolerance to the hypotensive effect of pindolol in spontaneously hypertensive rats (SHR)

The development and mechanism of acute tolerance to hypotension produced by pindolol in conscious SHR were examined. At a daily dose of 3 mg/kg, i.p., the hypotensive effect of pindolol (50 +/- 4 mmHg) on the first day was attenuated to 12 +/- 2 mmHg on the fourth day. The development of this acute tolerance was not reduced by combined administration with captopril or trichlormethiazide. The hypotensive effect of pindolol was not reduced by repeated administration of isoproterenol. Thus, activation of the renin-angiotensin system, fluid retention and beta-adrenoceptor subsensitivity seemed to be ruled out from the mechanism of this acute tolerance to pindolol. SHR tolerant to pindolol displayed marked hypotensive effects to prazosin, clonidine, hydralazine, nifedipine and captopril, which were similar to those in saline-treated SHR. However, the depressor response to isoproterenol was markedly reduced in SHR tolerant to pindolol. The correlation between the hypotensive responses to isoproterenol (X) and pindolol (Y) in these SHR could be expressed by: Y = 1.00 X + 0.56, gamma = 0.837 (P less than 0.001). Therefore, acute tolerance to pindolol seemed to be mainly due to "autoblockade" by the remaining pindolol in the body.     

The influence of pindolol and hydrochlorothiazide on blood pressure, and plasma renin and plasma lipid levels

After three weeks' administration of placebo, three groups of eight patients with moderate hypertension were randomly assigned to single daily dose, double-blind treatment with either pindolol 15 mg, hydrochlorothiazide 50 mg, or a combination of both for eight weeks. All determinations were made 24 hours after ingestion of a dose. Reductions in supine, sitting, and standing systolic and diastolic blood pressure were greater in patients receiving hydrochlorothiazide than in those administered pindolol; however, the greatest reductions were registered in individuals receiving combination therapy. Mean basal plasma renin activity rose significantly from 0.45 +/- 0.44 to 1.42 +/- 1.31 ng/mL/hr and from 0.67 +/- 0.46 to 1.27 +/- 0.83 ng/mL/hr in patients receiving hydrochlorothiazide and combination therapy, respectively, but there was no change in those administered pindolol. Hydrochlorothiazide and combination therapy increased mean total cholesterol levels from 247 +/- 25 to 263 +/- 37 mg/dL and 198 +/- 36 to 211 +/- 33 mg/dL, respectively, at eight weeks, and both increased mean triglyceride concentrations at two weeks. Pindolol did not show any tendency to alter lipid levels. Pindolol should be given twice daily. At 15 mg daily, it has little or no effect on basal plasma renin activity or plasma lipid levels.     

Effects and plasma levels of propranolol and metoprolol in hyperthyroid patients

Summary The effects and plasma concentrations of different doses of propranolol and metoprolol were studied in 34 hyperthyroid patients. The initial daily doses were propranolol 160 mg or metoprolol 200 mg. If the resting heart rate remained above 75 beats per min after treatment for 4–7 days, the dose was increased and the patient re-examined after a further 4–7 days. Propranolol (n=17) caused a reduced heart rate, a decrease in serum 3,3,5-triiodothyronine (T3) and an increase in serum 3,3,5-triiodothyronine (reverse T3, rT3). In 10 patients, there was no change in T3 or rT3 until the daily dose of propranolol had been increased to 240 or 320 mg. The plasma level of propranolol was significantly correlated with the decrease in T3 and the increase in rT3. Metoprolol (n=17) caused a reduction in heart rate similar to that following propranolol. However, serum T3 was only slightly reduced even after an increase in dose to 300 or 400 mg, and serum rT3 was not altered. Metoprolol concentrations were not significantly correlated with the fall in T3. It appears that the influence of-blockers on T4 conversion is of little importance for the clinical improvement in hyperthyroid patients, and rather it is a consequence of ₁-adrenergic blockade interfering with the effect of T3. In addition, the findings support the assumption that therapeutic failure with-blockers in hyperthyroidism may be due to suboptimal treatment, and that individualized dosage is necessary.     

The effect of hydralazine on steady-state plasma concentrations of metoprolol in pregnant hypertensive women

Summary We have studied the plasma concentrations levels of metoprolol after its twice daily administration in a dose of 50 mg for 4 days in ten, hypertensive pregnant women to the during monotherapy and in combination with 25 mg of hydralazine given twice daily.Hydralazine increased the median AUC and C_max of metoprolol by 38% and 88% respectively, and decreased the t_max from 1.5 h to 1.0 h.Hydralazine had no effect on the plasma concentrations of alpha-OH-metoprolol.These results suggest that the effect of hydralazine on metoprolol plasma concentrations is primarily due to a reduction in first-pass elimination.     

Effect of a single-dose of olanzapine on sleep in healthy females and males

The effect of a single dose of 10 mg olanzapine on healthy volunteers of both sexes was examined using polysomnography and power spectral analysis. The structure and continuity of sleep were unaffected by olanzapine in both sexes. The increase in both actual sleep time and slow wave sleep in females correlated with the increase in theta power, while delta power was not significantly elevated, suggesting that theta power may be a sensitive indicator of changes in sleep. The changes in sleep had the same tendency in men, but they were not significant. The difference between the sexes could not be explained by differences in body mass index. Olanzapine affects sleep probably through 5-HT(2C) receptors. The receptor gene is located on the X-chromosome, inducing an allelic difference between the females and males. This difference may contribute to the different effects of olanzapine on sleep. Olanzapine seems to preserve the normal structure of sleep and increase the amount of slow-wave sleep, which might be of additional benefit in treatment of schizophrenia. The effective clinical dose may be lower for females than males.     

Effect of metoprolol and propranolol on platelet aggregation and cAMP level in hypertensive patients

Summary Ten patients with uncomplicated moderate essential hypertension were recruited to evaluate the effect of the non-selective beta-blocker propranolol and the beta₁-selective beta-blocker metoprolol on platelet aggregation and cAMP formation. Five patients began treatment with propranolol 80 mg b. i. d. and 5 with metoprolol 100 mg b. i. d., and after 2 weeks the treatments were exchanged. ADP- and adrenaline-induced platelet aggregation and the basal level of platelet cAMP were measured at the end of each treatment period. Platelet aggregation was tested turbidometrically, using the threshold value for irreversible aggregation, and cAMP measurements were performed using a protein-binding assay.Both ADP and adrenaline thrshold values were significantly lower after propranolol than after metoprolol.The basal cAMP level was lower during propranolol than metoprolol treatment.The results indicate that platelet aggregation and basal cAMP level are influenced by beta-blockers in proportion to their affinity to different beta-adrenoceptors. This may be of value in the beta-blocker treatment of patients at high thrombotic risk.     

甲氧乙心安及吲哚洛尔对大鼠心肌及尿中去甲肾上腺素和肾上腺素含量的影响

给大鼠连续7d(dl—d7)sc吲哚洛尔200μg/kg·d或甲氧乙心安12.5mg/kg·d,用荧光分光法测心肌及尿中NA及A的含量。在d2及d6吲哚洛尔分别使心肌中NA降到正常值的69％及19％(p<0.01),A的变化相仿。尿中NA在d2亦降低。停药后尿中NA反而比正常增多(p<0.001)。甲氧乙心安在d2使心肌中NA降低(p<0.01),d6时增多(p<0.01)。d2尿中NA增多,但停药后未见反跳现象。讨论了吲哚洛尔与甲氧乙心安对组胺中NA影响的差别,与吲哚洛尔的内在活性及甲氧乙心安的β_1选择性的关系。     

Transdermal clonidine (Catapres-TTS) monotherapy in the management of mild hypertension in general practice

The efficacy and patient acceptance of transdermal clonidine applied once a week were assessed in 62 mild hypertensives previously controlled on a diuretic and/or beta-blocker in a general practice setting involving 18 general practitioners. Patients underwent 3-5 week wash-out period and those patients whose mean seated diastolic blood pressure returned to levels between 91-105 mmHg or increased by greater than 10 mmHg above the initial value, were titrated with transdermal clonidine (Catapres-TTS-1, 2, or 3) and maintained on the optimal dose for 3 months with monthly check-ups. Satisfactory response of blood pressure to levels below 90 mmHg or greater than 10 mmHg reduction from the wash-out level was obtained in 85% of patients who completed the titration phase; nine patients failed to achieve a satisfactory blood pressure control. There was no significant difference in blood pressure response between previous therapy and transdermal clonidine treatment. Systemic side effects were minimal. Eight patients withdrew because of local allergic contact dermatitis. This study confirms that transdermal clonidine is at least as effective in reducing blood pressure as diuretic and/or beta-blocker therapy.     

Effect of statin therapy on plasma high-density lipoprotein-cholesterol levels is modified by paraoxonase 1 in Chinese patients with coronary heart disease

1. We sought to determine the effects of Q192R polymorphism of paraoxonase 1 (PON1) gene on plasma high-density lipoprotein-cholesterol (HDL-C) levels and the response to statin therapy in Chinese patients with coronary heart disease (CHD). 2. Two hundred and thirty-six patients with CHD were treated with simvastatin 20 mg/day. Fasting serum lipids were determined before and after 12 weeks of treatment. 3. No significant differences were detected among the PON1 Q192R polymorphism with respect to plasma lipids. In addition, the effects of simvastatin to increase HDL-C levels were significantly greater in patients with the RR genotype compared with patients with the QR or RR genotypes (P < 0.05). 4. We conclude that the Q192R polymorphism of PON1 significantly modulates the HDL-C response to simvastatin in Chinese patients with CHD.     

Effect of alpha-lipoic acid on the peripheral conversion of thyroxine to triiodothyronine and on serum lipid-, protein- and glucose levels.

The influence of alpha-lipoic acid (LA, thioctic acid, CAS 62-46-4) on thyroid hormone metabolism and serum lipid-, protein- and glucose levels was investigated. In the first setup of experiments administration of LA together with thyroxine (T4) for 9 days suppressed the T4 induced increase of T3 generation by 56%. This suppression was similar to that affected by 6-propylthiouracil (54%). LA or T4 alone did not affect the cholesterol level, but together they led to a reduction. LA decreased the triglyceride level by 45%; the decrease induced by T4 or LA plus T4 was not significant. Total protein and albumin levels decreased by LA plus T4 treatment when compared to the LA control. The slight increase in glucose level by LA or T4 alone was not observed when they were administered together. In the second setup of experiments the administration of T4 for 22 days increased the serum T3 level 3-fold. When LA was combined with T4 and the treatment continued, the T3 production decreased by 22%. T4 reduced cholesterol level by 30%, and LA plus T4 further reduced it by 47%. The triglycerides were not affected. A moderate decrease in total protein was observed after treatment with T4 plus LA; T4 and LA plus T4 decreased the albumin level. The decrease in serum glucose by T4 recovers by LA treatment. These results demonstrate that LA interferes with the production of T3 from T4 when it is co-administered with T4. The elevated level of T3, after T4 administration, is reduced by treatment with LA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of simvastatin (MK-733) on plasma triacylglycerol levels in rats

The effect of simvastatin (MK-733), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on plasma triacylglycerol (TG) levels was studied in rats. Dietary administration of MK-733 (0.055%, w/w) for 7 days significantly (P less than 0.05) reduced plasma TG levels by 30.6% associated with a 44.3% significant (P less than 0.01) reduction in very low density lipoprotein TG (VLDL-TG) as compared to those in the concurrent control rats. Clofibrate (0.08%, w/w) also significantly (P less than 0.05) decreased plasma TG levels by 26.1%. MK-733 did not affect the triacylglycerol secretion rate (TGSR) during 0-1.5 hr after administration of Triton WR-1339, but reduced it by 33.9% during 1.5-3.0 hr. Clofibrate also decreased TGSR during 1.5-3.0 hr. MK-733 increased lipoprotein lipase (LPL) activity in epididymal adipose tissue and thigh muscle by 36.3 and 55.0% respectively. MK-733 significantly (P less than 0.05) increased LPL activity in the post-heparin plasma by 21.5%, although it did not affect hepatic triacylglycerol lipase (H-TGL) activity. Clofibrate did not affect LPL activity in the tissues or LPL and H-TGL activities in the post-heparin plasma. It is considered that the mechanism of plasma TG-lowering effect of MK-733 is the removal of VLDL-TG by an increase in LPL activity in the tissues as well as a decrease in the TGSR.     

Effect of Buthus minax (L. Koch) scorpion venom on plasma and urinary electrolyte levels

B. minax venom was injected into rats in a total dose equal to the ld₅₀ and divided into five doses (days 0, 1, 3, 4, 5). The venom caused a significant decrease in urine volume in days 1, 2, 4, 5 and 6 with an increase on day 3. The oliguria was suggested to be due to the release of the antidiuretic hormone secondary to acetylcholine release by the venom and anticholinesterase activity of the venom. Urinary sodium and potassium were significantly decreased the first day of venom injection possibly due to stress and secondary shock resulting from acute adrenal insufficiency. In the subsequent days of venom injection urinary sodium was significantly decreased and that of potassium significantly increased. The effect was suggested to be due to secretion of aldosterone. Urinary calcium was significantly decreased and phosphate significantly increased. A parallelism was found between the urinary excretion of sodium and calcium. The effect was suggested to be partly due to decreased calcium absorption from the intestine as the venom significantly decreased the in vitro absorption of calcium through the everted rat duodenum.     

UGT1A polymorphisms in a Swedish cohort and a human diversity panel, and the relation to bilirubin plasma levels in males and females

Objectives The objective of this study was to investigate the prevalence of different polymorphisms and haplotypes associated with individual variations in pharmacokinetics and drug toxicity in the uridine-diphosphate glucuronosyl transferase (UGT) 1A gene in a Swedish cohort (248 healthy volunteers) and in 14 different ethnic groups. We also estimated UGT1A genotype-dependent glucuronidation efficiency using the endogenous substrate bilirubin as an indicator.Methods Pyrosequencing-based genotyping assays were used to determine the different polymorphisms and haplotypes.Results Haplotype analysis of the UGT1A1 (*1*28), UGT1A6 (*1*2), and UGT1A7(*1*2*3*4) allelic variants showed that three major haplotypes constituted 84% of the allelic variants in the cohort. We identified 15 haplotypes altogether from all groups, including previously undescribed haplotypes.Testing for the association of genotype and total bilirubin levels (nonfasting) in plasma disclosed that homozygous carriers of the TA allele, irrespective of haplotype combinations, had increased levels of bilirubin compared with noncarriers, but a gender-associated difference was observed.Conclusions In a Swedish cohort, several genetic variants in the UGT1A gene are common, but prevalence in a population may differ because of ethnicity. A phenotype based on bilirubin levels has limitations in serving as an indicator of pharmacogenetic differences in glucuronidation due to the influence of gender. Because of possible substrate overlap regarding different UGT1A isoforms, determination of haplotypes of potential cis-acting polymorphisms in the UGT1A gene should be considered in pharmacogenetic association studies regarding drugs that undergo glucuronidation.     

Blockade of isoprenaline-induced changes in plasma free fatty acids, immunoreactive insulin levels and plasma renin activity in healthy human subjects, by propranolol, pindolol, practolol, atenolol, metoprolol and acebutolol

1 The effects of intravenously administered propranolol 0.01 and 0.03, pindolol 0.001 and 0.003, practolol 0.12 and 0.36, atenolol 0.03 and 0.09, metoprolol 0.045 and 0.135 and acebutolol 0.12 and 0.36 mg/kg, on isoprenaline-induced changes in heart rate, blood pressure, plasma free fatty acids, immunoreactive insulin plasma levels and plasma renin activity were determined in six healthy human subjects.

2 Propranolol, atenolol and metoprolol had a stronger effect on resting heart rate than practolol, acebutolol and pindolol, probably reflecting differences in intrinsic β-sympathomimetic activity. Antagonist potencies against isoprenaline-induced changes in heart rate and blood pressure suggested cardioselectivity for practolol, atenolol, metoprolol and the lower dose of acebutolol and non-cardioselectivity for propranolol, pindolol and the higher dose of acebutolol.

3 All six β-adrenoceptor blocking agents were able, to a varying extent, to antagonize the isoprenaline-induced increases in plasma free fatty acids and plasma immunoreactive insulin levels. In general, the cardioselective agents were relatively less effective antagonists than the non-cardioselective agents.

4 Resting plasma renin activity was reduced by all six β-adrenoceptor blocking agents, suggestive of the presence of β₁-adrenoceptors mediating renin release, but the non-cardioselective agents propranolol and pindolol seemed relatively more effective in antagonizing isoprenaline-induced increases in plasma renin activity than the cardioselective agents, which indicates that β₂-adrenoceptors might also be involved.

5 The results are compatible with the hypothesis that both β₁- and β₂-adrenoceptors are involved in the regulation of lipolysis, insulin release and renin release.

     

Studies on the cardiovascular effects of pindolol in DOCA/saline hypertensive rats

1 A hypotensive response to orally administered pindolol in conscious normotensive and deoxycorticosterone acetate (DOCA)/saline hypertensive rats (DS-rats) is described. In DS-rats, pindolol (10-50 μg/kg) produced a dose-dependent fall in blood pressure and elevation of resting heart rate.

2 The hypotensive response and tachycardia produced by oral pindolol (50 μg/kg) in DS-rats were prevented by propranolol (5 mg/kg), suggesting that pindolol's effects are mediated by β-adrenoceptor stimulation.

3 After mecamylamine (10 mg/kg), oral pindolol (50 μg/kg) produced a further fall in blood pressure in DS-rats, suggesting that its hypotensive effects are probably mediated in the peripheral vasculature.

4 Pretreatment with oral pindolol (10 or 50 μg/kg) resulted in a reduction of neuronally-induced tachycardia in pithed DS-rats; neuronally-evoked pressor effects were also antagonized by pindolol (50 μg/kg, orally).

5 Whereas pindolol, 50 μg/kg orally or intraperitoneally, produced a marked and progressive hypotensive response of rapid onset (20 min) in DS-rats the same dose intravenously produced a smaller response of delayed onset (80 minutes).

6 In anaesthetized DS-rats, an equivalent degree of cardiac β-adrenoceptor blockade was produced by pretreatment with pindolol, 50 μg/kg orally (2 h previously) or intravenously (1 h previously).

7 After administration of pindolol, 2 mg/kg intravenously, to conscious DS-rats, the tachycardia produced by intravenous isoprenaline, 3 μg/kg, was almost abolished for the first 60 min of the study, whereas a hypotensive response to pindolol was delayed in onset (100 minutes).

8 The hypotensive response and tachycardia produced by oral pindolol 50 μg/kg, in DS-rats were prevented by inhibition of metabolic enzyme activity by pretreatment with Proadifen (SKF 525-A), 80 mg/kg.

9 The results suggest that pindolol's effects on blood pressure and heart rate in the conscious DS-rat are mediated by a metabolite(s) acting by stimulation of peripheral β-adrenoceptors.