THE EFFECTS OF PROPRANOLOL, PRACTOLOL AND METOPROLOL ON EXERCISE-INDUCED TACHYCARDIA IN RELATION TO PLASMA LEVELS IN MAN

1. The effects of single oral doses of propranolol, practolol and a new cardio-selective β-adrenoceptor blocking drug, metoprolol, on exercise-induced tachycardia in relation to plasma levels were studied in six normal volunteers. 2. Exercise undertaken on treadmill was submaximal which, under control conditions, increased the heart rate from 74·3 (s.e.m. = 6·8) to 153·8 (s.e.m. = 9·8) beats/min. 3. Plasma concentrations of propranolol and practolol were assayed fluoro-metrically and of metoprolol by electron-capture gas liquid chromatography, the details of which are described. 4. Between 1·5 and 2 h after drug ingestion 80 mg of propranolol associated with plasma level of 50–60 ng/ml (half-life 2·75 h), reduced the exercise-induced tachycardia by 27%, 250 mg of practolol with plasma levels of 1050–1100 ng/ml reduced it by 28% and 100 mg of metoprolol with plasma concentrations of 140–150 ng/ml (half-life 1·7 h), reduced it by 30%. 5. The resting heart rates were reduced significantly by propranolol and metoprolol but not by practolol. 6. Metoprolol is a potent short-acting β-adrenoceptor antagonist; its advantages as a cardioselective agent over practolol in therapeutic use are discussed.     

CARDIAC AND BRONCHIAL β-ADRENOCEPTOR ANTAGONISTIC POTENCIES OF ATENOLOL, METOPROLOL, ACEBUTOLOL, PRACTOLOL, PROPRANOLOL AND PINDOLOL IN THE ANAESTHETIZED DOG

1. The β-adrenoceptor antagonists atenolol, metoprolol, acebutolol, practolol, propranolol and pindolol have been tested for their ability to reduce isoprenaline-induced bronchodilation and tachycardia in the anaesthetized dog. 2. Atenolol, metoprolol, acebutolol and practolol all possessed a similar degree of cardioselectivity in this animal model.     

EFFECTS OF PROPRANOLOL ON DEVELOPMENT AND MAINTENANCE OF SEVERE RENAL HYPERTENSION IN RATS

1. The effect of chronic administration of propranolol on the development and maintenance of severe renal hypertension in rats subjected to unilateral renal artery constriction was studied in relation to possible changes in peripheral PRA and the blood and tissue levels of propranolol. Propranolol was administered s.c. twice daily in doses of 1, 10 and 25 mg/kg, starting 2 days before operation. 2. Contrary to expectations, not only did the initial rise in systolic blood pressure become accelerated, but the established level of hypertension attained in the propranolol treated rats was of the same severity as that attained in placebo treated rats. Moreover, the progressive rise in peripheral plasma renin activity following unilateral renal artery constriction was not affected by propranolol administration. 3. The same doses of propranolol were also administered daily for 8 days to rats with established severe hypertension. A slight further rise in blood pressure occurred initially, followed by a moderate decrease of 15–25 mmHg. Propranolol failed to exert this minor hypotensive effect in hypertensive rats treated concomitantly with furosemide. No suppressive effect on the markedly increased levels of plasma renin activity was observed in these severely hypertensive rats in the presence or absence of furosemide administration. 4. These results indicate that in severely renal hypertensive rats propranolol has only a minor hypotensive effect and no blocking action on renin release under the conditions of study.     

PLASMA PHOSPHOLIPASE A2 ACTIVITY IN CLINICAL ACUTE MYOCARDIAL INFARCTION

1. Phospholipase A2 (PLA2) cleaves phospholipids to produce a lyso-phospholipid and free fatty acid and, in view of the biological activity of the products, PLA2 may play a role in many disease states. Lyso-phospholipids and free arachidonic acid increase in ischaemic myocardium, indicating that ischaemia activates the enzyme. 2. Plasma PLA2 activity was measured in patients with acute myocardial infarction, based on the release of labelled arachidonic acid from Escherichia coli cell membrane. Fourteen males (peak serum creatine phosphokinase (CK) above twice upper normal) were studied on day 1 (within 6 h of chest pain onset), days 2-4, and days 6-9. Normal age matched males (n = 13) were also studied. 3. Plasma PLA2 in patients with uncomplicated myocardial infarction (n = 12) was, initially, 1.14 +/- 0.10 (s.e.m.) nmol/min per mL plasma, similar to that in the normal group (1.52 +/- 0.14). On days 2-4, PLA2 activity increased to 1.94 +/- 0.18 (P less than 0.001) and this activity was correlated with the earlier peak CK level (P less than 0.02). On days 6-9, PLA2 activity was 1.49 +/- 0.13 while in two patients who developed complications and underwent open-heart surgery between the last two measurements, there were further increases to 4.22 and 4.04 nmol/min per mL. 4. The increase in plasma PLA2 in uncomplicated myocardial infarction is likely to be due to release from the damaged myocardium; whether it contributes to pathophysiology is uncertain.     

THE EFFECT OF INHALED FENOTEROL AND IPRATROPIUM BROMIDE ON PROPRANOLOL INDUCED BRONCHOCONSTRICTION IN THE ASTHMATIC AIRWAYS

1. The provocative dose of inhaled propranolol, (PC20P, mg/mL) needed to induce a 20% reduction in the forced expired volume in 1 s (FEV1, L) was determined for 15 adult asthmatics following randomized pre-treatment with placebo, ipratropium bromide (40, 160 micrograms) and fenoterol (200, 800 micrograms) aerosols using a double-blind protocol. 2. Fenoterol 200 micrograms, 800 micrograms increased the baseline FEV1 0.28 +/- 0.16, 0.32 +/- 0.16 L (P = 0.04, P = 0.008 respectively). Fenoterol 800 micrograms moved the PC20 P rightwards from placebo geometric mean 10.95, 95% Confidence Intervals (95% CI) 4.43-27.22 mg/mL to mean 20.41, 95% CI 10.13 to 40.64 mg/mL (P = 0.01). Fenoterol 200 micrograms was not protective; mean PC20 16.22, 95% CI 7.83-34.35 mg/mL (P = 0.08). Neither 40 or 160 micrograms ipratropium changed the FEV1 or PC20P values compared with placebo; increase in FEV1 0.15 +/- 0.27 L (P = 0.22), 0.24 +/- 0.12 L (P = 0.14) and geometric mean PC20P 16.59 +/- 0.57 mg/mL, 95% CI 8.01-34.51 mg/mL (P = 0.90), 15.58 +/- 0.66 mg/mL, 95% CI 6.72-36.05 mg/mL (P = 0.34) respectively after ipratropium treatments. 3. Bronchoconstriction induced by inhaled propranolol (P) appears to be only weakly antagonized by inhaled beta-agonist and not reduced by antimuscarinic anticholinergic aerosol. This finding argues against the activation of a cholinergic reflex to explain propranolol induced bronchoconstriction (PIB).     

藻酸双酯钠和甘糖酯对急性心肌梗死患者红细胞变形能力保护作用的机制探讨

为探讨藻藻酯双酯钠(PSS)和甘糖酯(PGMS)对急性心肌梗死(AMI)患者红细胞变形能力(ED)保护作用的机制,检测了52例AMI患者红细胞滤过指数(EFI)、红细胞膜Na~ ,K~ -ATP酶和谷胱甘肽过氧化物酶GSH-Px活性及红细胞膜脂质过氧化物(LPO)的变化,同时观察了PSS和PGMS在体外对ED、Na~ ,K~ -ATP酶、GSH-Px和LPO的影响。结果显示,AMI患者EFI、LPO明显增高,Na~ ,K~ -ATP酶和GSH-Px活性明显降低,与对照组比较差异有极显著性(P<0.001)。AMI患者红细胞与PSS或PGMS在体外温育24h后,EFI、LPO明显降低,Na~ ,K~ -ATP酶和GSH-Px活性明显增高。与温育前比较差异有极显著性(P<0.001),与对照组比较差异无显著性(P>0.05)。提示PSS和PGMS具有保护和提高AMI患者ED的作用,其机制与增强红细胞膜ATP酶和抗氧化酶活性有关。     

NEUTROPHIL PLATELET-ACTIVATING FACTOR PRODUCTION AND ACETYLTRANSFERASE ACTIVITY IN CLINICAL ACUTE MYOCARDIAL INFARCTION

1. Neutrophil function was studied in 10 males presenting with acute myocardial infarction (MI) within 6 h of onset and in 10 normal males. Neutrophil production of platelet-activating factor (PAF), determined by bioassay, that of leukotriene B₄ by HPLC, and the activity of an enzyme involved in the synthesis of PAF, acetyltransferase (AT), were measured before and after stimulation with opsonized zymosan and calcium ionophore, A23187. 2. The neutrophil count was significantly raised at presentation in those with MI (8.2 ± 0.8 vs 2.8 ± 0.3 (s.e.m.) |MX 10⁹ cells/L, P<0.001; t-test, 18d.f.). Production of PAF per neutrophil in response to both stimulants was greater than normal in those with MI (zymosan: 21 ± 4 vs 12 ± 1ng/10⁷ cells, P<0.05; ionophore: 174 ± 18 vs 113 ± 11ng/10⁷ cells, P<0.02) despite normal leukotriene B₄ production and depressed AT activity. By 7 days, the neutrophil count had significantly fallen but it remained greater than normal as did PAF production. 3. Acute MI is associated with increased potential for production of PAF by neutrophils which may be important in the pathogenesis of MI.     

CHANGES IN CARDIAC ANGIOTENSIN CONVERTING ENZYME AFTER MYOCARDIAL INFARCTION AND HYPERTROPHY IN RATS

1. Cardiac angiotensin-converting enzyme (ACE) is localized in high concentration in cardiac valves, coronary vessels, right and left atrium and right and left ventricle. 2. Cardiac ACE is functionally active in converting angiotension I to angiotensin II. 3. The level of cardiac ACE measured by radioinhibitor binding or by quantitative in vitro autoradiography was greatly increased after experimental myocardial infarction in the rat. The increase was greatest in the fibrous scar tissue of the free left ventricular wall infarct, but there were also significant increases in the ACE concentration in the four chambers of the heart. 4. Treatment with enalapril for 4 weeks following coronary ligation inhibited cardiac ACE, including the high levels found in the scar in the left ventricular free wall. 5. There was a close relationship between the systolic blood pressure and left ventricular mass in several models of experimental hypertension, despite varying degrees of activation of the renin-angiotensin system. However no relationship between the degree of left ventricular hypertrophy and changes in cardiac ACE could be determined. 6. Inhibition of cardiac ACE may contribute to the beneficial effect of ACE inhibitors in cardiac hypertrophy and remodelling, and may play a part in the cardioprotective role of ACE inhibitor.     

EFFECTS OF COMBINATION THERAPY WITH PERINDOPRIL AND LOSARTAN ON LEFT VENTRICULAR REMODELLING IN PATIENTS WITH MYOCARDIAL INFARCTION

• 1 Inhibiting the renin–angiotensin–aldosterone system prevents left ventricular (LV) remodelling after myocardial infarction (MI).
• 2 The present study was designed to assess the effects of a combination of perindopril and losartan on LV remodelling, cardiac function and serum procollagen type III amino terminal peptide (PIIINP) levels in patients with acute MI.
• 3 Patients with anterior MI were divided into three groups: (i) MI + perindopril; (ii) MI + losartan; and (iii) MI + perindopril + losartan. After successful intervention therapy, perindopril (2–4 mg daily), losartan potassium (25–50 mg daily) or their combination were administered. All patients received aspirin, clopidogrel and statins, and some patients were given beta‐blockers, nitrate and a platelet glycoprotein IIb/IIIa receptor antagonist. Three months later, LV dimensions and LV ejection fraction (LVEF) were measured by ultrasonography. Plasma B‐type natriuretic peptide (BNP), serum C‐reactive protein (CRP) and PIIINP levels were evaluated using enzyme‐linked immunosorbent assay or radioimmunoassay.
• 4 The baseline characteristics of the three groups were the same. Three months after the initiation of therapy, all patients showed decreased CRP, increased BNP and PIIINP levels and LV dilation and dysfunction. Compared with the two monotherapy groups, patients in the combination group showed significantly lower CRP, BNP and PIIINP levels, less LV dilation and higher LVEF. Serum PIIINP levels were positively correlated with CRP levels (r = 0.597; P < 0.01) and LV end‐diastolic volume index (r = 0.543; P < 0.01) and were negatively correlated with LVEF (r = –0.565; P < 0.01).
• 5 For patients with acute MI, combination treatment with perindopril and losartan significantly inhibited LV remodelling and improved LV function. Inhibition of myocardial interstitial fibrosis may be part of the underlying mechanism.

     

EFFECT OF EXERCISE ON PLASMA ADRENOMEDULLIN AND NATRIURETIC PEPTIDE LEVELS IN MYOCARDIAL INFARCTION

1. We investigated the effect of exercise on plasma adreno-medullin, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations and studied the relationship between these peptides and haemodynamic parameters in nine patients with old myocardial infarction (MI) and in eight normal subjects. 2. The exercise protocol consisted of two fixed work loads (40 and 80 W) for 4 min each and venous blood samples were taken at rest, during each exercise stage and after exercise while monitoring the mean arterial pressure (MAP) and heart rate (HR). In MI, pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP) and cardiac output (CO) were measured throughout exercise. 3. Adrenomedullin levels did not significantly increase with exercise. Adrenomedullin levels correlated with PAP and PCWP at rest (P < 0.05). Atrial natriuretic peptide levels correlated with PAP, PCWP and LVEDP throughout exercise (P < 0.05) but, on multiple regression analysis, PCWP correlated only with ANP (P < 0.01). Brain natriuretic peptide levels correlated with LVEDP throughout exercise (P < 0.01) and its increment correlated closely with basal BNP levels at rest (P < 0.01). 4. These results suggest that adrenomedullin does not respond to the acute haemodynamic changes of exercise, whereas ANP responds to it and PCWP is the major stimulus factor. Brain natriuretic peptide responds to exercise in proportion to the basal synthesis of BNP in patients with left ventricular dysfunction and LVEDP may play a role in increasing BNP during exercise.     

CHANGE IN OPIOID PEPTIDE LEVEL IN THE HEART AND BLOOD PLASMA DURING ACUTE MYOCARDIAL ISCHAEMIA COMPLICATED BY VENTRICULAR FIBRILLATION

1. The influence of acute myocardial ischaemia (AMI) complicated by ventricular fibrillation (VF) on opioid peptide level in myocardium and blood plasma of rats has been studied. 2. Leu-enkephalin level in myocardium of rats with AMI and VF has been found to be significantly lower than in animals with AMI but without VF. 3. Met-enkephali level has been found to be significantly increased in both animals with VF and without it. We have not found a significant difference in met-enkephalin level in myocardium of animals with VF and without it. 4. AMI was induced to increase the enkephalin and β-endorphin level in blood plasma of all the animals, whether VF had occurred or not. 5. Preliminary administration of D-Ala², Leu⁵, Arg⁶-enkephalin, a synthetic analogue of leu-enkephalin, has prevented a decrease of ventricular fibrillation threshold in experimental coronary occlusion. 6. The obtained results allow us to conclude that enkephalins of myocardium but not opioid peptides of blood plasma play an important role in VF occurrence.     

THE ANTAGONISM BY PROPRANOLOL AND α-METHYLPROPRANOLOL (ICI 77602) OF VASCULAR AND CARDIAC RESPONSES TO ISOPRENALINE IN ANAESTHETIZED DOGS

1. In anaesthetized dogs, α-methylpropranolol was less potent than propranolol in antagonizing both vascular (hind limb perfusion pressure) and cardiac heart rate) responses to isoprenaline. 2. α-Methylpropranolol was more potent in antagonizing vascular than cardiac responses to isoprenaline, but this selectivity was no greater than that seen also with propranolol. 3. Isoprenaline sensitivity was greater in the hind limb than the heart and vascular-selective antagonism was more pronounced in those dogs in which this differential sensitivity was the greatest. 4. Introduction of an a-methyl group into propranolol decreases its 0-adrenoceptor antagonist potency but does not enhance vascular selectivity.     

HYPOTHESIS: ISCHAEMIC PLAQUE NECROSIS AS THE INITIATOR OF UNSTABLE ANGINA/ACUTE MYOCARDIAL INFARCTION?

1. Coronary atherosclerotic plaque complications are important in precipitating acute coronary events such as unstable angina and myocardial infarction. 2. The hypothesis is put forward that plaque complications are initiated by increases in local coronary artery tone sufficient to cut off the vasa vasorum blood supply to the plaque and result in its ischaemic necrosis.     

甘糖酯,藻酸双酯钠对急性脑梗死患者白细胞变形能力的影响

本文观察了急性脑梗死患者白细胞变形能力的变化及甘糖酯(PGMS)和藻酸双酯钠(PSS)对其影响。结果显示,急性脑梗死患者白细胞IF较对照组明显增高(P<0.001)。白细胞体外孵育2h后,其IF较孵育前明显增高(P<0.001),但加PGMS和PSS孵育的白细胞IF较空白对照管明显降低(P<0.001),且随着药物含量的增加IF逐渐减低,其中以PGMS作有较明显。结果提示,PGMS和PSS具有明显改善白细胞变形能力的作用,对改善急性脑梗死患者微循环,增加缺血脑组织的血流量,缩小梗死面积有重要的意义。     

HAEMODYNAMIC EFFECTS OF ISOMETRIC HANDGRIP EXERCISE IN PATIENTS CONVALESCENT FROM MYOCARDIAL INFARCTION

1. Cardiac performance in response to 30% maximal isometric handgrip exercise was studied in fourteen patients convalescing uneventfully from a first myocardial infarction. In each patient, heart rate, mean arterial blood pressure and cardiac index were measured, and total peripheral resistance was calculated. The covariance of changes in the mean arterial blood pressure and cardiac index in these patients was matched against tolerance limits calculated from published data for normal subjects. 2. All patients had normal haemodynamic values at rest, and showed the usual rise of heart rate and mean arterial pressure during handgrip exercise. However, in six patients (group 1) the rise in mean arterial pressure was, as in normal subjects, accounted for mainly by a rise in cardiac index, with no consistent change in peripheral resistance. In eight patients (group 2), the mean arterial pressure rose to the same level as in group 1, but with a consistent increase in peripheral resistance and a smaller rise in the cardiac index. 3. It is suggested that in a substantial proportion of patients who are making a seemingly uncomplicated recovery from myocardial infarction, it may be possible to unmask an impairment of left ventricular function by means of isometric handgrip exercise.     

不同年龄组急性心肌梗塞溶栓治疗的对比研究

４７例急性心肌梗塞（ＡＭＩ）患者按发病年龄随机分成三组，进行尿激酶（ＵＫ）溶栓疗效的对比研究。结果表明，１２小时内溶栓的４７例ＡＭＩ患者再通率、死亡率和并发症发生率分别为５５．３％、１４．９％和８．５％。６小时内溶栓再通率老年组（５０％）明显低于青年组（８０％）和老年前期组（７０％）。老年组住院病死率为２５．９％，且有出血并发症发生，而青年组和老年前期组无一例死亡且无一例出血并发症发生。提示ＵＫ溶栓疗效与患者年龄有关，老年人溶栓疗效较差，病死率和出血并发症发生率较高。     

EFFECT OF ACUTE ADMINISTRATION OF PRAZOSIN ON BLOOD PRESSURE, HEART RATE AND PLASMA RENIN LEVEL IN THE CONSCIOUS NORMOTENSIVE RAT

This study investigated whether the specific alpha-antagonist, prazosin, stimulated basal plasma renin levels and heart rate. Furthermore the beta-adrenergic nervous system was also investigated to ascertain whether it was involved in this effect. Prazosin (0.1 or 1 mg/kg) was injected subcutaneously (s.c.) to conscious normotensive rats, either alone or in combination with the beta-adrenoceptor antagonist, DL-propranolol (1 or 3 mg/kg). Rats bore chronically implanted dorsal aorta cannula for measurement of blood pressure and heart rate and blood sampling for renin determinations. Acute administration of prazosin (1 mg/kg, s.c.) produced a fall in mean arterial pressure accompanied by renin release and tachycardia. A tenfold lower dose of prazosin did not alter blood pressure or heart rate but did stimulate renin release. Acute administration of DL-propranolol, (1 or 3 mg/kg, s.c.) produced falls in blood pressure and heart rate but did not affect plasma renin level. Combinations of prazosin with propranolol gave falls in blood pressure similar to those predicted on the basis of a simple addition of the effects of the two drugs given separately. Prazosin-induced tachycardia and renin release were attenuated by propranolol. It appears that prazosin produces renin release and tachycardia via stimulation of the beta-adrenergic adrenoceptor.     

THE EFFECT OF β-ADRENOCEPTOR BLOCKERS ON THE ABSORPTION AND EXCRETION OF CHLOROTHIAZIDE IN MAN

The effect of beta-adrenoceptor blockers on the absorption and elimination of the diuretic chlorothiazide was studied in healthy subjects. A week of pretreatment with either pindolol (10 mg twice daily) or propranolol (80 mg twice daily) resulted in significant reduction in 36 h mean cumulative urinary recovery of chlorothiazide in two groups of six subjects compared with a control (untreated) group. A week of pretreatment with atenolol (100 mg daily) did not significantly alter 36 h cumulative urinary excretion in another group of six subjects. None of the beta-blockers significantly changed chlorothiazide half-life. It is suggested that the non-selective (as opposed to the cardioselective) beta-blockers reduce chlorothiazide absorption by the mechanism(s) discussed.     

HAEMODYNAMIC AND HORMONAL EFFECTS OF PRAZOSIN ON HEAD-UP TILT IN ESSENTIAL HYPERTENSIVE PATIENTS: COMPARISON WITH THOSE OF PROPRANOLOL

1. To evaluate the haemodynamic and hormonal effects of prazosin, head-up tilt was performed in 10 essential hypertensive patients, and these effects of prazosin on the tilt were compared with those of propranolol. The tilts were performed in control phase and the last days of treatment for two weeks with propranolol (90 mg/day) or prazosin (3–6 mg/day). 2. Each drug significantly lowered the mean blood pressure at rest, and also suppressed its rise on the tilt. Heart rates were significantly increased by the tilt in the control phase, in the propranolol phase and in the prazosin phase. Cardiac index was significantly reduced by the tilt from 2.66 (s.e.m. =0.22) 1/min per m² to 2.08 (s.e.m. =0.20) in the propranolol phase. However, there were not significant changes in other phases. Total peripheral resistance indices were significantly increased by the tilt in all three phases. Plasma renin activity and plasma aldosterone were significantly increased by the tilt from 2.14 (s.e.m. =0.47) ng/ml per h to 2.46 (s.e.m. =0.54) and from 50.6 (s.e.m. =12.9) pg/ml to 74.9 (s.e.m. =14.9) respectively, in the control phase. And they were also significantly increased from 1.06 (s.e.m. =0.29) to 1.65 (s.e.m. =0.45) and from 41.4 (s.e.m. =16.3) to 54.0 (s.e.m. =17.4) in the prazosin phase. There were no significant increases during the administration of propranolol. 3. We observed that prazosin did not alter heart rate and cardiac index, but suppressed the renin-angiotensin system at rest. It is suggested that prazosin did not influence haemodynamic and hormonal responses to the tilt.