Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale.

OBJECTIVES: Angiotensin II (ANG II) is known to be a potent vasoconstrictor agent in the pulmonary circulation. Furthermore, type 1 ANG II receptor blockade with losartan attenuates acute hypoxic pulmonary vasoconstriction in normal subjects. The aim of this study was therefore to evaluate the haemodynamic and endocrine sequelae of type 1 ANG II receptor blockade in patients with hypoxaemic cor pulmonale. METHODS: Nine patients with chronic obstructive pulmonary disease (COPD) age 67 +/- 3 years with pulmonary hypertension and normal left ventricular systolic function were studied on two separate occasions in a double-blind, placebo-controlled, crossover study. They were randomised to receive either 50 mg of oral losartan or matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Haemodynamic measurements and venous blood samples were taken at baseline and after 2 and 4 h. RESULTS: Maximal effects were observed at 4 h where losartan compared to placebo resulted in a significant reduction in both MPAP (28.6 +/- 2.0 vs 32.4 +/- 1.5 mmHg) and TPR (428 +/- 40 vs 510 +/- dyn.s.cm-5), respectively. Similarly losartan compared to placebo resulted in a significant reduction in MAP (87 +/- 4.5 vs 93 +/- 3.2 mmHg) and SVR (1293 +/- 94 vs 1462 +/- 112 dyn.s.cm-5), and significantly increased CO (5.58 +/- 0.43 vs 5.31 +/- 0.42 l/min). In addition, plasma aldosterone was significantly lower after treatment with losartan compared to placebo: 76 +/- 23 vs 164 +/- 43 pg/ml respectively. CONCLUSIONS: Thus, selective type 1 ANG II receptor blockade appears to have beneficial pulmonary and endocrine effects, suggesting a possible therapeutic role in the management of hypoxaemic cor pulmonale.

A double-blind comparison of bisoprolol and atenolol in patients with essential hypertension.

We compared the beta 1-selective adrenoceptor antagonists bisoprolol and atenolol in a double-blind, randomized crossover study. After 4 weeks placebo phase, 59 patients with essential hypertension received either 10 mg bisoprolol or 50 mg atenolol once daily for 8 weeks, increased if necessary (target BP < or = 150/90 mmHg) to 20 and 100 mg, respectively, after 4 weeks. After a second placebo phase, crossover occurred to the alternative drug. We measured resting systolic and diastolic blood pressures and heart rate at 24 h post-dose baseline and after 4 and 8 weeks treatment. Both drugs significantly lowered systolic and diastolic blood pressures and heart rate at 8 weeks compared to baseline (all p < 0.05). Bisoprolol reduced heart rate significantly more than atenolol (p < 0.01), but systolic and diastolic blood pressure changes were not different between the two drugs. There was no difference in patient acceptability of the drugs as assessed by visual analogue scale. Despite theoretical and circumstantial evidence to suggest superiority of bisoprolol over atenolol, no significant difference between the two was found except for greater heart rate reduction with bisoprolol.

The relationship between blood pressure and left ventricular mass in essential hypertension is observed only in the presence of the angiotensin-converting enzyme gene deletion allele.

An insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene accounts for approximately 50% of the variance in plasma ACE concentration: deletion homozygotes (DD) have the highest, and insertion homozygotes (II) the lowest ACE concentrations. ACE is responsible for the generation of angiotensin II, which is implicated in the development of left ventricular hypertrophy, an independent risk factor for morbidity and mortality in hypertension. The aim of this study was to investigate the contribution of ACE genotype to the development of left ventricular hypertrophy in patients with essential hypertension. Eighty-five patients with essential hypertension underwent echocardiographic assessment of left ventricular mass index (LVMI) and determination of ACE genotype from leukocyte DNA by polymerase chain reaction. There was no significant difference in LVMI among the genotypes (II, ID, DD). Analysis of covariance modelled for LVMI showed a significant interaction with systolic blood pressure (p = 0.036) but not diastolic blood pressure (p = 0.453). The relationship between LVMI and systolic blood pressure was strongest in the deletion homozygotes (p = 0.002, R2 = 0.47), and also present in the heterozygotes (p = 0.013, R2 = 0.40). No relationship was seen in the insertion homozygotes (p = 0.914, R2 = 0.23). These findings suggest that the effect of blood pressure on LVMI in essential hypertension is expressed only in the presence of the ACE gene deletion allele.

Screening for atrial fibrillation in primary care.

OBJECTIVE: To investigate a population of elderly people for atrial fibrillation and to determine how many of the cases identified might benefit from treatment with anticoagulants. METHODS: From a practice of four primary care physicians, 1422 patients aged 65 years and over were identified, of whom 1207 (85% of the total population) underwent electrocardiographic screening to detect the presence of atrial fibrillation. Patients with the arrhythmia were further evaluated by echocardiography and interview, to stratify their risk of stroke based on echocardiographic and clinical risk factors, their perceived risk from anticoagulation, and their attitude towards this treatment. Their primary care physician was also interviewed to determine the factors influencing the prescription of anticoagulants. RESULTS: The arrhythmia occurred in 65 patients (5.4% overall), its prevalence increasing markedly with age (2.3% in 65 to 69 years age group; 8.1% in those over 85). Warfarin was being prescribed to 21.4% of these patients, although the findings of the study indicate that a further 20% were eligible for this treatment. Symptoms suggestive of cardiac failure were common (32.1%) and coexisting pathology was often identified by cardiac ultrasound in these patients (left ventricular hypertrophy, 32.1%; impaired left ventricular contractility, 21.4%; left atrial dilation, 80.4%; mitral annular calcification, 42.9%; mitral stenosis, 7.1%; mitral regurgitation, 48.2%; aortic stenosis, 8.9%). In all but one case, the decision to anticoagulate was based on the clinical rather than the echocardiographic findings. CONCLUSIONS: Individual risk-benefit assessment in elderly patients with atrial fibrillation suggests that almost half (41.4%) are eligible for full anticoagulation with warfarin, whereas presently only one fifth are receiving this treatment. The decision to anticoagulate can be made on clinical grounds in most cases. If these results are confirmed, a doubling of the current number of patients taking anticoagulants can be anticipated.

Wolff-Parkinson-White syndrome mimicking myocardial infarction on ECG--exploitation by a heroin addict.

Wolff-Parkinson-White (WPW) syndrome produces several electrocardiographic features, including mimicking the changes of myocardial infarction. A case is described of an astonishingly well-informed heroin addict, who himself had WPW syndrome and who exploited his condition attempting to obtain opiates from hospital.

Selectivity of antagonist and partial agonist activity of celiprolol in normal subjects.

1. The aims of this study were to assess the relative beta 1/beta 2 selectivity of the antagonist and partial agonist activity (PAA) of celiprolol in man. 2. Eight normal males received single oral doses of celiprolol 200 mg (C200), 400 mg (C400) and 800 mg (C800); atenolol 50 mg (A50), 100 mg (A100) and 200 mg (A200); nadolol 40 mg (N40) and placebo (PL), administered in a single-blind, randomised crossover design. 3. At rest, in the presence of low levels of circulating adrenaline and noradrenergic tone, a low dose of celiprolol (C200) showed evidence of beta 1-PAA by significant increases in systolic blood pressure and resting heart rate. At higher doses (C400, C800), beta 2-PAA became evident by a significant increase in postural finger tremor, whereas C200 had no effect. 4. In the presence of a beta 1-adrenoceptor agonist, as assessed by reduction of exercise tachycardia, increasing doses of celiprolol produced significantly less beta 1-adrenoceptor blockade compared with atenolol. Furthermore, there was no increase in beta 1-adrenoceptor blockade beyond C400. 5. In the presence of a beta 2-adrenoceptor agonist, as assessed by blunting of terbutaline-induced chronotropic, hypokalaemic and finger tremor responses, celiprolol exhibited less beta 2-adrenoceptor blockade than comparable doses of atenolol used in clinical practice. 6. Exercise hyperkalaemia was blunted significantly by C400 and C800 in comparison with all doses of atenolol and nadolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of in vivo partial beta 1/beta 2-agonist activity: a dose-ranging study with carteolol.

1. The aims of this study were to investigate the partial agonist profile of carteolol and evaluate methodology for differentiating relative beta 1 and beta 2 partial agonist activity (PAA) in vivo. 2. Eight normal subjects received single oral doses of carteolol 10 mg, 30 mg and 60 mg; nadolol 40 mg; pindolol 30 mg and placebo, given in a single-blind, randomised crossover design. 3. beta 1-PAA was demonstrated with carteolol by dose-related increases in resting heart rate and systolic blood pressure, and a plateau in the dose-response curve for attenuation of exercise tachycardia. beta 2-PAA with carteolol was evidenced by a dose-related increase in resting finger tremor and progressive attenuation of exercise-induced hyperkalaemia. beta 2-adrenoceptor antagonism was shown by attenuation of terbutaline induced hypokalaemic, chronotropic and finger tremor responses. 4. Carteolol behaved as a non-selective beta-adrenoceptor antagonist with both beta 1 and beta 2-PAA components. In the standard clinical dose range of 10-30 mg, its in vivo PAA effects were relatively beta 1-selective. Thus at low doses, there appeared to be a dissociation between selectivity of antagonist and partial agonist activity. 5. Attenuation of exercise hyperkalaemia appears to be a novel and sensitive method for the evaluation of beta 2-PAA in vivo.

Obstructive left ventricular hypertrophy. Reversibility of outflow tract obstruction by drug therapy.

We report the cases of four patients with secondary left ventricular hypertrophy (three due to hypertension and one to aortic stenosis) in whom Doppler echocardiography showed dynamic left ventricular outflow tract obstruction and marked impairment of diastolic filling. Each patient derived marked symptomatic benefit from treatment with either a beta-blocker (atenolol) or calcium antagonist (verapamil). Repeat Doppler studies in three patients revealed a substantial improvement in systolic and diastolic flow abnormalities. Ventricular outflow tract obstruction should be recognized as occurring in a subgroup of patients with secondary left ventricular hypertrophy, and its presence should be sought by Doppler echocardiography before embarking on therapy. Negatively inotropic or positively lusitropic agents such as beta-blockers and rate-limiting calcium antagonists appear to be logical therapy for this condition.

Effect of combined atenolol and nifedipine administration on psychomotor performance in normal subjects.

The aim of the present study was to evaluate the central effects of single doses of the beta-adrenoceptor antagonist atenolol and the calcium antagonist nifedipine retard, alone and in combination, in normal subjects. Twelve normal males received single oral doses of atenolol 100 mg, nifedipine retard 20 mg, atenolol 100 mg and nifedipine retard 20 mg in combination, diazepam 5 mg (active control), and each of two matching placebos in a double-blind, randomised fashion. Psychomotor performance was assessed using digit symbol substitution, letter cancellation (LCT), continuous attention, choice reaction time, finger tapping, immediate recall and short-term memory. Two flash fusion and critical flicker fusion thresholds were measured and subjective assessments made using visual analogue scales (VAS). Diazepam 5 mg significantly worsened LCT scores at 4h, significantly impaired alertness at 2 h and 4 h, and tended to increase reaction time and impair continuous attention and physiological measurements. Atenolol 100 mg alone significantly reduced alertness at 2 h and 4 h, and also tended to impair physiological measurements. Nifedipine retard 20 mg produced no significant psychomotor effects. Combined atenolol and nifedipine retard administration produced a small but significant improvement in continuous attention and a reduction in body sway, with no adverse effects being evident on performance or subjective awareness. The results suggest that no significant adverse effects on psychomotor performance are produced by single doses of atenolol 100 mg and nifedipine retard 20 mg when given together in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Isotope renography in the investigation of renal artery stenosis in hypertensive patients.

Isotope renography is a commonly used investigation for the detection of renal artery stenosis (RAS) in hypertensive patients, although its predictive accuracy is poor in an unselected population with a low prevalence of RAS. The aim of the present study was to identify characteristics of hypertensive patients that raise the clinical suspicion of underlying RAS, and which are predictive of an abnormal isotope renogram. The characteristics of 75 patients who had undergone either conventional or ACE-inhibitor-enhanced renography were retrospectively assessed and correlated with the renogram results. The presence of a raised serum creatinine, severe systolic hypertension at presentation and the requirement for triple drug therapy best predicted abnormalities on renography. However, it would appear that the false-positive rate of this investigation is high and its predictive accuracy is poor even in a highly selected group of patients. We conclude that isotope renography is of no practical value in the screening of hypertensive patients for RAS. Renal angiography remains the investigation of choice.

Evaluating the use of a semiautomated cuff-oscillometric sphygmomanometer in the hypertension clinic.

Measuring blood pressure in the clinic setting is confounded by 'white coat' hypertension, observer bias and digit preference. In this study a semiautomatic blood pressure measuring device (the UA-751) was tested for its use as a reliable assessment of blood pressure and improved patient management in the hypertension clinic. Blood pressures were recorded in 156 patients and compared with physicians' readings measured using a standard mercury sphygmomanometer. The mean blood pressure differences between the two methods showed that the device gave consistently higher readings for both systolic (1.4-3.6 mmHg) and diastolic (3.6-3.8 mmHg) pressure, whether it was used before or after physician consultation. No reduction in 'white coat' hypertension was thus apparent. There was considerable variability between recordings made by the two methods on the same individual. Digit preference was apparent with physician readings, with zero recorded in 57.8% of systolic readings compared with 12.2% using the machine. Different management decisions would have been taken in 20 (13.6%) patients had the UA-751 recordings been used. The device is thus of no value in patient management in the setting of the hypertension clinic.

The effects of lower than conventional doses of oral nadolol on relative beta 1/beta 2-adrenoceptor blockade.

1. The aim of the present study was to evaluate the relative beta 1/beta 2 antagonist selectivity of the beta-adrenoceptor blocker nadolol, in lower than conventional clinical doses. 2. Eight normal volunteers received single oral doses of either placebo (PL), nadolol 5 mg (N5), 20 mg (N20) or 80 mg (N80) in a single-blind, randomised crossover design. beta 1-adrenoceptor antagonism was assessed by attenuation of exercise tachycardia, and beta 2-adrenoceptor blockade by effects on salbutamol-induced chronotropic, hypokalaemic and finger tremor responses. The relative percentage attenuation of beta 2 and beta 1-mediated responses was calculated and expressed as beta 2:beta 1 selectivity ratios. 3. Nadolol produced dose-related reductions in exercise tachycardia in keeping with increasing beta 1-adrenoceptor blockade; mean % reduction (95% CI) compared with placebo: N5 10.7 (6.6 to 14.8), N20 21.4 (17.3 to 25.4), N80 38.9 (34.8 to 42.9). However, even the lowest dose of nadolol (5 mg) produced almost complete blunting of beta 2-mediated effects and significantly increase exercise hyperkalaemia; peak exercise hyperkalaemia (mmol l-1) (means and 95% CI): PL 4.88 (4.68 to 5.07), N5 5.36 (5.17 to 5.55), N20 5.48 (5.28 to 5.67), N80 5.42 (5.22 to 5.61). beta 2:beta 1 selectivity ratios significantly increased as the dose of nadolol was reduced. 4. These data suggest that whereas in the clinical dose range nadolol behaves as a non-selective beta-adrenoceptor antagonist, as the dose is reduced this drug demonstrates an increasing degree of selectivity for the beta 2-adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac effects of the beta 3-adrenoceptor agonist BRL35135 in man.

The aim of the present study was to evaluate the cardiac effects of the beta 3-adrenoceptor agonist BRL35135, and determine whether beta 3-receptors are involved in mediating chronotropic or inotropic responses in man. Eight normal males received single oral doses of BRL35135 8 mg (BRL) or the selective beta 2-adrenoceptor agonist salbutamol 8 mg (SAL), after pretreatment with either placebo (PL), bisoprolol 5 mg (B5) as a selective beta 1-adrenoceptor antagonist, or nadolol 20 mg (N20) to block beta 1- and beta 2- but not beta 3-receptors. Both BRL and SAL produced a significant increase in postural finger tremor in keeping with beta 2-adrenoceptor stimulation, and this response was totally abolished by pretreatment with N20. Significant increases in systolic blood pressure and Doppler stroke distance occurred with BRL and SAL which were unaffected by pretreatment with B5 and completely blocked by N20, in keeping with beta 2-mediated effects. BRL and SAL produced significant chronotropic and minute distance responses which were unaffected by beta 1-adrenoceptor blockade. However, whereas N20 blocked these responses to SAL, a small but significant response occurred with BRL in comparison with placebo despite complete blockade of co-existing beta 2-mediated effects. Compared with PL, the mean responses to N20/BRL, and the 95% confidence interval for the differences between the means were 7.4 beats min-1 [3.2 to 11.6] (P = 0.002) for heart rate, and 208.8 cm [38.3 to 379.3] (P = 0.02) for minute distance responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Do beta 3-adrenoceptors mediate metabolic responses to isoprenaline.

We investigated whether the putative beta 3-adrenoceptors mediated metabolic responses to isoprenaline. Seven normal volunteers received infusions of isoprenaline, a (beta 1, beta 2 and beta 3-agonist), at 0.5-3.0 micrograms/min. They were pretreated with either placebo, 25 mg atenolol (a selective beta 1 antagonist), or 5, 20 and 80 mg nadolol (which blocks beta 1 and beta 2 but not beta 3-adrenoceptors). Isoprenaline markedly (30.6%) increased basal metabolic rate (BMR): this increase was significantly reduced by 25 mg atenolol but not by 5 mg nadolol. Significant beta 2-blockade (from tremor data) occurred with 5 mg nadolol but not with 25 mg atenolol. This suggests that beta 1 but not beta 2-adrenoceptors are involved in the mediating thermogenic effects of isoprenaline. However, the rise in BMR was not totally blocked even by 80 mg nadolol (9.5%), which produced complete beta 1/beta 2 blockade, as evidenced by the elimination of the chronotropic effect of isoprenaline. This implies that the thermogenic response has a non-beta 1/beta 2-mediated component. There were also significant increases in plasma free fatty acids, glycerol, glucose, insulin and lactate, but these were completely abolished by beta 1/beta 2 blockade. Overall, isoprenaline produced an increase in BMR which is only partly due to stimulation of beta 1-adrenoceptors, and which is not associated with beta 1/beta 2-mediated effects on carbohydrate and fat metabolism. This suggests the possibility of thermogenic beta 3-adrenoceptors in man, although their location and role remain unknown.