EFFECT OF SODIUM INTAKE ON INTRAERYTHROCYTE SODIUM CONCENTRATION IN NORMOTENSIVE SUBJECTS AND PATIENTS WITH UNTREATED MILD HYPERTENSION

1. The effect of changing sodium intake for 2 weeks was studied. Twelve nor-motensive subjects and five patients with mild essential hypertension were given two different levels of sodium intake for 2 weeks. 2. Overall there was no significant rise in blood pressure but all patients with hypertension had a rise in blood pressure as they went from a low to a high sodium intake. 3. Plasma sodium was not altered but red cell sodium concentration was higher on the high sodium intake. This effect was observed in both normotensive and hypertensive people. 4. Alterations observed in cell sodium concentration provide support for the hypothesis that increased dietary intake of sodium may induce hypertension by causing changes in cellular transport systems.     

DEVELOPMENT OF HYPERTENSION AND PROTEINURIA WITH AGE IN FAWN-HOODED RATS

Blood pressure and urinary protein excretion were monitored in male fawn hooded rats (FH rats) from 8 until 46 weeks of age. Mild hypertension was already observed at 8 weeks of age. Between the age of 5 and 7 months the blood pressure rose steeply to a plateau of about 200 mmHg. Then it stabilized and the level was different for animals of different litters but similar for littermates. Concomitantly with the increase in blood pressure, proteinuria increased with age. Examination of renal tissue at 6.5 and 9 months of age revealed the presence of focal and segmental glomerulosclerosis. The renal changes were not accompanied by gross alterations in renal function. In animals with severe hypertension pronounced proteinuria occurred, and they appeared to form a distinct class. In some of the animals intermittent haematuria occurred. Persistent haematuria, however, had a bad prognosis. There was no glucosuria. Water intake of the animals with severe hypertension was increased. Water intake of young FH rats was found to be of value for predicting the severity of the hypertension in these animals at a later age. It is concluded that the FH rat is an example of a non-inbred rat strain showing spontaneous hypertension. This hypertension may result from an aberrant renal water handling and/or volume regulation.     

THE EFFECT OF PRAZOSIN THERAPY ON PLATELET ACTIVATION IN ESSENTIAL HYPERTENSION

1. Plasma levels of beta-thromboglobulin, initial and total platelet aggregation (induced by adrenaline or adenosine diphosphate [ADP]) were determined in 26 normotensive subjects and 26 patients with untreated essential hypertension. Groups of 18 essential hypertensive patients and 18 age- and sex-matched normotensives were compared. 2. After 7 days of treatment with prazosin in a dose of 2-8 mg daily the above measures were repeated in 18 essential hypertensive patients. A significant increase in plasma levels of beta-thromboglobulin, initial and total adrenaline-induced as well as ADP-induced platelet aggregation was found in hypertensives. Prazosin restored the mean arterial blood pressure in hypertensives to normal, but it had no significant influence either on increased beta-thromboglobulin levels or on initial and total aggregability. 3. The results confirm increased platelet aggregation and in vivo platelet activation in patients with essential hypertension; however there is a discrepancy with previous reports about those results obtained after prazosin therapy. The results suggest that increased platelet aggregation and in vivo activation need not be restored to normal after effective antihypertensive therapy alone. They give reason for the combination of antihypertensive together with anti-aggregatory therapy in essential hypertension.     

THE INFLUENCE OF A HIGH K INTAKE ON THE HYPERTENSIVE EFFECT OF ACTH AND DOC IN SHEEP

The effect of 5 days administration of ACTH or DOC, was examined before and after chronic potassium (K) loading in sheep. K loading raised plasma [K], urine volume and K excretion but had no effect on mean arterial pressure (MAP). On a normal K intake DOC (5 mg/day i.v.) increased MAP and plasma sodium [Na]. Plasma [K], urinary Na (day 1) and K (day 1) excretion were decreased. On a high K intake (congruent to 800 mmol K/day), DOC lowered plasma [K] but had no effect on MAP or Na excretion. The hypertensive effects of ACTH were not affected by K intake.     

SIMILARITY OF BLOOD PRESSURE FOR EACH GENOTYPE OF THE INSERTION/DELETION POLYMORPHISM OF THE DIPEPTIDYL CARBOXYPEPTIDASE-1 GENE IN DIFFERENT AGE GROUPS OF PATIENTS WITH SEVERE, FAMILIAL ESSENTIAL HYPERTENSION

1. The association of alleles of an insertion/deletion polymorphism (I/D) of the dipeptidyl carboxypeptidase-1 gene with hypertension is controversial. If a particular allele makes a major contribution to blood pressure, then hypertensives homozygous for this allele could be expected to have higher high blood pressure than those homozygous for the alternate allele. 2. The present study examined this hypothesis by comparing pretreatment blood pressures of hypertensives who had been genotyped for the I/D polymorphism. Blood pressures for different age groups (< 50, 50–59 and ≥60 years) were also examined for each genotype. In addition, several other parameters were examined. 3. Systolic blood pressures were found to be 167 ± 3, 167 ± 3 and 170 ± 6 mmHg (mean ± s.e.) for the genotypes II, ID and DD, respectively. Diastolic blood pressures were 113 ± 4, 111 ± 2 and 111 ± 4, for the respective genotypes. One-way anova showed that the respective blood pressure values did not differ significantly across genotypes. Blood pressures for different age groups of hypertensives were also similar. 4. In addition, body mass index, mean age and sex did not differ between genotypes, either for the group as a whole or for the different age groups. 5. In conclusion, the present study could find no evidence to support a genetic association between the I/D polymorphism of DCP1 and blood pressure in a group with severe, familial hypertension living in Sydney.     

A RANDOMIZED CONTROLLED TRIAL OF WEIGHT REDUCTION AND METOPROLOL IN THE TREATMENT OF HYPERTENSION IN YOUNG OVERWEIGHT PATIENTS

The effects of weight reduction and metoprolol (100 mg, b.d.) in the treatment of hypertension (diastolic blood pressure 90-109 mmHg) in 56 young, overweight patients were investigated in a randomized placebo controlled trial. After a 4-week baseline, subjects were followed up for 21 weeks. In the weight reduction group, the fall in systolic and diastolic blood pressure (13/10 mmHg), associated with a mean group weight loss of 7.4 kg, was greater (P less than 0.001) than that in the placebo group (7/3 mmHg); the fall in diastolic pressure but not systolic pressure was also greater than that in the metoprolol group (10/6 mmHg). At the end of follow-up, 50% of the weight reduction group, 39% of the metoprolol group and 17% of the placebo group had a diastolic blood pressure of less than 90 mmHg. In the weight reduction group there was a fall in total cholesterol and the ratio of total to HDL-cholesterol (P less than 0.001); in the metoprolol group there was a fall in HDL-cholesterol and an increase in the ratio of total to HDL-cholesterol (P less than 0.001). The results suggest that in the first step of treatment for hypertension in overweight patients, modest weight reduction produces significant and clinically important reductions in blood pressure, without incurring the adverse effects on plasma lipids and lipoproteins often associated with the first step of drug therapy.     

EFFECT OF MAGNESIUM DEPLETION AND POTASSIUM DEPLETION AND CHLOROTHIAZIDE ON INTRACELLULAR pH IN THE RAT, STUDIED BY 31P NMR

1. Both dietary magnesium depletion and potassium depletion (confirmed by tissue analysis) were induced in rats which were then compared with rats treated with chlorothiazide (250 mg/kg diet) and rats on a control synthetic diet. 2. Brain and muscle intracellular pH was measured by using a surface coil and [31P]-NMR to measure the chemical shift of inorganic phosphate. pH was also measured in isolated perfused hearts from control and magnesium-deficient rats. Intracellular magnesium status was assessed by measuring the chemical shift of beta-ATP in brain. 3. There was no evidence for magnesium deficiency in the chlorothiazide-treated rats on tissue analysis or on chemical shift of beta-ATP in brain. Both magnesium and potassium deficiency, but not chlorothiazide treatment, were associated with an extracellular alkalosis. 4. Magnesium deficiency led to an intracellular alkalosis in brain, muscle and heart. Chlorothiazide treatment led to an alkalosis in brain. Potassium deficiency was associated with a normal intracellular pH in brain and muscle. 5. Magnesium depletion and chlorothiazide treatment produce intracellular alkalosis by unknown mechanism(s).     

苄基四氢巴马汀细胞内用药对豚鼠乳头状肌动作电位和心室肌细胞延迟整流钾电流的作用

目的　研究将苄基四氢巴马汀(BTHP)导入细胞内对豚鼠乳头状肌动作电位及单个心室肌细胞延迟整流钾电流的影响。方法　利用外加电压脉冲将药物导入乳头状肌细胞内，并用标准微电极方法测定动作电位；利用浓度差扩散方式使药物进入单个心室肌细胞内，采用全细胞膜片钳技术记录延迟整流钾电流（I_K）。结果　100 μmol.L^-1 BTHP使APD₂₀和APD₉₀分别延长13.5%和20.5%。30 μmol.L^-1 BTHP使I_K和I_K,tail分别从（14.1±2.2) pA.pF^-1和(4.0±0.6) pA.pF^-1降至(9.4±1.3) pA.pF^-1和(2.1±1.0) pA.pF^-1，下降率分别为33.2%和35.3%。 该药使I_K和I_K,tail的I-V曲线幅度降低，对曲线形状影响不明显。结论　BTHP入细胞内后可阻滞延迟整流钾电流和延长动作电位时程。     

苄基四氢巴马汀细胞内用药对豚鼠乳头状肌动作电位和 心室肌细胞延迟整流钾电流的作用

目的　研究将苄基四氢巴马汀 (BTHP)导入细胞内对豚鼠乳头状肌动作电位及单个心室肌细胞延迟整流钾电流的影响。方法　利用外加电压脉冲将药物导入乳头状肌细胞内 ,并用标准微电极方法测定动作电位 ;利用浓度差扩散方式使药物进入单个心室肌细胞内 ,采用全细胞膜片钳技术记录延迟整流钾电流 (IK)。结果　 10 0 μmol·L-1BTHP使APD2 0 和APD90 分别延长 13 5 %和 2 0 5 %。 30 μmol·L-1BTHP使IK 和IK ,tail分别从 (14 1± 2 2 )pA·pF-1和 (4 0± 0 6 ) pA·pF-1降至 (9 4± 1 3) pA·pF-1和 (2 1± 1 0 ) pA·pF-1,下降率分别为 33 2 %和 35 3%。该药使IK 和IK ,tail的I V曲线幅度降低 ,对曲线形状影响不明显。结论　BTHP入细胞内后可阻滞延迟整流钾电流和延长动作电位时程。     

THE EFFECT OF THE ''HYPERTENSINOGENIC STEROID, 9α-FLUORO-CORTISOL ON BLOOD PRESSURE IN SHEEP WITH ACTH-INDUCED HYPERTENSION

The effect of treatment with 9 alpha-fluorocortisol (9 alpha FF), a steroid which causes hypertension in sheep, was examined in sheep with ACTH-induced hypertension. ACTH treatment alone increased mean arterial pressure (MAP), plasma Na concentration, water intake and urine volume and decreased plasma K concentration. 9 alpha FF treatment, for 3 days during continuing ACTH administration, did not change blood pressure but increased heart rate, water intake and urine volume and decreased urinary K excretion. As 9 alpha FF did not cause a further increment in blood pressure in sheep with ACTH-induced hypertension it is possible that both ACTH and 9 alpha FF may produce hypertension by similar mechanisms.     

THE EFFECT OF EPANOLOL ON INTRA-ARTERIAL AMBULATORY BLOOD PRESSURE AND BARORECEPTOR HEART RATE REFLEX IN ESSENTIAL HYPERTENSION

1. The effect of chronic treatment with epanolol, a new cardioselective beta-adrenoreceptor antagonist with moderate beta 1-selective intrinsic sympathomimetic activity (ISA), on 24 h ambulatory intra-arterial blood pressure (24 h IABP) and the sino-aortic baroreceptor heart rate (SAB/HR) reflex was investigated in six hypertensive subjects. 2. All subjects demonstrated a greater than 10% reduction in mean arterial pressure with atenolol therapy (100 mg once daily) before entering a randomized, double-blind, placebo-controlled, crossover protocol with epanolol (100 mg twice daily for 4 weeks). 3. Epanolol treatment at this dose was not associated with significant reduction in systolic or diastolic 24 h IABP or heart rate. There was no change in SAB/HR reflex set point, sensitivity or latency with epanolol. 4. beta 1-selective ISA may be undesirable in beta-adrenoceptor antagonists used to treat hypertension.     

METABOLIC STUDIES OF URIDINE IN RATS WITH DOCA-SALT HYPERTENSION AND ON HIGH SODIUM DIET

1. The steady-state metabolic clearance and calculated secretion rate of the pyrimidine nucleoside uridine were studied by equilibrium infusion in normal rats, rats on a high sodium diet, rats made hypertensive by subcutaneous injection of deoxycorticosterone acetate (DOCA), unilateral nephrectomy and high sodium drinking fluid, and two control groups of rats for the hypertensive group. 2. Basal plasma uridine concentration in DOCA-salt hypertension rats was found to be significantly reduced to 3.99 ± 0.31 pmol/L (mean ± s.e.m.) compared with control rats (11.98 ±1.64 μmol/L). Metabolic clearance (MCR) in DOCA-salt hypertensive rats was significantly raised (200.54±10.77 mL/kg per min) compared with control rats (65.17 ± 1.99 mL/kg per min). No difference was found in plasma uridine concentration and MCR among the other two control groups and high sodium diet rats. Calculated secretion rate was unchanged in all animals. No significant differences were found between different groups of rats in blood pressure responses to uridine. 3. The raised metabolic clearance and reduced plasma uridine concentration in DOCA-salt hypertension may be consistent with increased intracellular transport and phosphorylation of uridine to the physiologically active compound uridine monophosphate (UMP) which would lead to arteriolar constriction, hypertension and natriuresis. The results contrast with those in humans with extracellular fluid (ECF) expansion from endstage renal failure and rats with one-kidney, one-clip (1K1C) hypertension but are not due to the pharmacological effects of deoxycorticosterone. The difference may be due to the haemodynamic consequences of reduced renal perfusion pressure or reduced renal mass compared with DOCA-salt model.     

EFFECT OF DIETARY UREA ON BLOOD PRESSURE IN SPONTANEOUSLY HYPERTENSIVE RATS

The feeding of a normal diet containing 13.5% urea (in place of protein in a high protein diet) attenuated the development of severe hypertension and decreased the incidence of stroke in spontaneously hypertensive rats (SHR), when 1% NaCl solution was given to them. The urea not only increased urine volume, but also increased urinary sodium excretion in SHR given 1% NaCl for drinking. Although there was no obvious difference in erythrocyte size between the urea and the control groups, there was a significant inverse correlation between plasma urea level and erythrocyte size. These results suggest that a high protein diet reduced blood pressure partly through the diuretic effect of urea, the common metabolite of various proteins.     

ALTERATIONS IN CEREBROSPINAL FLUID SODIUM AND OSMOLALITY IN RATS DURING ONE-KIDNEY, ONE-WRAP RENAL HYPERTENSION

Measurements of plasma and cerebrospinal fluid (CSF) sodium and osmolality were made throughout the course of one-kidney, one-wrap Grollman renal hypertension. Although the plasma sodium and osmolality did not rise after 28 days, CSF sodium and osmolality was increased significantly at 3 days postwrap. As a result, the CSF to plasma ratio for both sodium and osmolality was significantly elevated during the initial postwrap period. These observations suggest that an increase in CSF sodium may provide an initiating stimulus for an elevated arterial pressure in one-kidney, one-wrap renal hypertension.     

THE INFLUENCE OF RENAL PROSTAGLANDINS, CENTRAL NERVOUS SYSTEM AND NaCl ON HYPERTENSION OF DAHL S RATS

1.Kidney factors and central nervous system (CNS) factors appear to have powerful influences on NaCl-induced hypertension. In quick-frozen kidneys the prostaglandin E₂ (PGE₂) concentration in the renal papilla is 60% lower in Dahl S rats than in Dahl R rats (17 ng/100 mg vs 42 ng/100 mg; P<0.01) when both S and R rats are on a 0.3% low NaCl diet. When S and R rats eat a 4% high NaCl diet for 4 weeks or 11 weeks, the PGE₂ concentration doubles in both strains (P<0.05) but the papillary PGE₂ concentration in the S rats is always about half that in the R rats (P<0.01). 2.Through effects on Na excretion and papillary plasma flow, the low PGE₂ in S papillas may account in part for the large rises of blood pressure in S rats after eating a high NaCl diet. This proposition was explored by utilizing high fat diets with either normal or high linoleic acid content. Arachidonic acid is the precursor of PGE₂ and linoleic acid is the precursor of arachidonic acid. It turned out that the low PGE₂ level in S papillae could be tripled by a diet high in linoleic acid. Sixteen S rats on a 16 week diet with 5% NaCl/1.5% linoleic had a mean papillary PGE₂ level of 30 compared to a level of 89 in fifteen other S rats on a diet with 5% NaCl/16% linoleic. The 16% high linoleic diet tripled the PGE₂ concentration in S papillae (P< 0.005). It also increased the PGE₂ concentration in R papillae 2.5 times, 137 vs 53 (P<0.02). On either high or normal linoleic diets the PGE₂ in S papillae was always at least 35% less than that in R papillae. However the 16% high linoleic diet did raise the papillary PGE₂ level in S rats up to that found in normal rats on regular rat chow of equivalent NaCl content. Moreover this change in PGE₂ level was associated with greatly reduced blood pressure rises in S rats. 3. The blood pressures of S rats on a 5% NaCl/1.5% linoleic diet began to rise after 5 weeks on the diet and reached 183 mmHg after 16 weeks. The blood pressures of S rats on a 5% NaCl/16% linoleic diet did not begin to rise until 12 weeks on the diet and reached only 166 after 16 weeks. The high linoleic diet greatly delayed the onset of the rise in blood pressure and significantly reduced the ultimately attained level (P< 0.001). In fact, on a low 0.3% NaCl diet, S rats of comparable age will reach approximately the same mildly hypertensive level of 166. Thus in S rats the high linoleic diet brings papillary POE₂ up to normal and also prevents the large rises in blood pressure usually related to a high NaCl intake. These two changes may well be causally related. 4. The CNS also influences NaCl hypertension in S rats. Bilateral electrolytic lesions of the paraventricular nuclei bordering the third brain ventricle cause S rats to attain only half of the NaCl-induced hypertension seen in sham-lesioned S rats (163 vs 197 mmHg, P< 0.001). Destroying catecholaminergic neurons in the brain of S rats using 6-hydroxydopamine put into the lateral brain ventricle also abolishes half of the NaCl hypertension (165 vs 210; P<0.001). Bilateral lesions of the suprachiasmatic nuclei near the third brain ventricle significantly worsen NaCl hypertension in S rats (blood pressure 201 with SCN lesions vs blood pressure 186 with sham lesions, P<0.001). Thus the kidney, the CNS and sodium influence the degree of hypertension in the Dahl S rat.     

EFFECT OF TEMOCAPRIL ON HAEMODYNAMIC AND HUMORAL RESPONSES TO EXERCISE IN PATIENTS WITH MILD ESSENTIAL HYPERTENSION

1. This study was carried out to evaluate the effect of temocapril on haemodynamic and humoral responses to exercise in nine patients with mild essential hypertension (WHO stages I and II). 2. After a 4-week placebo period, temocapril was administered at a dose of 1.0 mg once daily for 2–4 weeks. Graded submaximal bicycle ergometer exercise was performed before and after temocapril treatment, and the changes in arterial blood pressure, heart rate, cardiac output (CO), and systemic vascular resistance (SVR) were evaluated. In addition, the plasma norepinephrine (NE) level was determined both at rest and peak exercise before and after temocapril treatment. 3. Both the systolic and diastolic blood pressure were reduced at rest and during exercise by temocapril treatment. No significant change in the resting heart rate and CO was observed, and the exercise-induced increase of these parameters was also not affected by temocapril. In contrast, the resting SVR was significantly decreased by temocapril, although the exercise SVR was similar during both temocapril and placebo treatment. 4. Although there was no significant change in the plasma NE level with temocapril treatment, the exercise-induced increase of plasma NE was significantly suppressed by temocapril. 5. These results indicate that temocapril reduces the blood pressure without causing any significant changes in the heart rate and CO at rest, and that it does not produce any changes in the haemodynamic response to exercise.     

EFFECT OF PARATHYROIDECTOMY ON DEVELOPMENT OF HYPERTENSION AND ATRIAL RESPONSIVENESS IN SPONTANEOUS HYPERTENSIVE RATS

1. In order to further clarify the relationships between parathyroid function and development of hypertension, the effects of parathyroidectomy (PTX) on blood pressure and on responsiveness of atria isolated from spontaneous hypertensive rats (SHR) were examined. 2. PTX was carried out in 6-week-old SHR and normotensive Wistar rats. The experiments were performed 2 weeks after surgery. 3. PTX reduced the plasma calcium concentration and decreased atrial calcium content in SHR. On the other hand, basal contractile force and beat frequency of isolated atria were higher in PTX SHR than in sham-operated SHR. In response to cumulative addition of isoprenaline, atria from PTX SHR displayed diminished inotropic and chronotropic responses compared with sham-operated SHR. Similar results were obtained in atria isolated from Wistar rats. When calcium sensitivity was studied in atria from Wistar rats, basal and isoprenaline-induced maximum contractile forces were higher in PTX group than in the sham-operated group. Nevertheless, basal and isoprenaline-induced maximum contractile forces, determined at the respective plasma ionized calcium concentration of PTX and sham-operated groups (0.83 and 1.22 mmol/L), were not significantly different. 4. Our results do not favour a role for alteration in atrial activity as a causal mechanism in delayed development of experimental genetic hypertension after parathyroidectomy.     

DIFFERING NORADRENALINE KINETICS IN ESSENTIAL HYPERTENSION AND DEPRESSIVE ILLNESS, TWO DISEASES IN WHICH THE PLASMA CONCENTRATION OF NORADRENALINE IS SOMETIMES ELEVATED

1. The rate of spill-over of noradrenaline to plasma, and neuronal noradrenaline uptake, which influences spill-over, were studied in patients with essential hypertension and depressive illness. 2. Noradrenaline spill-over was increased in seven of thirty-four patients with essential hypertension and five of eleven patients with primary depressive illness, compared with values in seventeen normal subjects (range 1.0–3.63 nmol/min perm²). 3. Faulty neuronal reuptake of noradrenaline seemed to be the cause of higher noradrenaline spill-over in patients with essential hypertension. Increased sympathetic nerve firing rates apparently were responsible in the primary depres-sives, despite their normal blood pressure. 4. These puzzling findings suggest that hypertension occurs when neurotransmitter excess is due to defective noradrenaline reuptake (in essential hypertension), but not chronically increased nerve firing (in depressive illness).     

EFFECTS OF AMIODARONE AND L8040, NOVEL ANTIANGINAL AND ANTIARRHYTHIC DRUGS, ON CARDIAC AND CORONARY HAEMODYNAMICS AND ON CARDIAC INTRACELLULAR POTENTIALS

1. The effects on the coronary and systemic haemodynamics of intravenous and intracoronary injections of two benzfuran derivatives, amiodarone and its brominated analogue (L8040), were studied in open-chest anaesthetized dogs. The effects of L8040 on cardiac intracellular potentials after 6 weeks of 20 mg/kg intraperitoneal injections in rabbits were also investigated. 2. Both compounds produced dose-related and quantitatively similar decreases in coronary vascular resistance following their intracoronary administration; threshold effects occurred with about 0.25 mg of each drug and maximal effects with 4 mg. Larger intracoronary doses produced measurable systemic effects. 3. Intravenous injections of amiodarone and L8040 (2·5·10 mg/kg) produced dose-related decreases in heart rate and aortic pressure with a fall in total peripheral resistance. The left ventricular output was either unaffected or increased with a consistent augmentation in stroke volume. 4. The bradycardia produced by both drugs was associated with prolongation of the P–R interval of the electrocardiogram with no significant effect on the QRS duration or the Q–T interval. 5. Each drug produced a decrease in the total peripheral vascular resistance with no change in left ventricular end diastolic pressure except after 10 mg/kg doses which led to an increase in this parameter. 6. Cardiac contractile force and peak LV dp/dt were reduced by both drugs in a dose-related manner. 7. Chronic intraperitoneal administration of L8040 in rabbits caused a prolongation of the duration of the atrial and ventricular intracellular potential without an effect on the maximal rate of depolarization. 8. The effects of amiodarone or L8040 on the coronary circulation and arterial pressure may be attributed to their vasodilator properties but their depressant actions on cardiac contractile force and peak LV dp/dt with an increase in left ventricular end diastolic pressure at high doses, also suggest intrinsic negative inotropic propensity for both compounds. 9. It is concluded that the overall effects on coronary and systemic haemodynamics of amiodarone and its brominated analogue are likely to permit a favourable influence on the balance of oxygen supply and demand in myocardial ischaemia; in addition, their actions on sinoatrial and atrio-ventricular conduction as well as those on cardiac repolarization suggest potential antiarrhythmic properties which merit investigation.