1 We assessed the relaxant effect of 17f,-oestradiol (10 -, 10-6 and 10-M) on rabbit isolated coronary arteries precontracted with prostaglandin F2,, (3 x 10-6M), high extracellular potassium (30mM) and Bay K 8644 (10-6M) plus high extracellular potassium (15 mM) by measuring isometric tension. 17fl-Oestradiol (10-6 and 10-5M) induced significant relaxation in coronary arteries from male and female rabbits. No differences were seen between arteries with or without endothelium. There were also' no differences between coronary arteries isolated from male and female rabbits. 2 Inhibitors of endothelium-derived relaxing factor and vasodilator prostanoids, namely, reduced haemoglobin, Nw-nitro-L-arginine methyl ester and indomethacin, did not affect the relaxation induced by 17fl-oestradiol in endothelium-intact coronary arteries.3 Methylene blue, an inhibitor of guanylate cyclase, did not affect the coronary artery relaxation induced by 17/1-oestradiol. 4 The' calcium concentration-dependent contraction curve in potassium-depolarization medium was shifted to the right by 17fl-oestradiol (10-6 and 10-5M) in the rabbit coronary artery and rat aorta. The -log EC50 s of calcium in control and after incubation with 17fi-oestradiol (10-6 and 10 -M) were 3.7 + 0.09, 3.1 + 0.10 and 2.8 + 0.08 respectively in rabbit coronary arteries and 3.8 + 0.11, 3.3 + 0.14 and 2.9 + 0.15 in rat aorta. 5 The results indicate that 17fi-oestradiol induces rabbit coronary artery relaxation by an endotheliumindependent mechanism in vitro. A calcium antagonistic property may be involved in the mechanism of rabbit coronary arterial relaxation by 17fi-oestradiol.

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The aim of the study was to compare histological findings in limb and respiratory muscles from control subjects and patients with heart failure of two different aetiologies. Biopsies of the quadriceps femoris, strap, diaphragm and pectoralis major muscles were taken from each group. The control subjects all had normal left ventricular function, and comprised seven undergoing surgical ablation of electrical pathways and 10 undergoing coronary artery surgery. The heart failure group had severely impaired left ventricular function, and were undergoing cardiac transplantation in all except one case. Ten patients with idiopathic dilated cardiomyopathy and seven with heart failure of ischaemic origin were studied. Conventional histochemical techniques and specific anti-myosin immunofluorescent stains were used. There were no consistent differences in fibre type prevalence or diameter between the groups. There were no important histological abnormalities in the two control groups. There were minor/major changes in four of seven patients with ischaemic heart failure but no major abnormality, whilst in the dilated cardiomyopathy group there were five of 10 patients with minor/major changes and three of 10 with major abnormalities (P < 0.001 vs controls). A variety of changes were seen in both groups of heart failure subjects. These were more marked in the dilated cardiomyopathy than ischaemic group, and suggest the presence of fibre type regeneration and/or transformation. Amongst the findings were tubular aggregates, internalization of nuclei, bizzare staining of myosin and staining of neonatal myosin (seven of 14) and the presence of cores (five of 14). Such changes were more prominent in the diaphragm than in the other muscles. In conclusion, histological abnormalities are present in the limb and respiratory muscles from subjects with heart failure. The changes are most marked in subjects with idiopathic dilated cardiomyopathy, suggesting that there may be a generalized cardiac and skeletal myopathy in these subjects. The presence of histological abnormalities in the respiratory muscles may contribute to the pathogenesis of dyspnoea in heart failure.

This study was undertaken to ascertain whether gynaecological history or a reduction in ovarian hormones are triggers of angina in menopausal women with a positive exercise test and normal coronary arteries. The majority of patients with angina pectoris, a positive exercise test and normal coronary arteries are female, suggesting that the female gender may be important in the aetiology. We studied the gynaecological features of 107 women (age 53 +/- 9 years) with syndrome X, taken from a population of 134 patients including 27 males. Cardiological investigations were undertaken and detailed gynaecological history obtained from all the female patients. Menopausal status was confirmed by plasma levels of oestradiol-17 beta < or = 100 pmol.l-1. In 95 of the 107 female patients, chest pain began either during the perimenopausal period (32) or after the menopause (63). Of the 63 menopausal patients, 43 had undergone hysterectomy at an average of 8 +/- 6 years prior to the onset of chest pain. The incidence of hysterectomy in the study population (40%) was four times greater than that of an age-matched population. These findings confirm that the majority of patients with syndrome X are women in whom the chest pain began after the onset of menopause. Ovarian hormone deficiency may, therefore, play a role in the onset of syndrome X in female patients.

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Skeletal muscle metabolic abnormalities exist in chronic heart failure. The influence of physical training on muscle metabolism after myocardial infarction was studied in a rat model. 31P magnetic resonance spectroscopy and enzyme assays were performed in Wistar rats 12 weeks after coronary artery ligation. Infarcted rats were allocated randomly to either 6 weeks of training or non-training. Spectra were collected from the calf muscles during sciatic nerve stimulation at 2 Hz. Fibre typing and enzymatic assays were performed on the muscles of the contralateral non stimulated leg. Post-mortem rats were also divided into severe and moderate heart failure according to the lung weight per body weight. At 200 g twitch tension, phosphocreatine and pH were found to be significantly lower in the non-trained severe heart failure group compared with the other groups. Phosphocreatine recovery half-time was significantly longer in the non-trained group with severe heart failure and correlated with the citrate synthase activity in the muscle. The training did not induce a change in the enzyme activities in the infarcted animals with moderate heart failure but did correct the lower citrate synthase activity in the non-trained severe heart failure animals. This normalization of muscle metabolism was achieved by training without any change in calf muscle mass, making atrophy unlikely to be the sole cause of the metabolic changes in heart failure. Training in rats with severe heart failure can reverse the abnormalities of skeletal muscle metabolism, implicating decreased physical activity in the aetiology of these changes.

Background-Limitation of the blood supply to skeletal muscle in chronic heart failure may contribute to the symptoms of fatigue and diminished exercise capacity. The pathophysiology underlying this abnormality is not known. The purpose of this study was to assess the effect of endothelium dependent and independent vasodilator agents on blood flow in the leg of patients with heart failure. Methods and results-Blood flow in the leg was measured in patients with heart failure (n = 20) and compared with that in patients with ischaemic heart disease and normal left ventricular function (n = 16) and patients with chest pain and normal coronary arteries (n = 8). External iliac artery blood flow was measured using intravascular Doppler ultrasound and quantitative angiography. Flow was recorded at rest and in response to bolus doses of the endothelium independent vasodilator, papaverine. Endothelium dependent responses were measured by infusion of acetylcholine and substance P. Mean (SEM) baseline blood flow was reduced at rest (2-9 (0-4) v 4 5 (0.3) mVs, P < 0 001) and vascular resistance was raised (37.4 (3.6) v 27'1 (3.0) units, P < 0.05) in patients with heart failure compared with that in controls. The peak blood flow response to papaverine (8 mg), acetylcholine (10-7-10-5 moIl), and substance P (5 pmollmin) was reduced in heart failure, with greater impairment of the response to acetylcholine than substance P. There was a correlation between baseline blood flow in the heart failure group and diuretic dose (r = -0-62, P = 0 003), New York Heart Association classification (r = -0 65, P = 0.002), and left ventricular ejection fraction (r = 0-80, P = 0.0004). Conclusions-There is reduced blood flow and raised vascular resistance at rest in the legs of patients with heart failure. The degree of impaired blood flow in the leg correlates with the severity of heart failure. There is impairment of the response to both endothelium dependent and independent vasodilators. Abnormal function of the vascular myocyte in heart failure may explain these results as would structural abnormalities of the resistance vessels. (Heart 1996;75:469-476)