Biomedical subjects
Publications and source records attributed to P Poole-Wilson.
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Neuropeptide Y (NPY) has been shown to cause direct vasoconstriction of coronary arteries in many species, including dogs, rabbits and man, which is selectively inhibited by calcium-channel blocking agents. Recently, NPY has also been reported to inhibit the relaxation to noradrenaline in isolated rabbit coronary arteries, but the composition of the Krebs solution described in this study indicated that it contained no magnesium. Since magnesium is known to be a physiological antagonist of calcium and to have a profound influence on the contraction of coronary vascular smooth muscle, we examined the importance of magnesium in modulating both the direct vasoconstrictor response to NPY and the NPY-induced inhibition of relaxation to noradrenaline, using ring preparations of rabbit circumflex coronary artery.
STUDY OBJECTIVE: The aim was to identify the role of the endothelium in mediating the responses to acetylcholine in the rabbit coronary artery, and to determine whether alpha or beta adrenergic stimulation may cause relaxation via endothelial receptors in the coronary arteries of this species. DESIGN: Responses to acetylcholine and adrenoceptor agonists were compared in isolated ring preparations with and without endothelium. The adrenoceptor agonists were examined in the presence of phentolamine or propranolol to block alpha and beta adrenoceptors, respectively. EXPERIMENTAL MATERIAL: 30 New Zealand white rabbits (2.3-3.4 kg) were killed by an overdose of barbiturate and exsanguination, and the left epicardial coronary artery was dissected free. Ring preparations were suspended in organ baths under isometric tension and, where required, the tone of the preparations was raised by KC1. MEASUREMENTS AND MAIN RESULTS: Concentrations of acetylcholine up to 10(-6) mol.litre-1 produced dose dependent relaxation of the preparations with endothelium intact, but no relaxation in preparations denuded of endothelium. At higher concentrations, a marked vasoconstrictor response was seen in all preparations regardless of the presence of endothelium. At basal tone, acetylcholine produced vasoconstriction which reached a maximum of 1.0 (SEM 0.14)g tension in preparations with endothelium and 1.74(0.27) g tension in those without endothelium (p less than 0.05). In coronary arteries pretreated with 50 mumol.litre-1 phenoxybenzamine to block alpha adrenoceptors, noradrenaline, isoprenaline, and salbutamol produced dose dependent relaxation of the preparations; this was unaffected by the absence of endothelium. In vessels not pretreated with phenoxybenzamine, propranolol inhibited the relaxation to noradrenaline and isoprenaline but again there was no difference between vessels with and without endothelium. CONCLUSIONS: In the rabbit isolated epicardial coronary artery, acetylcholine produces an endothelium dependent relaxant response over a limited concentration range; a vasoconstrictor response via smooth muscle dominates at higher concentrations. beta Adrenoceptors mediating relaxation are present on the smooth muscle, but there was no evidence for either alpha or beta adrenoceptor mediated responses via the endothelium. Important differences with coronary arteries from other species are discussed.
Vasomotor responses of isolated coronary arteries to peptide and nonpeptide neurotransmitter agents changed with the development of sexual maturity in female New Zealand white rabbits aged 4-12 months. There was a significant reduction from 4- to 12-month-old animals in both the direct smooth muscle vasodilator responses to calcitonin gene-related peptide (p less than 0.01) and vasoactive intestinal polypeptide (p less than 0.001), and in the endothelium-mediated response to substance P (p less than 0.005). Vasodilator responses to concentrations of acetylcholine (ACh) greater than 0.1 microM were virtually absent in the 6- and 12-month-old animals. No change in maximal relaxation to noradrenaline was seen with maturation, although there was a small significant increase in potency. The contractile response of the smooth muscle to 30 mM KCl declined steadily as the animals matured, but the maximal contraction to ACh (p less than 0.05), neuropeptide Y (p less than 0.02), and serotonin (p less than 0.05) increased significantly between 4 and 12 months of age. These results indicate that following sexual maturation in the female rabbit, the epicardial coronary artery shows a significant increase in maximum responses to vasoconstrictor neurotransmitter agents and, at the same time, a marked decline in responses to some vasodilator agents, both those acting directly on the smooth muscle and those acting via the endothelium.
Dopexamine (FPL 60278) is a new vasodilator possessing both postjunctional dopaminergic and beta 2-adrenoceptor agonist actions. Its acute haemodynamic effects were compared in a cross-over study with those of dobutamine, captopril, and glyceryl trinitrate (GTN) in eight adult patients with chronic heart failure. Dopexamine, 1 microgram/kg/min intravenously (i.v.) for 10 min, increased cardiac index, systolic blood pressure, and heart rate while reducing systemic vascular resistance. Pulmonary artery end-diastolic pressure was unchanged. Plasma norepinephrine (NE) increased during dopexamine infusion. No arrhythmias occurred. Dobutamine, 5 micrograms/kg/min i.v. for 10 min, increased cardiac index and systolic blood pressure similarly but did not increase heart rate or reduce vascular resistance. Captopril, 25 mg orally, did not alter cardiac index at 1 h, but reduced heart rate, blood pressure, pulmonary diastolic pressure, and vascular resistance. GTN, 100 micrograms sublingually, reduced pulmonary diastolic pressure but did not affect other variables at 5 min. Dopexamine, because it combines some of the properties of dopamine and salbutamol, may have a role in the management of severe low output cardiac failure.
The clinical and neuroendocrine response to diuretic treatment was assessed at rest and on exercise in 12 patients with heart failure. Before treatment all patients were limited by breathlessness on exercise; one was oedematous. Plasma renin activity and aldosterone were normal but plasma noradrenaline was raised both at rest and on exercise. After one month's treatment with frusemide (40 mg) and amiloride (5 mg) weight was significantly reduced by a mean of 3.5 kg and exercise capacity had doubled. Plasma noradrenaline fell to normal at rest but remained abnormally raised on exercise. Plasma renin activity and aldosterone increased significantly both at rest and on exercise. Diuretics bring about a considerable clinical improvement in patients with chronic heart failure but they stimulate the renin-angiotensin system. Activation of the renin-angiotensin system in moderate heart failure occurs as a response to diuretic treatment rather than as a result of the disease process itself.
Activation of the renin-angiotensin and sympathetic systems in chronic heart failure causes important renal vasoconstriction. In a double-blind cross-over study, treatment with captopril for one month reduced systemic and renal vascular resistance by 14% and 25%, increased renal blood flow by 12%, and increased the percentage of the cardiac output perfusion to the kidney by 13%. Treatment with prazosin for one month also reduced systemic vascular resistance by 8%, renal vascular resistance increased by 20%, and renal blood flow and the percentage of the cardiac output going to the kidney fell by 14% and 26%. During captopril treatment, plasma aldosterone concentration was reduced to normal, but during prazosin treatment there was an initial increase in aldosterone of 45%, and a sustained increase in plasma noradrenaline concentration of 26%. Body weight decreased by 1.7 kg on captopril, but increased by 3.0 kg on prazosin, correlating inversely with the changes in renal blood flow. Sympathetic inhibition with prazosin causes systemic vasodilatation which diverts blood from the kidney and may result in fluid retention. Inhibition of the renin system with captopril causes preferential renal vasodilatation and can improve renal perfusion in chronic heart failure.
A double blind cross over study was performed to compare the long term hormonal, haemodynamic, and clinical responses to specific inhibition of the renin-angiotensin-aldosterone system (captopril) and of the alpha 1 adrenoceptors of the sympathetic system (prazosin) both at rest and during upright exercise in patients with chronic heart failure. Sixteen patients completed one month's treatment with each drug. During conventional diuretic treatment (control) plasma renin activity, aldosterone, and noradrenaline were increased at rest and on exercise. Control left ventricular filling pressures were raised, and correlated significantly with plasma renin activity both at rest and on exercise. Systemic vascular resistance was increased at rest, and its reduction during exercise correlated inversely with the increase in plasma renin activity and plasma noradrenaline. After one month's treatment with captopril there were reductions in plasma aldosterone, weight, left ventricular filling pressure, and systemic vascular resistance at rest and on exercise. Dyspnoea was relieved and exercise capacity increased. The greater fall in systemic vascular resistance on exercise no longer correlated with the increase in plasma renin activity. During treatment with prazosin there were increases in plasma noradrenaline and, transiently, in plasma aldosterone. Fluid retention occurred, and left ventricular filling pressure was unchanged. Compared with control values systemic vascular resistance was reduced at rest but not on exercise. Dyspnoea and exercise capacity did not improve. In chronic heart failure, vasodilatation by inhibition of the alpha adrenergic system with prazosin causes compensatory stimulation of the renin-angiotensin-aldosterone system and does not result in clinical benefit. Inhibition of the renin-angiotensin-aldosterone system with captopril causes secondary vasodilatation at rest and on exercise and results in improvement in symptoms and exercise capacity.
Nineteen patients with chronic heart failure participated in a double blind crossover trial of captopril and prazosin--two drugs with differing neuroendocrine effects--to determine whether neuroendocrine changes could explain clinical and haemodynamic responses to treatment. Patients were assessed before and after acute and long term (four weeks') treatment with each drug given in random order. Sixteen patients completed the study. During captopril haemodynamic improvement was maintained by inhibition of the renin-angiotensin system. Breathlessness was relieved in 15 patients and exercise capacity increased. During prazosin a reduction in systemic vascular resistance was maintained, but plasma renin activity and aldosterone and noradrenaline concentrations increased, fluid retention developed, and clinical benefit did not occur. These results suggest that clinical and haemodynamic responses to long term vasodilator treatment for chronic heart failure are related to neuroendocrine changes. In patients with chronic heart failure inhibition of the renin-angiotensin system results in clinical benefit, whereas inhibition of the alpha adrenergic system does not.
Exercise electrocardiography in women with chest pain is associated with a high incidence of false positive ST segment depression. The recent observation that changes in R wave amplitude during exercise can also be used diagnostically may improve the value of stress testing in women. The results of 12 lead treadmill exercise and coronary angiography were reviewed in 62 women, mean age 51 years, presenting with "angina" without previous myocardial infarction. These were compared with exercise results in 14 healthy asymptomatic volunteers with a mean age of 26 years. In addition to conventional ST analysis, R wave amplitude changes during exercise, measured in leads II, III, a VF, and V4 to 6, were examined. While the sensitivity and specificity of ST and R wave changes were similar at about 67%, their combined interpretation was helpful. If both ST and R wave criteria were negative the predictive accuracy for normal coronary angiography was 94% (17/18). Alternatively, in tests showing both ST depression and an abnormal R wave response, coronary angiography was always abnormal (13/13). None of the normal volunteers developed ST segment depression and 93% (13/14) had a normal R wave response. If both were positive, however, coronary angiography was always abnormal (13/13). Although stress test interpretation in women is difficult, R wave analysis is a useful adjunct to ST change and can improve the predictive accuracy of the test in a significant number of patients.
The relationship between R-wave amplitude and left ventricular volume was examined using two groups of patients, undergoing diagnostic cardiac catheterisation for investigation of chest pain, who had simultaneous R-wave recording and left ventricular angiography. R-wave amplitude was measured in leads 1, 2, 3 and V4-6. Left ventricular volume was altered by nitroglycerine (n = 18) and atrial pacing (n = 13). In both groups, increase or decrease in left ventricular volume was associated with a concomitant change of R-wave amplitude. We conclude that left ventricular volume is an important determinant of surface-recorded R waves with increased amplitude reflecting increased left ventricular volume and vice versa.
The term "calcium antagonist" has been used for more than a decade to describe a group of drugs whose negative inotropism is overcome by calcium. Because this term lacks specificity with respect to a precise mode of action, and implies a classical receptor-agonist-antagonist relationship, its continued use should be questioned. Drugs belonging to this group are verapamil, D600, nifedipine and diltiazem. They inhibit the slow inward current of the action potential and would more appropriately be called "slow channel inhibitors". The group is heterogenous and may have to be subclassified. The negative inotropism of these drugs can be attributed to a reduction of the slow calcium current. The function of most intracellular organelles is unaffected. Studies with radioactively labelled verapamil show tight binding to glycolipids or glycoproteins in the sarcolemma. Consequent change in the conformational state of the cell membrane could inhibit the slow calcium current. The ability of these drugs to protect heart muscle against the deleterious effects of ischaemia and reperfusion may reflect their negative inotropism, with consequent maintenance of tissue ATP above the levels needed to maintain intracellular Ca2+ homeostasis, rather than a direct inhibitory effect on calcium influx during ischaemia or on reperfusion.
In coronary arteries from New Zealand White (NZW) rabbits up to 12 months of age, both direct vasoconstriction to neuropeptide Y (NPY) and inhibition of relaxation to norepinephrine (NE) by NPY were age dependent (p < 0.02 and p < 0.05, respectively); maximal relaxation to NE was unaffected. NPY had no significant effect on arteries from NZW rabbits at 4 months of age, while vessels from Watanabe Hereditable Hyperlipidaemic (WHHL) rabbits showed enhanced direct (p < 0.001) and indirect effects of NPY (p < 0.02). We conclude that the postsynaptic vasoconstrictor effects of NPY on the epicardial coronary artery increase with age and the presence of hyperlipidemia.
BACKGROUND: The long-term outcome of an interventional strategy in patients with non-ST-elevation acute coronary syndrome is unknown. We tested whether an interventional strategy (routine angiography followed by revascularisation) was better than a conservative strategy (ischaemia-driven or symptom-driven angiography) over 5 years' follow-up. METHODS: In a multicentre randomised trial, 1810 patients (from 45 hospitals in England and Scotland, UK) with non-ST-elevation acute coronary syndrome were randomly assigned to receive an early intervention (n=895) or a conservative strategy (n=915) within 48 h of the index episode of cardiac pain. In each group, the aim was to provide the best medical treatment, and also to undertake coronary arteriography within 72 h in the interventional strategy with subsequent management guided by the angiographic findings. Analysis was by intention to treat and the primary outcome (composite of death or non-fatal myocardial infarction) had masked independent adjudication. RITA 3 has been assigned the International Standard Randomised Control Trial Number ISRCTN07752711. FINDINGS: At 1-year follow-up, rates of death or non-fatal myocardial infarction were similar. However, at a median of 5 years' follow-up (IQR 4.6-5.0), 142 (16.6%) patients with intervention treatment and 178 (20.0%) with conservative treatment died or had non-fatal myocardial infarction (odds ratio 0.78, 95% CI 0.61-0.99, p=0.044), with a similar benefit for cardiovascular death or myocardial infarction (0.74, 0.56-0.97, p=0.030). 234 (102 [12%] intervention, 132 [15%] conservative) patients died during follow-up (0.76, 0.58-1.00, p=0.054). The benefits of an intervention strategy were mainly seen in patients at high risk of death or myocardial infarction (p=0.004), and for the highest risk group, the odds ratio of death or non-fatal myocardial infarction was 0.44 (0.25-0.76). INTERPRETATION: In patients with non-ST-elevation acute coronary syndrome, a routine invasive strategy leads to long-term reduction in risk of death or non-fatal myocardial infarction, and this benefit is mainly in high-risk patients. The findings provide support for national and international guidelines in the need for more robust risk stratification in acute coronary syndrome.