THE PRESENT STATUS OF THE AUTOREGULATION THEORY OF THE PATHOGENESIS OF HYPERTENSION

1. The autoregulation theory of hypertension has been attractive because it postulates a mechanism whereby an early rise in cardiac output becomes ‘transformed’ through normal autoregulatory processes into an elevated total peripheral resistance. 2. ‘Normal’ autoregulation involved in control of blood flow of regional beds is a rapid process compared with the slow changes postulated by the autoregulation theory. 3. Evidence is presented that under appropriate experimental conditions ‘volume’ factors (cardiac output) and ‘constrictor’ factors exert independent long-term effects in developing and in established hypertension. There is little evidence to support the autoregulation theory of hypertension.     

PACEMAKING IN THE HEART: THE INTERPLAY OF IONIC CURRENTS

1. There is still a degree of controversy about which currents drive pacemaking in the sinoatrial node or sinus venosus. Early attempts to identify a single ‘pacemaker current’ in these tissues, based on voltage-clamp data, were largely unsuccessful, prompting the search for other mechanisms that may contribute to rhythmic activity. 2. Whole-cell patch-clamp recording from single cells isolated from the sinus venosus of the toad has shown that a voltage-dependent sodium current may play a role in pacemaking. This current has a transient component that contributes to the action potential upstroke and an inactivation-resistant component that contributes to the diastolic depolarization. The relative importance of this current in pacemaking is still controversial. 3. The development of computer models of pacemaking has contributed greatly to our understanding of how ionic currents can interact to produce rhythmic activity. Results are presented from one such model, ‘Oxsoft Heart', to illustrate the different contributions of I_f and I_NA and to highlight the concept that pace-making is driven by the integrated activity of many processes, rather than by any one current in particular. 4. Present models of pacemaking fail to accurately reproduce biological observations for certain situations. It is becoming clear that many processes contribute to pacemaking and have yet to be fully incorporated into models. Recent results regarding the role of intracellular calcium buffering and release and their implications, are discussed in this context. 5. The control of pacemaking by neurotransmitters is discussed. The limitations of single cell models in reproducing many of the complex responses to nerve stimulation of multicellular tissue, such as postinhibitory rebound, are discussed and possible improvements to models are suggested.     

COMPARISON OF THE REFLEX EFFECTS OF ARTERIAL BARORECEPTORS AND CARDIAC RECEPTORS ON THE HEART RATE OF CONSCIOUS RABBITS

1. The reflex effects on heart rate (HR) of presumptive cardiac receptors have been differentiated from those of the arterial baroreceptors in conscious rabbits by inflating cuffs on the ascending aorta, descending aorta, inferior vena cava and pulmonary artery. 2. When the outflow from the right ventricle was progressively impeded the accompanying increase in HR was entirely explicable by unloading of the arterial baroreceptors. 3. As the outflow from the left ventricle was progressively impeded there was an initial increase in HR due to unloading of the arterial baroreceptors, followed by a progressive decline. This decline was attributed to a reflex arising from vagallyinnervated receptors in the left side of the heart. The threshold of this cardiac receptor-HR reflex occurred at a higher level of mean aortic pressure than that at which the effects of the arterial baroreceptors on HR were maximal. Cholinergic (vagal) efferent nerves were responsible for two-thirds of the decline in HR caused by the reflex. 4. The properties of the cardiac receptor-HR reflex were altered by drugs that affect myocardial contractility. Isoprenaline raised the mean aortic pressure at which the threshold occurred, but lowered the corresponding level of left ventricular end-diastolic pressure. Propranolol virtually abolished the reflex, even though left ventricular end-diastolic pressure reached a high level. 5. It is concluded that in the conscious rabbit the arterial baroreceptor reflexes normally prevent the threshold of the cardiac receptor-HR reflex from being attained.     

THE EFFECTS OF THYROID STATUS ON DIGOXIN DISTRIBUTION IN THE RAT

1. Tritiated digoxin was injected intravenously into euthyroid, hyperthyroid and hypothyroid rats. The rats were killed at intervals up to 24 h and tritium in serum and tissues counted. 2. Serum concentrations of tritium in the hyperthyroid animals were less than in the control group, whereas the concentrations in the hypothyroid group were similar to those in the control group. 3. Cardiac tissue concentrations of tritium were higher in the hyperthyroid group than in the control group, but in the hypothyroid group were similar to the control group. 4. The decreased serum levels in the hyperthyroid rats were probably due to an increased volume of distribution. 5. Pharmacological resistance to digoxin in hyperthyroidism must be due to some alteration in cardiac function and it is suggested that this is an increase in Na/K ATPase receptors.     

EFFERENT MECHANISMS RESPONSIBLE FOR THE BRADYCARDIA PRODUCED BY LESIONS COINCIDING WITH THE A1 GROUP OF CENTRAL CATECHOLAMINE NEURONS IN THE CONSCIOUS RABBIT

1. The effector mechanisms responsible for the bradycardia evoked by bilateral lesions of the brainstem coinciding with the A1 catecholamine cells were analyzed in four groups of rabbits. Sham or lesion operations were carried out in animals with intact cardiac effectors, with cardiac sympathetic block induced by propranolol, with cardiac vagal block induced by methylscopolamine and with total cardiac autonomic block induced by the use of both drugs together. 2. Lesions produced a transient increase in blood pressure of 25 (s.e.m. =4) mmHg and a transient bradycardia, or increase in heart period of 141 (s.e.m. =18) ms. The bradycardia had both baroreflex-independent and baroreflex-dependent components as determined from analysis of stimulus response curves relating heart period to mean arterial pressure. 3. The ‘baroindependent’ component of the bradycardia, measured as a lengthening in heart period, ranged from 35–49 ms in the four groups of animals and was unaffected by administration of propranolol alone, methylscopolamine alone, or of both together. These findings suggest that the baroindependent slowing of the heart is not mediated through changes in activity of either the cardiac sympathetic nerves or of the vagal fibres innervating the heart. 4. The ‘baroreceptor’ component of the bradycardia reflects that portion of the decrease in heart rate resulting directly from the increase in blood pressure. This component was found to account for a lengthening in the heart period of 81 (s.e.m. =23) ms in animals with intact effector mechanisms: it was virtually abolished by methylscopolamine (0 ms, s.e.m. =13) but not significantly affected by propranolol (54 ms, s.e.m. =25), indicating that this barodependent component is predominantly mediated through the vagus.     

INFLUENCE OF WORKLOAD ON THE ANTIHYPERTENSIVE EFFECT OF EXERCISE

1. The relation between workload and the antihypertensive effect of exercise therapy in hypertensive patients, and the mechanism of that effect, were investigated. 2. Twenty-six patients participated in the study and were randomly assigned to 10 weeks of either low or high workload exercise. In the low workload group, 16 mild hypertensive patients were treated with bicycle ergometer exercise at approximately 50% of their maximum oxygen consumption (VO2max) for 60 min three times a week for 10 weeks. In the high workload group, 10 mild hypertensive patients exercised on the same schedule, but at approximately 75% of VO2max. 3. After 10 weeks of exercise, the low workload group had significantly lower systolic (9 mmHg), mean (6 mmHg) and diastolic (6 mmHg) blood pressures. In the high workload group, decreases in systolic (3 mmHg), mean (4 mmHg) and diastolic (5 mmHg) blood pressure were not statistically significant. 4. In the low workload group, changes in haemodynamic and humoral variables were not significant, except for a reduction in plasma norepinephrine at week 7. Cardiac index and plasma norepinephrine tended to decrease. In the high workload group, plasma norepinephrine and the renin-angiotensin system were transiently stimulated after 4 weeks of exercise. Stroke volume significantly increased (+26.4%) after 10 weeks of high workload exercise. 5. Based on these results and better patient compliance with the exercise programme in the low workload group than in the high workload group, low workload exercise therapy was recommended to mild hypertensive patients.     

ELECTROPHYSIOLOGICAL PROPERTIES OF THE FIBRILLATING ATRIUM: IMPLICATIONS FOR THERAPY

1. Atrial fibrillation (AF) is the most commonly occurring cardiac dysrhythmia and remains a challenge to medical therapy. Although the disorder has been recognized for over 100 years, surprisingly very little is understood about its pathophysiology. Over the past decade, a variety of experimental and animal models of AF have been developed and these have provided insights into the mechanism of AF. 2. The pathophysiology of AF is complex. Atrial fibrillation can be caused either by a single source of very rapid impulses or, in the majority of cases, by multiple random re-entering wavelets. The notion that AF may be initiated by a single rapid firing focus and the perpetuation of AF may be partly dependent on macro re-entry around the natural atrial orifices provides a new potential curative therapy for AF by radiofrequency ablation. 3. Shortening of atrial wavelength, either by slow atrial conduction velocities, short atrial refractory periods or both, seems to predispose to development of intra-atrial re-entry and, thus, AF. The functional mechanism by which anti-arrhythmic drugs terminate AF appears to be by prolonging the wavelength and decreasing the number of re-entry wavelets. These understandings are important for the future development of effective anti-arrhythmic agents against AF. 4. The presence of a short and variable excitable gap during AF may be potentially important for termination of AF by pacing. 5. New insights are being gained into the potential role and mechanism of electrical remodelling of the atrium due to AF. Repeated induction of AF by rapid atrial pacing leads to a shortening of atrial refractoriness with loss of rate adaptation, which favours the induction and maintenance of AF. These electrophysiological changes were assumed to occur during repeated AF and to facilitate the generation of multiple re-entrant wavelets. These data suggest that prompt restoration of sinus rhythm and new novel therapy that prevents or diminishes electrical remodelling may promote maintenance of sinus rhythm after successful cardioversion.     

CHARACTERIZATION OF THE BARORECEPTOR HEART RATE REFLEX DURING DEVELOPMENT IN SPONTANEOUSLY HYPERTENSIVE RATS

1. We have examined the baroreceptor-heart rate (HR) reflex in weight-matched conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats during development. 2. Graded steady-state changes in mean arterial pressure (MAP) and the corresponding HR responses before and after vagal blockade with methylatropine were fitted to an S-shaped logistic function. 3. At 6 weeks of age, SHR had a 17% higher MAP than WKY and an increased baroreflex gain (slope) compared with WKY due to an increased curvature of the MAP-HR relationship. The HR range (the difference between the upper and lower HR plateaus) was similar in the two strains at this time. 4. From 9-14 weeks of age, the baroreflex gain progressively increased in WKY and decreased in SHR due to corresponding alterations in HR range. 5. By 20 weeks the baroreflex gain was 23% lower in SHR than WKY due to a 37% lower HR range. 6. There were no differences between the two strains in the sympathetic component of the baroreflex at any age, suggesting that the changes to baroreflex properties were confined to the cardiac vagus. 7. Pretreatment with enalapril from 4-9 weeks reduced the hypertension of SHR at 14 and 20 weeks by 38% and abolished all baroreceptor-HR reflex differences between the two strains. 8. These studies suggest that the major alteration to the baroreceptor-heart rate reflex in the SHR during development was a reduction in the maximum vagal capacity to respond to changes in blood pressure. This effect developed after the onset of hypertension and was prevented by antihypertensive treatment early in life. The lack of effect on the cardiac sympathetic component suggests that altered arterial baroreceptor afferents are not unlikely to be responsible.     

THE INFLUENCE OF ALTERATIONS IN THE CARDIAC LOADING CONDITIONS ON INDICES OF MYOCARDIAL CONTRACTILITY IN THE ANAESTHETIZED DOG

1. An online analogue computer was used to measure myocardial contractility as the ratio dP/dt/IIT where dP/dt is maximum rate of change of left ventricular pressure and IIT is integrated isometric tension. 2. In the open thorax anaesthetized dog, max (dP/dt) and dP/dt/IIT were compared during alterations in preload, by partial vena caval occlusion, and changes in after-load obtained by acetylcholine injections and by partial occlusion of the descending thoracic aorta. 3. A fall in preload lowered max (dP/dt) but did not alter dP/dt/IIT A rise and fall in afterload produced respectively an increase and decrease in max (dP/dt) but dp/dt/IIT was unaltered. 4. From expanded time base recordings, the time from the start of aortic flow (EM flowmeter) to max (dP/dt) was measured to indicate the relationship between valve opening and rnax (dP/dt). At low preload or elevated afterload the aortic valve opened well after max (dP/dt) had been reached. When the afterload fell, max (dP/dt) occurred after the opening of the aortic valve. 5. Positive inotropic stimulation following intravenous isoprenaline caused a marked elevation in dP/dt/IIT. However, the rise in max (dP/dt) was attenuated in comparison to dP/dt/IIT by a marked fall in afterload and thus early opening of the aortic valve. 6. It is concluded that max (dP/dt) is very sensitive to alterations in preload or afterload but the index——-dP/dt/IIT is normalized so that changes in end diastolic fibre length do not alter this index. When the afterload falls max (dP/dt) is no longer determined in the isovolumic phase of contraction so that magnitude of rnax (dP/dt) is reduced. However, it is an empirical finding that IIT also falls so that the ratio is unaltered. dP/dt/IIT is a useful index of myocardial contractility that is insensitive to changes in preload or afterload.     

THE EFFECTS OF m-AMSA ON RAT ISOLATED HEART

m-AMSA (4'[9-acridinylamino]methansulphon-m-anisidide) is a new cytoxic agent now under clinical trial. We used the rat isolated perfused heart model in order to investigate the cardiac effects of m-AMSA. The results of the dose-response study indicate that m-AMSA has an acute moderate negative inotropic effect. The 90% effect (25% decrease in developed force compared to the control) was observed at drug concentration of 1.5 micrograms/ml. The refractory period (as measured by stimuli of twice diastolic threshold intensity) increased progressively as the drug concentration was increased (up to 2.5 micrograms/ml). Measurements of the strength-duration and strength-interval relationship showed that m-AMSA induced a significant reduction (P less than 0.005) in excitability and prolongation of refactoriness. We suggest that m-AMSA has a membranal cardiotoxic effect in addition to its known intracellular cytotoxic effect.     

EVALUATION OF THE CO2 REBREATHING METHOD FOR THE NONINVASIVE MEASUREMENT OF RESTING CARDIAC OUTPUT IN MAN

We have compared the indirect Fick, a non-invasive CO2 rebreathing method for measuring resting cardiac output, with the thermodilution method in eleven subjects including some with cardiac and pulmonary disease. Three alternative methods for calculating veno-arterial CO2 content difference were used: (i) from end-tidal and rebreathing bag equilibrium PCO2 modified from the equations developed for use during exercise by Jones et al. (1975); (ii) by using the uncorrected difference between end-tidal and equilibrium PCO2 and the standard CO2 dissociation curve; (iii) by direct measurement of arterial PCO2. Each method was satisfactory in that reproducibility was similar to thermodilution (5-10%) and the equations relating thermodilution to indirect Fick cardiac output were linear with slope and intercept, close to 1 and 0, respectively. End-tidal PCO2 accurately predicted arterial PCO2 except in five patients with liver disease. Direct measurement of arterial PCO2 is recommended in such patients. In other subjects there was no advantage in either correcting non-invasive measurements of alveolar gas to obtain veno-arterial CO2 content difference, or in direct measurement. The indirect Fick is an accurate method for measuring cardiac output at rest in normal subjects and those with cardiovascular disease. Its use can be extended to other groups by a single arterial blood sample.     

钼对培养乳鼠心肌细胞电活动的影响

本文研究不同浓度的钼对培养乳鼠心肌细胞电活动的影响。用玻璃电极技术,在倒置显微镜下穿刺细胞,引导跨膜电位。结果见到动作电位复极50％的时程(APD_(50))在有效浓度时均呈现明显延长,而跨膜电位其他参数均未见显著变化。提示:钼对培养心肌细胞电活动的主要作用是显著延长APD_(50)。     

DIFFERENTIAL ACTIONS OF THE MEDIAL REGION OF CAUDAL MEDULLA ON AUTONOMIC NERVE ACTIVITIES

1. The inhibitory effects produced by activation of the medial region of caudal medulla on activities of the left and right cardiac sympathetic, vagus and greater splanchnic nerves were studied in chloralose-urethane anaesthetized cats. 2. Electrical stimulation of the medial region produced an 80-92% inhibition of the sympathetic nerve activities, and a 45% and 58% inhibition of the left and right cardiac vagal nerve activities, respectively. There were no significant differences between effects elicited in the left and right autonomic nerves. Similar but smaller inhibitory effects were produced by micro-injection of sodium glutamate (0.5 mol/L) or DL-homocysteic acid (50 mmol/L) to the same medullary sites. 3. These data suggest that neurons residing in the medial medullary region exert strong inhibitory effects on autonomic nerve activities. Since the vasculature is principally innervated by sympathetic nerves, inhibition of sympathetic nerve activities might be the principal factor responsible for the depressor effects caused by activation of the medial region of caudal medulla. The heart is innervated both by sympathetic and parasympathetic nerves. Thus, their simultaneous inhibition during activation of the medial region elicits only a weak and variable inhibition of the heart.     

ROLE OF CARDIAC AND VASCULAR AMPLIFIERS IN THE MAINTENANCE OF HYPERTENSION AND THE EFFECT OF REVERSAL OF CARDIOVASCULAR HYPERTROPHY

Changes in amplifying capacities of the hypertrophied heart and resistance vessels account for the characteristic evolution of haemodynamic patterns in the course of essential hypertension. Reversal of hypertrophy in established essential hypertension requires prolonged control of blood pressure. Redevelopment of hypertension on stopping drug therapy is slowest if there has been reversal of both vascular and cardiac hypertrophy. It may be possible to subsequently maintain normal blood pressure in a proportion of patients by non-pharmacological means following the initial period of drug therapy. Preliminary findings suggest that in a majority of patients the sympathetic nervous system may be overactive, whilst a smaller subset may have dysfunction of volume regulation.     

THE EFFECT OF TRICYCLIC ANTIDEPRESSANT DRUGS ON THE ISOLATED PERFUSED GUINEA-PIG HEART*

1. The effects of tricyclic antidepressants were studied on the isolated perfused guinea-pig heart simultaneously recording myocardial contractile force and cardiac electrogram. 2. Tricyclic antidepressants in a concentration 4 × 10^?-⁵ mol/1 decreased cardiac contractile force and increased cardiac conduction time. 3. Doxepin had significantly greater negative inotropic effect than nortriptyline, protriptyline, desipramine, amitriptyline and imipramine (P < 0.01). 4. There was no significant difference in the increase in P-R interval (P>0.5) and QRS width (P > 0.95) between the tricyclic antidepressants. 5. The isolated perfused guinea-pig heart can be used as a toxicological model for testing and treating cardiac arrhythmias induced by tricyclic antidepressants.     

RESISTANCE OF SYMPATHETIC CARDIAC NERVE FUNCTION IN THE PITHED RAT TO PREJUNCTIONAL EFFECTS OF ANGIOTENSIN II

1. The spinal sympathetic outflow (C7-T2) of pithed male Wistar rats was electrically stimulated (30-50 V, 0.5 ms, 0.1-1.0 Hz) and heart rate and arterial blood pressure were recorded. D-Tubocurarine (1 mg/kg) and atropine (1 mg/kg) were administered intravenously (i.v.) to reduce voluntary and parasympathetic nerve activity. 2. Angiotensin II (0.39-3.4 micrograms/kg per min) was infused at a rate which caused a sustained rise in diastolic blood pressure of at least 25 mmHg but which did not alter basal heart rate. 3. Chronotropic responses to sympathetic nerve stimulation were not affected by infusion of angiotensin II, and were also unaltered by pretreatment of rats with indomethacin (5 mg/kg, i.v.) 10 min prior to commencement of stimulation. 4. These results suggest that positive chronotropic responses to cardiac sympathetic nerve stimulation in pithed rats are not affected by increased angiotensin II levels. Indomethacin had no effect, which indicates that cyclo-oxygenase products were not involved in modulation of chronotropic responses to cardiac sympathetic nerve stimulation.     

EFFECT OF ACTH ADMINISTRATION ON THE HAEMODYNAMIC RESPONSE TO ARGININE-VASOPRESSIN IN SHEEP

1. Blood pressure, heart rate and cardiac output were studied in intact conscious sheep during AVP infusion at 0.1, 0.25, 0.5 and 10 μg/min for 30 minutes to determine whether pressor responsiveness to AVP was altered in ACTH-induced hypertension. 2. Prior to ACTH treatment, AVP produced rises in blood pressure associated with a fall in heart rate and cardiac output. 3. During ACTH treatment, pressor responsiveness to AVP and decrease in cardiac output were unchanged, but reflex bradycardia was reduced. 4. ACTH-induced hypertension in sheep is not associated with enhanced pressor responsiveness to AVP.     

THE CARDIOVASCULAR ACTIONS OF 1-METHYLISOGUANOSINE

1. 1-Methylisoguanosine was found to cause a potent long-lasting decrease in both blood pressure and heart rate after oral administration to conscious hypertensive rats. Dose-response curves to intravenously administered 1-methyliso-guanosine and adenosine in anaesthetized rats demonstrated qualitatively similar decreases in blood pressure and heart rate, with 1-methylisoguanosine being two to three times more potent than adenosine. 2. In guinea-pig isolated atria, 1-methylisoguanosine exhibited a negative inotropic and a negative chronotropic effect with a greater potency than adenosine. 3. In halothane-anaesthetized cats, 1-methylisoguanosine produced a biphasic response on cardiac output: a rapid initial decrease followed by a slow increase. 4. 1-Methylisoguanosine had no effect on the response to intralumenally administered noradrenaline in isolated perfused rat tail arteries but reduced the response to electrical stimulation. In these effects, 1-methylisoguanosine was similar to adenosine.