ELECTROPHYSIOLOGICAL PROPERTIES OF THE RAT MIDDLE CEREBRAL ARTERY AT DIFFERENT LEVELS OF PASSIVE WALL TENSION

1. Simultaneous measurements of intracellular membrane potential and myogenic tone of proximal segments of the rat middle cerebral artery, mounted in a small vessel myograph, were made at two levels of passive wall tension. 2. At low levels of passive tension (less than 0.25mN/mm) vessels had a resting membrane potential of approximately -65mV. Addition of KCl (5–60 mmol/L), BaCl₂ (0.01–3 mmol/L) or tetraethylammonium (TEA; 0.1–3 mmol/L) resulted in a concentration-dependent depolarization, to approximately—40 mV, generally associated with a contractile response. After the application of high levels of passive tension (to approximately 2mN/mm maximum) the resting membrane potential of the smooth muscle cells was—40 to—45 mV. This more positive membrane potential was generally associated with an increase in myogenic tone of the vessel. Under these conditions, addition of 5–20 mmol/L KCl resulted in a strong hyperpolarization of the cell along with a concomitant decrease in myogenic tone of the artery. The hyperpolarization and vasorelaxation induced by KCl (5–20 mmol/L) were blocked by BaCl₂ (0.5–1 mmol/L). 3. While the addition of ryanodine (10 μmol/L) to vessels under low tension had no effect, when added to a vessel under high tension, this agent caused a rhythmic oscillation in membrane potential. This oscillation was augmented by BaCl₂ (1mmol/L) and inhibited by nifedipine (10nmol/L) and 4-aminopyridine (1 mmol/L). 4. This study suggests that the electrophysiological and mechanical properties of the isolated rat middle cerebral artery depend on the passive resting conditions under which the vessel is studied. The depolarization of membrane potential observed with increased passive tension appears to result from the closure of an inward rectifying K⁺ channel. These results indicate that the inward rectifying K⁺ channel plays an important role in regulating vascular reactivity due to its functional dependence on the mechanical status of the blood vessel.     

HYPERTONICITY INCREASES RABBIT ATRIUM AND PULMONARY VEIN ARRHYTHMOGENESIS: A POTENTIAL CONTRIBUTOR TO THE GENESIS OF ATRIAL FIBRILLATION

• 1 Pulmonary veins are the most important focus for the initiation of atrial fibrillation. Diabetes mellitus may be associated with hypertonicity and increased occurrence of atrial fibrillation.
• 2 The purpose of the present study was to investigate whether hypertonicity alters the electrophysiological characteristics of pulmonary veins and atria to enhance the genesis of atrial fibrillation.
• 3 A whole‐cell patch‐clamp technique was used to investigate action potentials and ionic currents in rabbit isolated single pulmonary vein and atrial cardiomyocytes during immersion in isotonic and hypertonic (1.2× normal osmolality) solutions.
• 4 Hypertonicity increased the spontaneous beating rates of pulmonary vein cardiomyocytes from 2.3 ± 0.3 to 3.4 ± 0.3 Hz (n = 11; P < 0.001). Hypertonicity prolonged action potential duration to a greater extent in atrial cardiomyocytes than in pulmonary vein cardiomyocytes. Compared with atrial cardiomyocytes, hypertonicity increased the transient inward currents and Na⁺/Ca²⁺ exchange currents to a greater extent in pulmonary vein cardiomyocytes, but decreased the delayed rectified potassium currents to a lesser extent.
• 5 Hypertonicity plays an important role in the electrical activity of pulmonary vein and atrial cardiomyocytes, which may have a potential role in the pathophysiology of atrial fibrillation.

     

DILATATION OF THE RIGHT ATRIUM STIMULATES PHOSPHATIDYLINOSITOL TURNOVER

1. Dilatation of the rat right atria caused a stimulation of the phosphatidylinositol turnover pathway as measured by an increase in the accumulation of inositol phosphates in isolated, perfused hearts. 2. In right atria, increases were detected after 1 min dilatation and maximal increases were observed after 10 min. Dilatation for 10 min caused an increase in inositol monophosphate inositol bisphosphate and inositol trisphosphate from 23.3 +/- 0.9, 15.4 +/- 0.4, and 9.5 +/- 0.3 (mean and s.e.m., n = 7 ct/min per mg tissue) to 74.6 +/- 2.3, 20.2 +/- 1.3 and 13.6 +/- 1.5 (n = 8), respectively (P less than 0.01 for all inositol phosphates.) 3. These results show that the myocardium can respond to dilatation by an activation of the phosphatidylinositol turnover pathway.     

ELECTRICAL REMODELLING OF CHRONIC ATRIAL FIBRILLATION

1. It is now recognized that atrial fibrillation (AF) is not a benign condition, as it is associated with a 40% increase in mortality and a doubling of the risk of stroke. 2. The development of AF leads to mechanical, electrophysiological and cellular changes in the atria that tend to sustain AF. This process is known as atrial remodelling. 3. The three electrophysiological elements in the atria that initiate and sustain AF are: (i) shortening of the refractory period and an increase in dispersion; (ii) slowing of conduction velocity; and (iii) the presence of triggerin. foci. 4. As AF is a heterogeneous disorder, therapeutic strategies include the use of devices (pacemakers and atrial defibrillators), radiofrequency ablation (focal ablation or the creation of linear lines) and drug therapy that may reverse a remodelle. atrium.     

ATRIAL NATRIURETIC PEPTIDE RELEASE IN THE RABBIT IS INDEPENDENT OF CARDIAC NERVE ACTIVITY

1. Changes in plasma atrial natriuretic peptide (ANP) were examined in conscious rabbits in response to a 33% blood volume expansion in intact animals and after blockade of cardiac nerve activity. 2. Blood volume expansion by one-third markedly increased right atrial pressure and resulted in a four-fold increase in plasma ANP. 3. Cardiac nerve blockade with intrapericardial procaine had no effect on resting plasma ANP levels. The ANP responses to volume expansion in the presence of cardiac nerve blockade were similar to those seen in intact animals. 4. Release of ANP from its cardiac stores in response to volume expansion is not influenced by cardiac nerve activity.     

COMPETITION BY SECOND MESSENGER SYSTEMS FOR RECEPTOR INTERACTION AND ACTIVATION: IMPLICATIONS FOR TISSUE-SPECIFIC RESPONSES AND DISEASE THERAPY

1. At any one instant, most receptors are now recognized to be able to stimulate multiple signal transduction pathways in a cell when activated by an appropriate hormone. These different signalling pathways appear to allow for distinct cellular responses, such as cell proliferation, differentiation, and shape change. 2. In addition, many different types of cell will possess the same type of receptor. Therefore, for a hormone to be able to transmit differential signals to the various cell types able to respond to it, cells must discriminate the stimulus at some point. Such discrimination would seem to be an absolute requirement to allow a tissue-specific response to an identical initial stimulus. In theory, this specificity could occur at many points in the receptor signal transduction cascade, including cytosolic receptor coupling systems and tissue/cell-specific responsive genes. 3. The present paper summarizes our work and that of others which has determined some of the coupling systems of G-protein-coupled receptors and tyrosine kinase receptors and how these systems may be interacting. 4. In addition to these theoretical considerations, a potential therapeutic strategy underlies the ability of receptors to couple to more than one signal transduction system. If a response to a hormone were, for example, either cell proliferation or cell morphological change or differentiation and separate receptor-coupled signalling systems were responsible for these effects, pharmacological intervention may allow the transfer from one signalling system to another. If such a change allowed a permanent change to the differentiated phenotype, this could potentially form the basis of a signal-based cancer therapy.     

ACTIONS OF ANGIOTENSIN IN THE SUBFORNICAL ORGAN AND AREA POSTREMA: IMPLICATIONS FOR LONG TERM CONTROL OF AUTONOMIC OUTPUT

1. Considerable physiological and anatomical evidence indicates that circulating angiotensin II (AngII), plays important roles in the long-term regulation of autonomic output as a result of actions in two circumventricular structures, the subfornical organ (SFO) and area postrema (AP). 2. Extracellular recordings have demonstrated excitatory actions of AngII on neurons from both of these structures which are ATi receptor mediated, maintained when cells are placed in synaptic isolation, and are dose dependent. Interestingly SFO neurons appear to be an order of magnitude more sensitive to AngII than those in AP. 3. Recent calcium imaging studies have demonstrated that AngII induces increases in intracellular calcium in both SFO and AP neurons. Whole cell patch recordings have also begun to provide important information suggesting that AngII actions may modulate voltage activated ion channels in these two structures to elicit its observed actions on circumventricular organs (CVO) neurons at the blood-brain interface. 4. Through these actions circulating AngII is thus able to influence efferent projections from these CVO which in turn influence the output of hypothalamic cells projecting to the posterior pituitary (vasopressin secretion), nucleus tractus soli-tarius (NTS), and intermediolateral cell column of the spinal cord (to influence sympathetic preganglionics), and medullary neurons in the NTS.     

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.     

EFFECT OF SECRETIN ON PACEMAKER ACTIVITY AND CONTRACTILITY IN THE ISOLATED BLOOD-PERFUSED ATRIUM OF THE DOG

1. The effects of secretin on inotropic and chronotropic activity were investigated in nine isolated canine atrium preparations which were suspended in a bath and perfused with arterial blood from a carotid artery of a heparinized donor dog. 2. Secretin administered into the cannulated sinus node artery in a dose range of 0.1–10 units produced a dose-related positive inotropic and a biphasic chronotropic effect. 3. The positive chronotropic and inotropic responses to secretin were not suppressed by treatment with alprenolol in doses which blocked responses to noradrenaline. 4. The negative chronotropic response to secretin was not blocked by atropine in doses which blocked the response to acetylcholine. 5. After treatment with glucagon, secretin produced dose-related negative chronotropic and a positive inotropic effects. Thus glucagon may antagonize the positive chronotropic effect of secretin. 6. From these results, it is concluded that secretin has a direct effect on atrial rate and contractility.     

INFLUENCE OF BODY TEMPERATURE ON RESPONSES TO HYPOXIA AND HYPERCAPNIA: IMPLICATIONS FOR SIDS

1. This paper reviews current knowledge regarding interactions between body temperature and the respiratory responses to hypoxia and/or hypercapnia, with special emphasis on how these interactions might predispose towards sudden infant death syndrome (SIDS). 2. Use has been made of an adult rat model in which body core temperature is fixed by means of an intra-abdominal heat exchanger. Initial studies indicated that hyperthermia (T_b～ 41° C) enhanced the ventilatory response to hypercapnia, whereas hypothermia (T_b～35°C) interacted with hypoxia to depress respiration. 3. Studies involving hypothalamic lesions in urethane-anaesthetized rats have implicated the posterior hypothalamic area in the hypoxia/hypothermia interaction. Further studies are directed towards examining the role played by more caudal areas, including the raphe nuclei. 4. It has been shown that not only does the hypoxial hypothermia interaction depress breathing but it also reduces, or sometimes eliminates, the ventilatory response to hypercapnia, which under normal circumstances provides one of the most powerful excitatory inputs to the respiratory centres. This implies that an expected reversal of the respiratory depression by build up of CO₂ levels may not occur, which in turn has important implications for SIDS. 5. The literature dealing with the effects of hyperthermia on hypoxic and hypercapnic responses is also reviewed. It is concluded that environmental heat stress may only become a significant problem when it accompanies a febrile infection, under which circumstances it may seriously compromise thermo-regulatory ability and alter breathing responses to chemical stimuli.     

急性心房扩大对兔心房有效不应期的影响及维拉帕米的干预作用

目的:通过建立Langendorff灌流的离体兔心脏模型来研究急性心房扩大对心肌电生理参数及心房颤动(房颤)易感性的影响,了解维拉帕米对其的干预作用。方法:长耳白兔20只建立Langendorff灌流的离体兔心脏模型,随机分为对照组和维拉帕米组。起始右房压力为0,以步长为0.392kPa递增至1.176kPa,在每个压力水平分别测定窦性心动周长(SCL)、心房有效不应期(AERP);应用S1S2刺激评估房颤易感性。结果:随着右房压力由0升高至1.176kPa:(1)对照组AERP显著缩短(P<0.01),且右房压力与AERP呈显著性Spearman负等级相关(rs=-0.664,P<0.01)。(2)对照组S1S2刺激房颤诱发率显著升高(P<0.01)。(3)维拉帕米组不同右房压力水平下心肌各电生理参数及房颤诱发率均无统计学意义(P>0.05)。结论:急性心房扩大使AERP显著缩短,房颤易感性明显提高;维拉帕米可以减弱急性心房扩大对AERP的缩短作用及急性心房扩大对房颤易感性的升高作用。     

EVIDENCE FOR A ROLE FOR THE CARDIOVASCULAR AMPLIFIERS IN HUMAN PRIMARY HYPERTENSION

1. Hypertrophy of vascular and cardiac smooth muscle is present in human primary hypertension. The amplifier properties associated with hypertrophy play a major role in maintaining hypertension. 2. Long-term antihypertensive drug therapy causes substantial regression of the structural changes, assessed by the non-autonomic component of vascular resistance, and by left ventricular mass. The latter occurs more slowly. 3. The more complete the reversal of left ventricular hypertrophy, the more slowly hypertension redevelops if long-term antihypertensive therapy is discontinued. 4. Subjects who redevelop hypertension more rapidly tend to have higher cardiac output, suggesting that the cardiac amplifier may play a role in the pathogenesis. 5. Studies of small arteries and of veins from patients with primary hypertension suggest that there may be a general disturbance of vascular smooth muscle function, independent of the mechanical effects of elevated systemic blood pressure.     

Dronedarone as a new treatment option for atrial fibrillation patients: pharmacokinetics,pharmacodynamics and clinical practice

Importance of the field: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting 1 – 2% of the population. Despite several developments in antithrombotic, antiatherosclerotic and device-based cardiac therapies, few noteworthy antiarrhythmic drugs have been developed.

Areas covered in this review: Dronedarone, a modified analogue of amiodarone, has the pharmacological ability of blocking multiple ion channels. This overview summarizes the pharmacokinetic and pharmacodynamic properties of dronedarone, evaluates its potential application to daily clinical cardiology practice according to the evidence provided by clinical trials, and provides a future clinical perspective for the use of this drug.

What the reader will gain: The readers will gain an understanding of the findings of recent trials performed with dronedarone, which will provide important information for this relatively new antiarrhythmic drug, used for the treatment of atrial fibrillation.

Take home message: Dronedarone provides a reasonable efficacy and safety profile. Recent clinical trials indicate that dronedarone may support maintenance of sinus rhythm, decrease hospitalizations and reduce healthcare costs even in AF patients with structural heart disease but without severe or unstable cardiac failure.     

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.     

URODILATIN (INN: ULARITIDE) AS A NEW DRUG FOR THE THERAPY OF ACUTE RENAL FAILURE FOLLOWING CARDIAC SURGERY

1. Acute renal failure is a severe complication following major cardiac surgery. 2. The effects of urodilatin were evaluated in a randomized, double-blind trial in patients suffering from incipient acute renal failure following cardiac surgery. 3. In the urodilatin group (n= 7) acute renal failure was reverted, whereas in the placebo group (n= 7) six patients had to be haemofiltered or haemodialysed (P < 0.005). 4. Urodilatin induced a rapid onset of diuresis in contrast to placebo-treated patients, who remained oliguric. 5. In the placebo group four of seven patients died while still on haemodialysis (mortality rate 57.1 %) during a postoperative follow-up period of 60 days, while all patients treated with urodilatin survived. 6. On the basis of these results it would appear that urodilatin is an effective drug for the treatment of incipient oliguric acute renal failure following cardiac surgery and for avoiding haemodialysis/haemoflltration.     

A METHOD FOR LOCALIZING ATRIAL TYPE B RECEPTORS IN THE DOG

1. The effect of ectopic stimulation of atria (premature ventricular contraction) on the activity of atrial type B receptors has been studied in dogs. 2. In sixteen open-chest dogs, discharge from right or left atrial type B receptors (identified by their response to pulmonary artery occlusion) was recorded. Direct stimulation of either atrium produced an increase in the activity of the left atrial but a decrease in the right atrial receptors. The earlier during the ventricular systole that the premature ventricular contraction occurred the more marked was the effect. 3. In a separate series of fourteen closedchest experiments the right atrium was stimulated internally via the external jugular vein. The effects on the activity of the atrial type B receptors were similar to those observed during the open-chest experiments. 4. It is concluded that in the dog the technique of internal stimulation of the right atrium without opening the chest can be used to distinguish between the right and left atrial type B receptors.     

PROPERTIES OF MULTIPLE INTERSECTION-UNION TESTS FOR MULTIPLE ENDPOINTS IN COMBINATION THERAPY TRIALS

We consider intersection-union tests involving multiple endpoints in a combination drug trial, for which we control the familywise error rate in the strong sense using closed testing methods. Bonferroni-Holm, Simes-Hommel, and Resampling-Based methods all are considered in this context. Familywise error rate control heuristics are developed and evaluated using a simulation study that is specifically tailored to the intersection-union setting. Both Resampling-Based and Simes-Hommel uniformly outperform the Bonferroni-Holm. Using simulations of power, the choice of Simes-Hommel versus Resampling-Based is seen to depend on the particular alternative of interest. Because it is simpler and has generally good power, we recommend the Simes-Hommel intersection-union tests. The techniques are illustrated using real data from a clinical trial to evaluate a combination asthma therapy.

     

THE EFFECT OF SMOKING ON CAFFEINE ELIMINATION: IMPLICATIONS FOR ITS USE AS A SEMIQUANTITATIVE TEST OF LIVER FUNCTION

1. The effects of caffeine ingestion and cigarette smoking on caffeine and antipyrine pharmacokinetics were studied using normal subjects as their own controls before and after cessation of smoking in an attempt to minimize genetic and other environmental influences. 2. Moderate caffeine ingestion had no inducing effect on caffeine or antipyrine clearance. 3. Cessation of cigarette smoking significantly reduced clearance of caffeine and antipyrine. 4. These results demonstrate that cigarette smoking significantly affects caffeine pharmacokinetics and this may contribute to the variable results for caffeine kinetics found in patients with liver disease.     

吗啡对吗啡依赖大鼠腹侧苍白球神经元放电的影响

目的 :研究吗啡对吗啡依赖大鼠腹侧苍白球的电生理影响 ,探讨其在成瘾机制中的作用。方法 :通过单细胞细胞外记录吗啡依赖大鼠腹侧苍白球的电信号 ,观察吗啡对放电的影响。结果 :吗啡依赖大鼠腹侧苍白球神经元放电频率给药前为 3 76Hz±s 1 18Hz,注射吗啡后为 13 2 2Hz±s 2 37Hz;并且纳洛酮可以逆转这种兴奋效应。结论 :吗啡显著兴奋吗啡依赖大鼠腹侧苍白球神经元 ,腹侧苍白球在药物强化过程中起着重要作用。     

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.