Mechanism of alpha-2 adrenergic modulation of canine cardiac Purkinje action potential

We reported recently that stimulation of postjunctional alpha-2 adrenergic receptors prolongs the action potential durations (APD) of isolated canine Purkinje fibers. With standard microelectrode techniques, we examined the ionic mechanism through which alpha-2 adrenergic stimulation prolonged Purkinje APD, by measuring the effects of inhibitors of the various plateau currents on the alpha-2-mediated prolongation of APD. The alpha-2-specific agonist UK 14,304 (0.1 microM) prolonged the Purkinje APD at 50% repolarization and the APD at 90% repolarization, and these effects were inhibited by yohimbine (0.1 microM). The Purkinje APD at 50% repolarization and the APD at 90% repolarization were prolonged significantly with the transient outward potassium current inhibitor 4-aminopyridine (1 mM), the rapid component of delayed rectifier potassium current inhibitor d-sotalol (10 microM), the slow component of delayed rectifier potassium current inhibitor indapamide (0.1 microM) and the chloride current inhibitor mefenamic acid (10 nM) and were shortened significantly with the calcium current inhibitor nifedipine (0.3 microM). Prolongation of Purkinje APD at 50% repolarization and APD at 90% repolarization by UK 14,304 remained intact in the presence of d-sotalol, indapamide, mefenamic acid and nifedipine. All of these UK 14,304 effects were significantly reversed by yohimbine. Only in the presence of 4-aminopyridine did UK 14,304 fail to prolong Purkinje APD. The phase 1 magnitudes of Purkinje action potentials were also significantly inhibited by UK 14,304. This effect was completely abolished only in the presence of 4-aminopyridine. These results suggest that inhibition of the 4-aminopyridine-sensitive transient outward potassium current is the major ionic mechanism by which alpha-2 adrenergic stimulation prolongs Purkinje APD.     

Regional lung function in unilateral diaphragmatic paralysis

Radioactive xenon-133 was used to study the regional lung function of five patients with unilateral diaphragmatic paralysis unassociated with intrathoracic disease. All patients showed a reduction in total lung capacity to which the affected side contributed an average of 37%. There was a decrease in the amount of inhaled xenon and a lesser decrease in the amount of injected xenon reaching the lung base on the paralysed side.The distribution in the opposite lung did not differ significantly from that found in normal subjects although the proportion of inhaled xenon reaching the lung base was rather less than in the normal group. The washout of injected xenon was normal except for slight impairment at the lung base on the paralysed side in one patient and at both bases in another.     

Central venous pressure and cardiac function during spaceflight

Early in spaceflight, an apparently paradoxical condition occurs in which, despite an externally visible headward fluid shift, measured central venous pressure is lower but stroke volume and cardiac output are higher, and heart rate is unchanged from reference measurements made before flight. This paper presents a set of studies in which a simple three-compartment, steady-state model of cardiovascular function is used, providing insight into the contributions made by the major mechanisms that could be responsible for these events. On the basis of these studies, we conclude that, during weightless spaceflight, the chest relaxes with a concomitant shape change that increases the volume of the closed chest cavity. This leads to a decrease in intrapleural pressure, ultimately causing a shift of blood into the vessels of the chest, increasing the transmural filling pressure of the heart, and decreasing the central venous pressure. The increase in the transmural filling pressure of the heart is responsible, through a Starling-type mechanism, for the observed increases in heart size, left ventricular end-diastolic volume, stroke volume, and cardiac output.     

Effect of combined captopril-spironolactone therapy of cardiac insufficiency on kidney function and serum electrolyte values

A sample size justification is often a key component in securing funding to conduct a clinical trial. Sample size computations typically require supplying values of parameters that are unknown and subject to misspecification. As an alternative, we advocate a power analysis approach based on a range of reasonable values for such parameters. We illustrate this approach in the context of a secondary stroke prevention trial.     

Intraoperative modulation of alveolar macrophage function during isoflurane and propofol anesthesia

BACKGROUND: Alveolar macrophages are a critical part of the defense against pulmonary infection. Thus the authors determined time-dependent changes in alveolar macrophage functions in patients having surgery who were anesthetized with isoflurane or propofol. METHODS: Patients anesthetized with propofol (n = 30) or isoflurane (n = 30) during orthopedic surgery were studied. Alveolar macrophages were harvested by bronchoalveolar lavage immediately, and 2, 4, and 6 h after induction anesthesia and at the end of surgery. The fraction of aggregated and nonviable macrophages was determined. Then phagocytosis was measured by ingestion of opsonized and unopsonized particles. Finally, microbicidal activity was determined as the ability of the macrophages to kill Listeria monocytogenes directly. RESULTS: Demographic and morphometric characteristics of the patients given propofol and isoflurane were similar, as were their levels of pulmonary function and hemodynamic responses. The fraction of alveolar macrophages ingesting opsonized and unopsonized particles, and the number of particles ingested, decreased significantly over time, with the decrease slightly but significantly greater during isoflurane anesthesia. Microbicidal function decreased progressively during anesthesia and surgery, with the decrease almost twice as great during isoflurane compared with propofol anesthesia. The fraction of aggregated macrophages and recovered neutrophils increased over time in the patients given each anesthetic. CONCLUSIONS: Pulmonary immunologic function changed progressively during anesthesia and surgery. The data from this study suggest that pulmonary defenses are modulated by the type of anesthesia and by the duration of anesthesia and surgery.     

Chronic renal insufficiency: 1) adaptation of nephron function in chronic renal insufficiency and 2) progression of chronic renal insufficiency

In chronic renal insufficiency resulting from destruction of the vast majority of nephrons, the surviving nephrons adapt their functions to the conditions of vigorous haemodynamic and osmolar overloads. They acquire an appropriate behaviour to preserve the principal renal functions and to achieve the balance of inner space. In the long period of time, similarly as in healthy people. Glomerulotubular balance as well as tubuloglomerular balance distinguish the remaining nephron function, while autoregulation of perfusion pressure along the glomerulus rapidly vanishes. All three regulation mechanisms are characteristic of the nephron function under physiologic conditions. Intense work of the remaining nephrons in chronic renal failure is under the high level controls of the group of hormones, among them are rennin-angiotensin system, arginine-vasopressin and atrial natriuretic peptide playing very important and particular roles. Comparison of different published studies emerge the idea that chronically increased arginine-vasopressin levels in chronic renal failure could block the autoregulation of blood flow and hydraulic pressure in glomeruli, which together with other mediator actions give high and fluctuating tense within remaining glomeruli, during every single cardiac cycle. It is probably the main event in the further course of kidney disease progression resulting in definite damage of the overloaded nephrons. Angiotensin II is one of reliably recognised mediators of unfavourable outcome in the process of nephron adaptation in chronic renal failure. Knowing the pathophysiologic processes in the remaining functionally adapted nephrons in chronic renal insufficiency determines a more adequate therapeutic approach in these patients.     

Role of beta-blockers in the treatment of cardiac insufficiency

Despite Beta-blockade therapy has been considered as an absolute contraindication in the treatment of heart failure, it has been shown that they could have a beneficial effect, provided that they were introduced at very low dose, and very progressively in addition of the traditional treatment. The advances in the understanding of the neuro-hormonal mechanisms of heart failure have modified the therapeutic strategy: the deleterious effect of the activation of the sympathetic nervous system on the myocardium has served as the rationale for randomized clinical trials comparing beta-blockade to placebo: the current data are promising, suggesting a beneficial effect on survival as well as on quality of life. However, these results have to be confirmed by larger trials, currently underway, before to consider that beta-blockade should definitely be incorporated in the treatment of heart failure.     

Severe and early alteration of action potential during acute cardiac rejection in rats

INTRODUCTION: Alteration of cardiac action potential and its adaptation to heart rate could contribute to cardiac dysfunction and arrhythmias during acute cardiac rejection. METHODS AND RESULTS: Heterotopic heart transplantation was performed in allogeneic and syngeneic rats in which the action potentials of right and left ventricles were measured at 1, 2.5, 3.3, and 5.7 Hz successively using standard microelectrode techniques and compared with nontransplanted hearts. For each frequency, we measured action potential amplitude, action potential duration, transmembrane resting potential, and Vmax. In the right ventricle, at 1 Hz in the presence of rejection (n = 40), a significant increase was observed in action potential duration at 20%, 50%, and 70% repolarization (82.5%, 75.6%, and 70.8%, respectively) and in action potential amplitude (+17.9 mV), and the resting potential was decreased (-5.3 mV). A lack of adaptation of action potential duration to the driving frequency was observed in the rejecting heart group in contrast to controls (n = 20) and nonrejecting hearts (n = 13). Similar results were observed in the left ventricle and surprisingly in the native hearts (n = 11) of recipients with allografted rejecting hearts in the abdominal position. CONCLUSION: Action potential and its adaptation to the driving frequency is considerably altered during acute rejection. A humoral factor could contribute to cardiac dysfunction.     

Electroporation and shock-induced transmembrane potential in a cardiac fiber during defibrillation strength shocks

Differences in duration judgments made by younger and older adults were reviewed. Previous research is unclear about whether such differences exist and, if so, how they may be explained. The meta-analyses revealed substantial age-related differences. Older adults gave larger verbal estimates and made shorter productions of duration than did younger adults. There were no age-related differences in reproduction of duration or in psychophysical slope relating judged and target duration. Older adults' duration estimates were more variable than were those of younger ones. Findings are discussed in terms of pacemaker rate and attentional resources. An explanation regarding divided attention between nontemporal and temporal information processing best explains the findings.     

Effect of alterations in blood volume on cardiac function during maximal exercise

Recently, we proposed that the higher stroke volume (SV) and cardiac output (Q) of endurance-trained (ETR) versus untrained (UTR) individuals are attributable primarily to the enhanced diastolic filling of ETR consequent to a larger blood volume (BV). To test this hypothesis, we examined the effects of manipulating BV on the cardiac function of six ETR and six UTR males. Both groups were examined in the control BV condition (BVctl), then ETR were examined immediately following a 500 mL reduction in BV (BVred) and UTR were examined immediately following a 500 mL expansion of BV (BVexp). In BVctl, compared with UTR, ETR had significantly greater BV (16%), maximal diastolic filling rate (47.4%), maximal ventricular emptying rate (24.6%), SVmax (31.6%), Qmax (29%) and VO2max (54.5%). Following BVexp in UTR, there were immediate significant increases in maximal diastolic filling rate (22.5%), SVmax (9.1%), Qmax (8.9%), and VO2max (12.7%). Following BVred in ETR there were immediate significant decreases in maximal diastolic filling rate (27%), SVmax (14.3%), Qmax (14.7%), and VO2max (7.0%). Maximal systolic emptying rate did not change significantly following BVred or BVexp. We conclude that changes in SV and Q consequent to alterations in BV are attributable primarily to changes in diastolic function, and the majority of the higher diastolic filling rate of ETR is due to their larger BV.     

Evaluation of cardiac status in iron-loaded thalassaemia patients following bone marrow transplantation: improvement in cardiac function during reduction in body iron burden

Iron-induced cardiac disease is the primary cause of death in transfused patients with thalassaemia major. The beneficial effects of deferoxamine mesylate on clinical cardiac disease have been well described but the impact of therapy on subclinical cardiac dysfunction is unknown. To assess the reversibility of subclinical cardiac dysfunction we studied the cardiac status during iron depletion treatment (phlebotomy) in iron overloaded patients, cured of thalassaemia by marrow transplantation, without clinical manifestation of heart failure but with alteration in both left ventricular diastolic function and in contractility property. 32 patients were studied and demonstrated a slight but significant impairment in the morphology and function if compared with matched normal controls. 17 of these patients were submitted to sequential echocardiographic evaluations during the phlebotomy programme. Following completion of the programme, normalization of the indices of contractility and normalization of diastolic function were observed. This study indicates that transplanted thalassaemia patients with subclinical left ventricular diastolic dysfunction and impaired left ventricular contractility may reverse these processes with an effective regimen of iron reduction such as phlebotomy.     

Adjustments of cardiac function during prolonged exercise relative to lactate threshold

Alterations in cardiac function during prolonged submaximal exercise relative to lactate threshold (LT) were evaluated on 7 normal healthy males aged 30.3 +/- 5.7 years. Systolic time intervals were analyzed through simultaneous recordings of electrocardiogram, phonocardiogram, and impedance cardiogram at a paper speed of 50 mm/s. Determination of stroke volume (SV) was based upon the method described by Kubicek et al. ANOVA followed by the Scheffe post-hoc comparison revealed that SV and myocardial contractility indices (MSER and PEP/LVET) remained relatively unchanged throughout 40-min cycling exercise, although the changes in heart rate and oxygen uptake were statistically significant. In addition, systolic blood pressure remained almost unchanged during the exercise. These results may be interpreted as evidence of the "contractility reserve", i.e., the ability of maintaining heart muscle contractility during prolonged exercise at LT intensity.     

The pharmacology of adenylyl cyclase modulation by GABAB receptors in rat brain slices

GABAB receptor activation inhibits forskolin-stimulated adenylyl cyclase activity but augments noradrenaline-stimulated adenylyl cyclase activity. The present study investigated the pharmacology of these two GABAB receptor mediated responses. In a cross-chopped rat cortical slice preparation, it was confirmed that (-)baclofen inhibited forskolin-stimulated adenylyl cyclase activity and augmented noradrenaline-stimulated adenylyl cyclase activity. The potency of five further agonists was investigated (SKF97541, CGP47656, CGP44533, 3-APA and CGP44532). Of these agonists two compounds were significantly more potent as inhibitors of forskolin-stimulated adenylyl cyclase than as augmenters of noradrenaline-stimulated adenylyl cyclase activity, these were (-)baclofen (pEC50 = 6.07 +/- 0.29 and 5.04 +/- 0.17, respectively (p < 0.05)), and CGP47656 (pEC50 = 6.44 +/- 0.05 and 4.48 +/- 0.26, respectively (p < 0.05)). It is possible to explain this difference in potency by proposing that these compounds have low intrinsic efficacy, and the augmentation of noradrenaline-stimulated adenylyl cyclase has a low receptor reserve. In addition six antagonists (CGP49311A, CGP46381, CGP45024, CGP45397, CGP36742) were also tested for their ability to antagonize 10 microM (-)baclofen in these two assays. These antagonists ranged in potency as inhibitors of forskolin-stimulated adenylyl cyclase activity from CGP49311A (pEC50 = 5.45 +/- 0.30) to CGP36742 (pEC50 = 3.87 +/- 0.16). Each antagonist had similar potency in the two assays, suggesting that these two responses are mediated by pharmacologically similar receptors.     

Mechanism for improved cardiac performance with arteriolar dilators in aortic insufficiency

To determine how arteriolar dilation improves cardiac performance in aortic insufficiency, we evaluated the acute effects of hydralazine in 10 patients with chronic severe aortic insufficiency. Control measurements of intracardiac and intravascular pressures, cardiac output and left ventricular volumes were obtained at cardiac catheterization. Hydralazine, 0.3 mg/kg i.v. (maximal dose 20 mg), was administered and all measurements were repeated 30 minutes later. A reduction in systemic vascular resistance from 1264 to 710 dyn-sec-cm-5 was associated with significant increases in forward cardiac index (2.9 to 5.1 l/min/m2) and stroke volume index (37 to 55 ml/m2). Left ventricular end-diastolic pressure was reduced from 19 to 12 mm Hg. There was a significant reduction in mean arterial pressure (88 to 83 mm Hg) and a significant increase in heart rate (81 to 94 beats/min). Regurgitant stroke volume was reduced by more than 10 ml/m2 in seven patients and for the group was significantly reduced, from 65 to 53 ml/m2. Regurgitant fraction was reduced in all patients; the overall reduction from 0.64 to 0.48 was highly significant. Ejection fraction increased more than 0.10 in four patients, by 0.08 in an additional patient and for the group increased significantly from 0.50 to 0.57. Left ventricular end-diastolic volume decreased by more than 25 ml/m2 in four patients, by 19 ml/m2 in an additional patient and was decreased significantly, from 208 to 190 ml/m2, for the group. Arteriolar dilators improve cardiac performance in aortic insufficiency by reducing the amount of aortic regurgitation and, in some patients, by substantially improving systolic pump fraction. These data suggest a role for arteriolar dilators in the management of selected patients with aortic insufficiency.     

Acute cardiac failure: the relation between coronary flow and cardiac function

To study the effects of acute coronary hypotension on the working dog heart in situ, both coronary arteries were cannulated and perfused with oxygenated blood at controlled pressures (40 to 120 mm Hg). At a perfusion pressure of 120 mm Hg, total coronary artery flow appeared to be sufficient (0.95+/-0.08 ml/min-g) to maintain normal cardiac performance for a 2.5-hour observation period. During incremental decreases in coronary perfusion pressure, significant linear correlations were found between coronary flow and cardiac index (r=0.84), left ventricular maximum dP/dt (r=0.83), stroke index (r=0.82), stroke work (r=0.83) and mean arterial pressure (r=0.62). During simulated shock conditions (systolic arterial pressure, less than 75 mm Hg), relative reductions in coronary flow (-60.9+/-4.0%) paralleled changes seen in cardiac function and persisted for 28+/-4 min.