Rediscovery of Otto Frank's contribution to science.

In the late 19th century, German physiologist Otto Frank (1865-1944) embarked on a near life-long research program of laying down the mathematical, methodological, and theoretical foundations in order to understand and define the performance of the heart and circulatory system in all their complexity. The existence of the "Frank-Starling law" testifies to this. Two of his seminal publications have been translated into English previously, introducing Frank's research on the dynamics of the heart and the arterial pulse to a wider audience. It is likely that there are a host of other comparable achievements and publications of Frank that are still unknown to the international scientific (cardiological and physiological) community. However, their influence can still be felt and seen in modern cardiology and cardio-physiology, such as in the development of modern interactive simulating and teaching programs. We have translated and commented on ten of these papers, which can be read in parallel with the German originals. These publications show a wealth of theoretical assumptions and projections regarding the importance of the sarcomere, the development of models of contraction, thermo-dynamical considerations for muscular activity, differences between cardiac and skeletal muscles, problems related to methodology and measurement, and the first pressure-volume diagram (published 120 years ago). These topics were envisioned by Frank long before they became a focus of subsequent modern research. Nowadays, frequent measurements of pressure-volume relationships are made in research using the pressure-volume conductance catheter technique. In commenting Frank's scientific topics, we try to show how interconnected his thinking was, and thus how it enabled him to cover such a wide range of subjects.

The Hyponatremia Epidemic: A Frontier Too Far?

Hyponatremia is the most common electrolyte abnormality and is often neglected, especially in elderly and seemingly terminal patients. Hyponatremia can be asymptomatic or can cause symptoms ranging from nausea and lethargy to convulsions and coma. This condition has become increasingly common over time with a similar time course to the increase in adoption of low salt diets. The popularization of low salt may not be justified in people with normal kidney function in whom the compatible statistically based evidence that salt causes hypertension has been challenged by experimental evidence to the contrary.

Abraham Guz memorial: Still unresolved hypotheses: Lung reflexes and perceptions of breathing.

This article constitutes a review of the studies performed by the group of the late A. Guz and other authors on the subjects of lung reflexes and perceptions of respiration. The experimental data suggest that the lung inflation and deflation reflexes are present in man, mediated by large myelinated afferent nerve fibres in the vagus nerves, but that the inflation reflex is weaker than in animals, possibly due to central neuronal inhibition. The authors of animal results on the deflation reflex differ as to the afferent fibres involved in the vagi, but it is argued, on the basis of the data, that the preferred hypothesis is that increased activity of the large myelinated mediates the inflation reflex, and decreased activity in these same fibres mediates the deflation reflex. Smaller myelinated fibres are thought to mediate cough and increased breathing in response to airway irritation, while small non-myelinated C fibres mediate hyperpnoea in response to parenchymal congestion and various disease states. The unpleasant sensation at the break point of breath-holding is not chemically mediated but may depend on a complex response involving vagal afferent, phrenic efferent and phrenic afferent pathways. Other experiments in humans on perception of various unpleasant respiratory sensations are discussed with unclear conclusions.

Intraluminal hyperglycaemia causes conduit and resistance artery dilatation and inhibits vascular autoregulation in the anaesthetised pig.

The effect of intraluminal hyperglycaemia was investigated in the iliac artery of 11 anaesthetised pigs. Following isolation of a test segment, hyperglycaemic blood (40 mmol·L(-1)) caused a significant dilatation of the artery of 167 ± 208 µm (mean ± SD; n = 6, P = 0.031). Dilatations were reduced by N(G)-nitro-l-arginine methyl esther (250 µg·mL(-1)) from 145 ± 199 to 38 ± 5 µm), but this was not statistically significant (n = 6, P = 0.18). Intra-arterial infusions of d-glucose (20-40 mmol·L(-1)·min(-1)), during graded constrictions, caused statistically significant increases in blood flow (n = 11, P = 0.0013). Vasodilatation was confirmed by measurements of the ratio of immediate pressure steps to flow steps (∂P/∂F) during the graded obstruction experiments, showing a decrease in instantaneous vascular resistance from a control of 0.62 ± 0.30 to 0.33 ± 0.34 mm Hg·mL(-1)·min(-1) (n = 7, P = 0.016). Autoregulation was assessed from the slopes of the plots of steady-state flow versus pressure. There were significant increases in the slope from 2.32 ± 1.03 to 5.88 ± 5.60 mL·min(-1)·(mm Hg)(-1) (n = 7, P = 0.0078), indicating significant impairment of autoregulation. In conclusion, luminal hyperglycaemia relaxes both arterial and resistance vessel smooth muscle.

What is the mechanism of flow-mediated arterial dilatation.

The present review attempts to explain the controversies concerning the mechanism of shear stress-mediated arterial dilatation, commonly called flow-mediated arterial dilatation (FMD). Flow-mediated dilatation occurs in an artery when the blood flow to the organ supplied by the artery is increased. There are two hypotheses regarding the stimulus for FMD: (i) a wave of endothelial and smooth muscle hyperpolarization, conducted in a retrograde fashion from the vasodilated peripheral vascular bed towards the relevant conduit artery; and (ii) an increase in shear stress sensed by the endothelial cells. The latter hypothesis is associated with two further postulates concerning the method of mechanotransduction of the shear stress stimulus: (i) direct transmission from endothelial cell cytoskeleton to the vascular smooth muscle to induce dilatation; and (ii) indirect transmission to the endothelial cell cytoskeleton via the glycocalyx. The virtues and inconsistencies of these hypotheses are discussed. The first hypothesis is excluded because a vasodilated peripheral vascular bed does not cause dilation of the upstream conduit artery if an increase in flow within the conduit artery is prevented and because FMD is completely blocked by inhibition of nitric oxide synthase (NOS). It is probable that the stimulus is an increase in shear stress between the blood and the adjacent layer of the arterial wall, the glycocalyx. Ultimately, a change in the endothelial cell cytoskeleton is the likely event that leads to activation of NOS and this activation does not occur without a functioning glycocalyx.

Metformin causes nitric oxide-mediated dilatation in a shorter time than insulin in the iliac artery of the anesthetized pig.

We tested the hypothesis that metformin produces arterial dilatation indirectly, by directly exposing the endothelial surface, of an occluded test segment of the pig iliac artery in vivo, to test blood containing metformin or excess insulin, with and without the presence of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester hydrochloride. Such exposure to metformin 1 µg/mL caused the artery to dilate at constant pressure, and this was abolished when NG-nitro-L-arginine methyl ester hydrochloride was coadministered with metformin. The onset of dilatation occurred approximately 4 minutes after the commencement of endothelial exposure to metformin; this contrasts with the approximate 10 minutes required for a similar response to luminal hyperinsulinemia. After the release of flow occlusion, the subsequent flow-mediated dilatation was slightly but significantly enhanced compared with control for metformin; the effect of insulin on flow-mediated dilatation was not statistically significant. The hypothesis was disproved, as we have shown that insulin and metformin, like insulin, directly stimulate NO production by endothelium of a conduit artery; this function may be of value in delaying the atherothrombotic process. The time taken for the commencement of NO production is shorter for metformin than for insulin; the clinical relevance of this finding is unclear.

Regional sympathetic denervation affects the relation between canine local myocardial blood flow and oxygen consumption.

Myocardial blood flow and oxygen consumption are heterogeneously distributed. Perfusion and myocardial oxygen consumption are closely correlated in the normal heart. It is unknown how this metabolism-perfusion relation is influenced by sympathetic denervation. We investigated this question in seven chloralose-anaesthetized dogs, 3-4 weeks after regional sympathetic denervation of the left circumflex coronary artery area of supply of the left ventricle. Measurements were made of local myocardial blood flow (MBF, in ml min(-1) (g dry wt)(-1)), measured with microspheres, and myocardial oxygen consumption ( , in mumol min(-1) (g dry wt)(-1)) in the same location, calculated from the (13)C spectrum of tissue extracts after intracoronary infusion of 3-(13)C-lactate. Since both innervated and denervated regions are subject to the same arterial pressure, lower blood flow indicates higher resistance. Mean MBF was 5.56 ml min(-1) (g dry wt)(-1) (heterogeneity of 3.47 ml min(-1) (g dry wt)(-1)) innervated, 7.48 ml min(-1) (g dry wt)(-1) (heterogeneity of 3.62 ml min(-1) (g dry wt)(-1)) denervated (n.s.). Significant linear relations were found between MBF and M Vo2 of individual samples within the innervated and denervated regions. The slopes of these relations were not significantly different, but the adjusted mean was significantly higher in the denervated regions (+1.92 ml min(-1) (g dry wt)(-1), an increase of 38% of the mean MBF at the pooled mean M Vo2, P = 0.028, ANCOVA). The ratio MBF/M Vo2(in ml micromol(-1)) was significantly higher, being 0.296 +/- 0.167 ml micromol(-1) in the denervated region compared with the innervated region, 0.216 +/- 0.126 ml micromol(-1), P = 0.0182, Mann-Whitney U test. These results indicate that sympathetic tone under chloralose anaesthesia imposes a moderate vasoconstrictive effect in the myocardium that is not detected by comparison of the mean blood flow or resistance.

Basal and hyperaemic myocardial blood flow in regionally denervated canine hearts: an in vivo study with positron emission tomography.

PURPOSE: Positron emission tomography (PET) studies in patients with diabetic autonomic neuropathy (DAN) have demonstrated the impact of this disease on cardiac sympathetic innervation and myocardial blood flow (MBF). To investigate the effects of selective partial sympathetic denervation of the left ventricle (LV) on baseline and hyperaemic MBF, we measured myocardial presynaptic catecholamine re-uptake (uptake-1), beta-adrenoceptor (beta-AR) density and MBF non-invasively by means of PET in a canine model of regional sympathetic denervation. METHODS: In 11 anaesthetised dogs, the sympathetic nerves of the free wall and septum of the LV were removed by means of dissection and phenol painting. Three weeks later, the animals were studied with PET. MBF was measured at baseline and following i.v. adenosine (140 microg kg(-1) min(-1)) and dobutamine (20 microg kg(-1) min(-1)) using(15)O-labelled water. Sympathetic denervation was confirmed by an 80+/-12% decrease in the volume of distribution (V(d)) of [(11)C]hydroxyephedrine (HED) compared with innervated regions. Myocardial beta-AR density was measured using [(11)C]CGP12177. RESULTS: Innervated and denervated regions showed no differences in MBF at baseline and during adenosine or dobutamine. [(11)C]HED V(d)was inversely correlated with MBF in both regions at baseline, and the correlation was lost during hyperaemia in denervated regions. However, for any given value of MBF, [(11)C]HED V(d)was significantly lower in the denervated regions. beta-AR density was comparable in denervated and innervated regions (17.9+/-4.2 vs 18.4+/-3.3 pmol g(-1); p=NS). CONCLUSION: In this experimental model, selective, regional sympathetic denervation of the LV, which results in a profound reduction in [(11)C]HED V(d), did not affect baseline or hyperaemic MBF. In addition, we demonstrated that, under baseline conditions, there was a significant inverse correlation between [(11)C]HED V(d)and MBF in both denervated and innervated regions.

The beat-to-beat decay of cardiac contractility from highly potentiated levels is bi-exponential.

In order to determine the mode of beat-to-beat decay of contractility from very high levels, we studied the beat-by-beat decay of cardiac contractility following potentiation. Such decay curves are normally analysed using a mono-exponential decay function, which assumes that a fixed fraction of activator calcium ions is recirculated from one beat to the next. We postulated that there might be deviations from such a mono-exponential expression at high levels of contractility. In single sucrose-gap voltage clamp experiments of isolated ferret papillary muscle, we obtained very high contractility by potentiation due to prolonged depolarisations. We found a bi-exponential decay in 9 of 11 muscles studied, in which the initial decay is much faster than the subsequent slower decay, as judged by residual variance of least-squares exponential fitting and by analysis of covariance using a linear equation (force of beat versus force of previous beat), p = 0.0089. In the slower decay period (physiological range), the decay was identical to that following post-extrasystolic potentiation in the same muscles studied with conventional stimulation.

Correction for the adverse influence of sodium-potassium cotransport on apparent sodium-lithium countertransport activity in human erythrocytes.

INTRODUCTION: Erythrocyte sodium-lithium countertransporter (SLC) has traditionally been characterised as the sodium-stimulated lithium efflux from lithium-loaded erythrocytes. Concurrent activity of the sodium-potassium cotransporter (NKCC) can be expected to lead to imprecise estimates of the activity of the SLC. In the present study, we have characterised this methodological problem and have shown that it can be corrected with the inclusion of bumetanide in the physiological salt solution. METHODS: Lithium efflux was studied in lithium-loaded erythrocytes from 35 healthy, normotensive subjects. Erythrocytes were divided into two identical samples (A and B) and lithium efflux characteristics in both samples studied simultaneously by incubating aliquots from each in 10 media of differing external sodium concentrations. Efflux media employed for A and B were the same except for 0.02 mM bumetanide in the media used in B. RESULTS: Increased external sodium was associated with increasing lithium efflux both in the absence and presence of bumetanide; efflux rates were consistently lower in media containing bumetanide (P<.05 in all cases). As external sodium increased, bumetanide-sensitive lithium efflux decreased in a manner that correlated inversely with external sodium concentration (r=-.77, P<.01). A small, nonsignificant increase in SLC activity was observed between measurements made under control conditions (median [range] in mmol Li/l RBC h; 0.272 [0.098-0.491]) and those made in the presence of bumetanide (0.286 [0.135-0.650]; P=.064). Bumetanide did not influence maximal rate of turnover or the affinity constant for external sodium. In contrast, the ratio of these variables was lower when determined in the absence than in the presence of bumetanide (5.5 [1.5-14.6] vs. 6.9 [2.8-24.2], respectively; P<.05). DISCUSSION: This work shows that a component of lithium efflux mediated by the NKCC changes substantially with alterations in external sodium, resulting in a variable contribution of this second transport pathway to apparent SLC activity. To eliminate this variability, bumetanide should be included in all media when studying SLC, and the relationship to external sodium concentration determined.