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Biomedical subjects

R Jacob

Publications and source records attributed to R Jacob.

At least 289 records · Page 16Linked to original sources
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Evaluation of left ventricular function in an experimental model of congestive heart failure due to combined pressure and volume overload.

During a 6 month observation period after operation, typical symptoms of congestive heart failure, such as cyanosis, systemic oedema, ascites and pleural effusion occur in the majority of rats which have a combined arteriovenous shunt (AV-shunt) and renal hypertension (Goldblatt II). In the present study, the left ventricle dilated to twice the size of that of age-matched Wistar controls. Developed wall stress increased significantly due to an augmented ratio of radius to wall thickness. Normalized stress-length (stress-midwall circumference) area and maximum rate of stress development (d sigma/dtmax) indicated decreased myocardial work and power capacity. Although the congestive symptoms can only partially be related to impaired cardiac function, this model may be useful for pathophysiological and pharmacological studies of chronic heart failure.

Animals↗
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Myocardial elasticity and left ventricular distensibility as related to oxygen deficiency and right ventricular filling. Analysis in a rat heart model.

Hypoxia-induced changes in diastolic left ventricular (LV) pressure volume (P-V) relationships and myocardial elasticity as well as the extent to which diastolic right ventricular (RV) interactions are involved under hypoxia were analysed in male open-chest Wistar rats under isovolumetric conditions. Wall stress sigma and differential elastic modulus E were calculated for the midwall region, assuming a spherical model. LV end-diastolic P-V relationship shifted significantly to the left only 2 min after the start of pure N2 ventilation. The slope of the E-sigma curve did not change, corresponding to the "contracture type" of decreased myocardial distensibility. Identical changes occurred when filling of the RV was increased under O2 ventilation. Hypoxia, under emptied RV, led within 8 min to substantially lower, non-significant steepening of the end-diastolic P-V relationships. There was a significant change in the diastolic P-V curve along with a parallel increase in stiffness constant b, 45 min after N2 ventilation and under emptied RV. However, as a result of failure of cardiac function, ischemia was by now prevailing. These findings led to the following conclusions: In the early phase of hypoxia, i.e. within the first 20 min (in the model used in the present study) no substantial rigor occurs but the increase of LV end-diastolic P-V values is essentially due to augmented RV filling, even under opened chest and removed pericardium. The geometrical influence of the RV mimics the "contracture type" of decreased myocardial distensibility and cannot be recognized on the basis of the E-sigma relationship. Without knowledge of RV pressure it is not feasible to distinguish early "contracture" or rigor from extraventricular influences, caused by changes in the filling of the neighbouring ventricle.

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Ventricular pressure-volume relations as the primary basis for evaluation of cardiac mechanics. Return to Frank's diagram.

Considering ventricular function from the vantage point of the pressure-volume (P-V) diagram permits not only quantification of ventricular working capacity under normal and pathophysiological conditions but also promotes understanding of cardiac dynamics including prediction of the effects of mechanical and pharmacological interventions. Therefore it seems appropriate, at least intellectually, to classify all measured volume and pressure data into the scheme of the P-V diagram. The use of so-called contractility indices and also the restriction to the end-systolic P-V relation alone means deliberate renunciation of important information. In principle, Frank's original concept can be confirmed which, under afterloaded conditions, implies the existence of distinct end-systolic P-V curves each related to a particular end-diastolic volume. As an approximation, however, the assumption of one common end-systolic P-V relation seems tolerable. Based on Frank's diagram, a concept for assessment of ventricular and myocardial function is presented following a discussion of the determinants of the diastolic and end-systolic P-V relations, as well as the methodological difficulties and different notions with regard to the end-systolic P-V curve. The P-V area between the curves of systolic maxima and diastolic minima, up to a defined end-diastolic pressure, is recommended as a measure for quantitative evaluation of ventricular working capacity. Transformation into stress-length (sigma-l) relations is indispensable for assessment of myocardial function under the conditions of changed ventricular geometry. The normalized sigma-l area yields a measure for interindividual evaluation of myocardial working capacity. This concept of evaluation does not mean acknowledgement of the visco-elastic theory of muscle contraction nor of the Emax concept. The P-V and sigma-l relations must, however, be complemented by time related parameters in order to estimate ventricular and myocardial power capacity. After a long-lasting search through international literature for "contractility indices" of general applicability and significance it seems appropriate to return to Frank's diagram as the primary basis for evaluating cardiac mechanics.

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Alterations in cardiac oxygen consumption under chronic pressure overload. Significance of the isoenzyme pattern of myosin.

Hypertension and resulting left ventricular hypertrophy was induced in young male Wistar rats (60 to 70 days old) by narrowing of one renal artery (Goldblatt II). 8 and 24 weeks after operation, myocardial oxygen consumption was measured on a modified in situ heart-lung preparation with nearly isovolumetric left ventricular contractions. Measured myocardial oxygen consumption was related to left ventricular wall stress. The myosin isoenzyme pattern of each heart was determined with pyrophosphate gel electrophoresis. Oxygen consumption related to wall stress averaged over the entire heart cycle amounted to 15 mumoles O2/g X min 8 weeks after operation, and 24.4 mumoles O2/g X min in age-matched controls (delta 38%, p less than 0.0005). When wall stress was averaged over systole, oxygen consumption of the hypertrophied hearts amounted to 0.112 mumoles O2/g x beat, and 0.149 mumoles O2/g x beat in the controls (delta 25%, p less than 0.05). The proportion of VM-3 (the cardiac myosin isoenzyme of lowest ATPase activity) increased from 26.3% in the controls to 30.1% in the Goldblatt hearts (delta 14%, n.s.). 24 weeks after operation, oxygen consumption related to wall stress averaged over the entire heart cycle amounted to 16.1 mumoles O2/g x min, in age-matched controls 20.5 mumoles O2/g x min (delta 21%, p less than 0.05). When wall stress was averaged over systole, oxygen consumption of the Goldblatt hearts amounted to 0.080 mumoles O2/g x beat, and in the controls 0.107 mumoles O2/g x beat (delta 25%, p less than 0.0005). The proportion of VM-3 increased from 33.5% in the controls to 43.2% in the hypertrophied hearts (delta 29%, p less than 0.05). The present findings indicate that the reduced oxygen consumption of the pressure-loaded heart should be attributed to a redistribution of myosin isoenzymes. The transformation of myocardium into a slower, but more efficiently working muscle due to an increase in VM-3 can be interpreted as an adaptational process.

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Diastolic tension of rat cardiac muscle during deficiency of oxygen and glucose. Stress-strain relationships and reversibility.

In the isometrically contracting rat trabecular muscle strip preparation, contracture tension was induced either by 10 min of hypoxia (low contracture tension) or by 30 min of joint oxygen and glucose withdrawal (severe contracture tension) at optimum length. Using stepwise 0.1 mm releases, length-tension relationships were recorded under control and contracture conditions in both types of contracture. Stress-strain relationships were evaluated as well as the linear function of the tangent elastic modulus delta sigma/delta epsilon versus stress sigma. The slope of the delta sigma/delta epsilon = f (sigma) function was not significantly changed in low contracture compared to control conditions (n = 8; p less than 0.001). When reversibility tests were performed by reoxygenation after 10 min hypoxia and reperfusion with oxygen and glucose after 30 min of glucose and oxygen withdrawal, low contracture tension was completely abolished after 15 min, whereas 28% of severe contracture was maintained even after 60 min of reperfusion. Additional morphological studies revealed uniform sarcomere lengths in low contracture, and two populations of sarcomere lengths in the severe contracture. On the basis of the present and earlier results, a model of contracture tension generation is proposed in which cross-bridges between actin and myosin cycle at a very low rate and are attached in a force-generating position for a long time.

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Alterations of mechanical parameters in chemically skinned preparations of rat myocardium as a function of isoenzyme pattern of myosin.

Myofibrillar ATPase activity, maximum unloaded shortening velocity, and isometric tension development were evaluated in left ventricular preparations of 5-week-old rats with a high endogeneous level of thyroid hormones and hypothyroid rats after 4-week treatment with propylthiouracil (PTU). The range of possible alterations of the above functional parameters was defined in relation to myosin isoenzyme distribution. The mechanical behaviour of the ventricular preparations was investigated in native myocardium as well as in the glycerinated state. The essential results of the present study is that alterations of myofibrillar ATPase activity and mechanical Vmax, evaluated in glycerinated preparations, are limited to a well-defined range of similar magnitude for both functional parameters: 32-40% of maximum values (obtained from rat myocardium with homogeneous myosin V1). Isometric tension was only insignificantly decreased in glycerinated preparations of the PTU-treated group. The alteration in the apparent maximum shortening velocity of native myocardium (V0) was of the same magnitude as changes in Vmax of chemically skinned preparations. Physical training revealed a shift in the direction of V1-type myosin with increased ATPase activity and shortening velocity; aging and pressure overload showed an opposite effect. The documented mechanical alterations do not contradict an adaptational interpretation of the myosin isoenzyme redistribution in pressure-induced hypertrophy.

Adenosine Triphosphatases↗
PubMedDate not supplied

Myocardial catecholamine responsiveness of spontaneously hypertensive rats as influenced by swimming training.

Alterations of myocardial mechanical catecholamine responsiveness by swimming training (2 X 90 min/day, 4 weeks) were examined in 13-week-old spontaneously hypertensive males rats (SHR). The relationships between myocardial mechanical catecholamine responsiveness and ventricular beta-adrenoceptors as well as myosin isoenzyme pattern were also examined. Compared with sedentary controls, trained rats showed a greater responsiveness to isoproterenol (10(-6) mol/l) on isometric tension (T) and its first derivative (dT/dt) (delta T: 0.45 +/- 0.55 vs. -0.15 +/- 0.11 10(-2) N/mm2, p less than 0.01, delta dT/dt: 17.1 +/- 10.1 vs. 8.3 +/- 3.6 10(-2) N/mm2 X s, p less than 0.05). In sedentary SHR, dT/dtmax increased significantly, whereas developed tension decreased slightly, coupled with a decrease of time to peak tension by high dose (10(-6) mol/l) isoproterenol. Therefore, it can be stated that dT/dt is a better indicator for catecholamine sensitivity than isometric tension. beta-adrenoceptor density [( 3H]-dihydroalprenolol binding) decreased significantly in trained rats (68.7 +/- 7.62 vs. 102.4 +/- 4.37 fmol/mg protein, p less than 0.01) with no significant difference in KD values (4.61 +/- 2.26 vs. 6.11 +/- 1.94 nM, ns). In addition, myosin isoenzyme pattern revealed by pyrophosphate gel electrophoresis shifted towards VM-1 after swimming training. The increased catecholamine sensitivity of fast contracting myocardium is, in principle, compatible with the assumption of cAMP-dependent regulation of myofibrillar ATPase activity (21) or cross bridge kinetics (9), although other postreceptor processes should also be taken into consideration for the increased catecholamine sensitivity.

Adenosine Triphosphatases↗
PubMedDate not supplied

Alterations in rat myocardial mechanics under Goldblatt hypertension and experimental aortic stenosis.

Left ventricular hypertrophy was induced in young male Wistar rats by unilateral renal artery constriction, either with (Goldblatt I [ = G I]) or without (Goldblatt II [ = G II]) simultaneous contralateral nephrectomy. An average increase in left ventricular weight of 55% and 18% respectively was reached within 4 weeks as compared with controls of the same age. Further increase in ventricular mass up to the 6-month stage was considerably dependent on the degree of inhibition of body growth of the experimental animals. Other rats underwent a stenosis of the Aorta ascendens (AO) with a reduction in diameter to 50%--60% of the original value, whereby a left ventricular hypertrophy of 10%--30% ensued. Isolated trabecular muscle strips of the left ventricle were examined 4, 8 and 24 weeks (G II), 4 and 8 weeks (G I), and 4 and 6 weeks (AO) after operation. Sham operations were performed for all models used.

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Noncompetitive catecholamine-antagonism of acetylcholine in the sympathectomized mammalian ventricular myocardium.

The effect of the vagus transmitter on the ventricular myocardium varies qualitatively as well as quantitatively in different warm-blood species. In the ventricular myocardium of birds (duck, hen), a part of the acetylcholine sensitivity remains even after catecholamine depletion. In contrast, the inhibitory effects of acetylcholine on the ventricular myocardium of mammals (rat, guinea pig, cat, dog, man) depend on the activity of the sympathicus. In the chemically sympathectomized (6-OH-DA) cat ventricular myocardium, a cholinergic innervation is, histochemically, clearly demonstrable. Correspondingly significant effects of endogenous (i.e. releasable by field stimulation) and exogenous acetylcholine can be seen if the contraction force is enhanced by exogenous catecholamines. This preparation is, therefore, a good model for the demonstration of a catecholamine antagonism of acetylcholine. Using this model, on the basis of dose-response relationships, it is possible to demonstrate that a noncompetitive catecholamine-antagonism of acetylcholine indeed exists in the mammalian ventricular myocardium independent of a cholinergically mediated reduction in the norepinephrine release.

Acetylcholine↗
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Prospects of X-ray microanalysis in the study of pathophysiology of myocardial contraction.

X-ray microanalysis was used to compare chemically untreated cryosections of quick-frozen myocardial tissue in "caffeine contracture" with cryosections of normal muscle. Our goal was to find out if it is possible by means of this method to detect changes in the calcium compartmentalization of the myocardial cell occurring by changes in its functional state. While it is possible to quantitate calcium in the cisternae of sarcoplasmic reticulum of the control muscle preparation, calcium could never be detected in these compartments of caffeine-contracted muscles. In active microsomal fraction of ventricular myocardium it is possible to quantitate calcium and also to distinguish two components on account of their different ability to accumulate this element. The calcium content is different in the two components of the fraction.

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Significance of geometrical reference models of the left ventricle for a new concept of evaluation of cardiac pumping function.

A methodological approach based on Frank's pressure-volume (P-V) diagram and model calculations for analyzing the determinants of stroke volume (SV) under conditions of altered ventricular geometrical configuration is discussed with respect to the underlying geometrical models. The approach is generalized in the sense that alterations in myocardial elasticity are considered. In addition, simplifying assumptions on which the stress-length (sigma-1) diagram in previous studies was based are now discarded. It can be shown that calculated stroke volume is only slightly affected by the choice of the models when referring to average wall stress. However, if we use the formula for midwall stress recommended by Mirsky, then the influence of the geometrical model becomes more important. Based on the example of a rat with experimental aortic stenosis in the decompensated stage it is demonstrated that this methodological approach is an indispensible completion of O. Frank's concept when evaluating ventricular dynamics, and could gain clinical significance in future.

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Effect of a diet rich in linseed oil on complex viscosity and blood pressure in spontaneously hypertensive rats (SHR).

The influence of a diet rich in linseed oil (10% in weight) with a content of 61.2% of alpha-linolenic fatty acid on blood pressure and complex blood viscosity was investigated in spontaneously hypertensive rats. A decrease in blood pressure by 59 mm Hg was found compared to the age-matched, untreated control group. The viscous (eta') and elastic (eta") components of viscosity were also reduced at various shear rates (gamma). The same applies to the aggregation index, which is a measure of the aggregation tendency of red blood cells (RBC). Of course, the effects on blood viscosity cannot explain the observed degree of blood-pressure-lowering. Nevertheless, a decrease in the viscosity can improve the flow conditions in the microcirculation, which may lead to a better oxygen supply.

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Imaging cytoplasmic free calcium in histamine stimulated endothelial cells and in fMet-Leu-Phe stimulated neutrophils.

Intracellular free [Ca2+] ([Ca2+]i) was imaged in Fura-2 loaded human umbilical vein endothelial cells, using dual excitation light, an inverted epifluorescence microscope and a silicon intensified target camera. Oscillations of [Ca2+]i were induced in these cells by 0.5 microM histamine. Because the image processor contained a large random access memory of 32 Mbyte, it was possible to follow these oscillations over a period of several minutes with a time resolution of approximately 2 s. Plots of the variation of average [Ca2+]i measured from these images in neighbouring cells showed that not only were the oscillations asynchronous but also that they occurred at different frequencies. This indicates that there is no strong coupling of [Ca2+]i in adjacent endothelial cells. The rise in [Ca2+]i stimulated by 0.5 microM histamine was qualitatively imaged at 80 ms intervals by recording images at 380 nm only. [Ca2+]i-independent variations in image intensity were removed by ratioing these images against a 380 nm image obtained before the stimulation by histamine. Such images revealed that [Ca2+]i rises first locally and then propagates across the cell at approximately 50 microns.s-1. Neutrophils were imaged following stimulation by fMet-Leu-Phe, also with a time resolution of 2 s. Three responses were determined from the images: (a) the rise in [Ca2+]i; (b) the cell spreading; and (c) the chemokinesis. Measuring these responses in single cells clearly showed the temporal relationships with the responses occurring in the order listed above.

Benzofurans↗