摘要:

In the present study, the pathophysiologic role of glomerular hemodynamic factors in the early phase of HgCl2-induced acute renal failure is evaluated in the dog. This model of moderate ARF is characterized by a parallel fall in glomerular filtration rate (ΔGFR, -43%) and renal blood flow (ΔRBF, -38%) within the first three hours after HgCl2administration. Glomerular hemodynamics were studied by analysis of PVP-sieving curves. There was a significant shift of these curves upward and to the right during the 3 hours that followed the injection of HgCl2. From this analysis, no arguments for tubular back-leak could be found. Mathematical analysis of the curves revealed a fall in effective filtration pressure (EFP) in presence of an unchanged glomerular ultrafiltration coefficient (Kf) (ΔEFP, -40±4%; p<0.01; AKf, +5± 1%; p>0.05 vs. control). No major changes occurred in glomerular colloid osmotic pressure. Subsequently, the early fall of GFR in this toxic model of acute renal failure was essentially attributed to a decrease of effective filtration pressure due to either tubular obstruction and/or mainly to renal hemodynamic changes.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The ventricular systolic pressure-volume area correlates well with myocardial oxygen consumption. However, in isolated muscle preparations, there are experimental data based on both mechanical and energetic measurements that suggest that the pressure-volume area concept may not obtain. In the present study, force-length area, the analog of pressure-volume area for a linear muscle, was examined in the ferret papillary muscle preparation under a wide range of loading conditions. There were two major findings: first, force-length area is closely correlated with oxygen consumption (r = 0.94–0.98); this correlation is better than those for such other indexes as peak force and force-time integral. Furthermore, this relation of oxygen consumption with force-length area is independent of the mode of contraction (isometric or shortening), while the relations with the other indexes are not. Second, quick release imposed after end-systole during isometric contraction was found to curtail oxygen consumption. The first finding, the optimal correlation of force-length area with oxygen consumption, suggests both that the correlation of pressure-volume area with oxygen consumption on the ventricular level arises from a basic property of cardiac muscle and that force-length area may be the best mechanical index to use in calculating regional oxygen consumption for a ventricular segment. The second finding, however, suggests that the time-varying elastance model, on which the concepts of pressure-volume area and force-length area are based, may not provide a complete description of the mechanical basis of cardiac muscle energetics, especially during the isometric contraction.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

With monoclonal antibodies (Mab) specific for myosin heavy chain (MHC) isozymes, we have investigated the isomyosin content of atrial, ventricular and conductive fibers of 19 human fetuses (ranging from 14-36 weeks of gestation) and 3 newborns (2 days-2 weeks). In addition, the conduction system of 2 human adult hearts was studied. The fetal atrium is composed mostly of α-MHC during the first 23 weeks of gestation. β-MHC is already expressed as traces at 14 weeks of gestation, and its expression increases progressively until birth, resulting in a great augmentation in β-MHC. During this course, β-MHC always predominates in certain areas (the crista terminalis and the interatrial septum) but not in other areas (the auricles). Preceding birth, the fetal ventricle is composed mostly of β-MHC. From 14 weeks of gestation to birth, α-MHC is expressed in very rare fibers. Then, after birth, a large number of fibers simultaneously synthesize α-MHC. The AV node and His bundle system were labelled with anti-α and anti-β Mab in fetal, newborn, and adult hearts with a double gradient of distribution: spatial (a higher proportion of α-containing fibers in the AV node than in the distal portion of the bundle of branches) and temporal (a higher proportion of α-containing fibers at a given point in fetal development than in the adult heart). One of the twenty-five hearts studied had an isomyosin distribution pattern not accorded to its age. Interestingly, it was clinically diagnosed as having idiopathic hypertrophic cardiomyopathy.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

To test the hypothesis that the capacity ito develop left ventricular (LV) hypertrophy might diminish with advancing age, we examined the hypertrophic response to ascending aortic constriction in 3 groups of adult Fischer 344 rats (9 months, 18 months, and 22 months of age). Aortic constriction was created so that aortic cross-sectional areas would be the same for the 3 groups of rats. Four weeks after imposition of aortic constriction, there was no significant difference in peak LV pressure, peak-to-peak and mean systolic pressure gradients between left ventricle and aorta, cardiac output, LV minute work, or cross-sectional area of the aortic constrictions in the 3 groups. In 9-month-old aortic-constricted rats, LV dry wt (LVDW)/body wt, LVDW/tibial length, and myocyte width increased by 23% (p<0.01), 14% (p<0.01), and 27% (p<0.01), respectively, compared with sham-operated rats. In contrast, in 18-month-old and 22-month-old aortic-constricted rats, LVDW/body wt and LVDW/tibial length were unchanged compared with sham-operated controls, and increases in myocyte width were only modest 4 weeks following constriction. RNA concentration in the myocardium 5 days after constriction increased by 21 % (p<0.001) in 9-month-old rats but showed no significant rise in 18-month-old rats. These results suggest that advancing age is associated with a diminished capacity to develop myocardial hypertrophy in response to acute pressure overload and that a reduced ability to synthesize protein may be one of the major contributing factors to a diminished capacity for hypertrophy in advanced age.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Diet-induced atherosclerosis in primates impairs vasodilator responses and greatly potentiates vasoconstrictor responses to serotonin. Serotonin may play an important role in the pathogenesis of vasospasm. In diet-induced regression of atherosclerosis, intimal lesions are reduced, but maximal vasodilator responses do not improve, perhaps because of vascular fibrosis. Our goal was to determine whether dietary treatment of atherosclerosis reverses the augmented vasoconstrictor responses to serotonin and thus might reduce susceptibility to vasospasm. Normal cynomolgus monkeys, atherosclerotic monkeys, and atherosclerotic monkeys that were given a normal (regression) diet for 18 months were studied. Morphometric studies indicated that the regression diet reduced lesions in the iliac and femoral artery since intimal area was reduced by about 50%. In the hind limb perfused at constant flow, residual resistance during maximal vasodilatation produced by infusion of adenosine tended to be greater in atherosclerotic monkeys than in normals and failed to improve in regression monkeys. In contrast, vasoconstrictor responses to serotonin were greatly potentiated in atherosclerotic monkeys and were restored to normal in regression monkeys. Serotonin (20 μg i.a.) decreased hind limb resistance (in mm Hg/ml/min) 0.34 ± 0.06 (mean ± SE) in normal monkeys, increased resistance 0.58 ± 0.17 in atherosclerotic monkeys (p < 0.05 vs. normal), and decreased resistance 0.70 ± 0.15 in regression monkeys (p < 0.05 vs. atherosclerotic). Thus, dietary treatment of atherosclerosis abolishes augmented vasoconstrictor responses to serotonin. It is proposed that treatment of atherosclerosis may be beneficial, even when vasodilator responses fail to improve, by reducing susceptibility to serotonin-induced vasospasm.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The present study assessed the mechanisms responsible for the initiation and maintenance of premature ventricular complexes (PVCs) and ventricular tachycardia (VT) during early ischemia using a unique computerized mapping system capable of recording simultaneously from 232 individual intramural sites. In the chloralose-anesthetized cat, during normal sinus rhythm prior to ischemia, ventricular activation was rapid with a total activation time of 25 ± 2 msec. Five minutes after occlusion of the left anterior descending (LAD) coronary artery, activation was delayed during sinus rhythm (64 ± 6 msec) (p<0.001 vs. control) and was characterized by slow conduction in the same plane and block in both the same plane and in the endocardial-to-epicardial direction. In 76% of cases (16 of 21), initiation of single PVCs and the first beat of VT occurred through intramural reentry. In all but one case, initiation occurred in the subendocardium, adjacent to the site of delayed subendocardial and midmyocardial activation of the preceding sinus beat. The activation time of the sinus beat preceding the PVC or VT was significantly prolonged (149 ± 7 msec, p<0.001 vs. sinus beats during ischemia not followed by a PVC or VT) with most of the delayed activity occurring in the subendocardium and midmyocardium, a finding that would not have been apparent by epicardial mapping alone. The length of the reentrant pathway ranged from 1.8–3.0 cm. Marked delay was a necessary, but not a sufficient, condition for reentry to occur since, in some cases, delays as large as 220 msec was found without initiation of reentry or the occurrence of nonreentrant PVCs or VT. Maintenance of VT by intramural reentry arose in either the subendocardium or the subepicardium and was primarily dependent on the continued presence of marked transmural delay (159 ± 8 msec). In contrast, in 24% of cases (5 of 21), initiation of the first beat of VT arose in either the subendocardium or subepicardium by a mechanism other than reentry as evidenced by the lack of intervening electrical activity between the end of the preceding sinus beat and the initiation of the ectopic beat. The preceding sinus beat was characterized by delay (129 ± 12 msec) comparable to that of sinus beats preceding reentrant ectopic beats (p = NS), but the marked delay was distant from the site of nonreentrant initiation. Ventricular tachycardia could be initiated by one mechanism (reentrant or nonreentrant) and maintained or terminated by another mechanism. Both mechanisms could also occur during the initiation of the same beat and during the same tachycardia. Thus, the initiation and maintenance of VT during early ischemia is due to both intramural reentry and nonreentrant mechanisms. Therapeutic interventions designed to inhibit the malignant arrhythmias associated with early ischemia and, hence, sudden death in man will likely require demonstration of efficacy against not only the reentrant but also nonreentrant mechanisms.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Activation of protein kinase C has been implicated in the regulation of a variety of cellular reactions. Although we, and others, have found protein kinase C and its substrate proteins to be present in both membrane and cytosolic fractions in the heart, the physiologic role of this kinase in the regulation of cardiac functions remains unknown. In the present study, we found that in isolated perfused rat heart, administration of phorbol esters 4β-phorbol 12,13-dibutyrate(PDBu) and 12-0-tetradecanoyl-phorbol 13-acetate(TPA), which are specific activators of protein kinase C, produced marked dose-dependent negative changes in inotropy and chronotropy. A dose-dependent decrease in coronary flow was also observed. The diacylglycerol analogues, 1,2-oleoylacetyl-glycerol and 1,2-dioctanoyl-glycerol, produced similar effects as the active phorbol esters on these isolated perfused hearts. An inactive analogue of phorbol ester, 4α-phorbol, failed to produce any effect. Protein kinase C activity in both membrane and cytosolic fractions prepared from rat heart could be activated by TPA and PDBu at the same concentration range as used in the experiments with perfused hearts. Following perfusion of the hearts with PDBu, a rapid translocation of protein kinase C from cytosolic to membrane fractions was also observed. Our findings provide the first direct evidence that protein kinase C may play a potentially important role in the regulation of cardiac functions.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The interaction of 1,4-dihydropyridine derivatives with their receptors on voltage-dependent calcium channels in cardiac membranes was studied to determine if there are basic differences in the binding properties of ligands that cause inhibition or activation of calcium channels. The binding characteristics of 6 pure stereoisomers, (-) and (+)202-791, (-) and (+)Bay k 8644, (-) and (+)PN 200-110, as well as racemic Bay k 8644 and nitrendipine, were compared. Competition studies using the cold ligands and 3 different radiolabelled dihydropyridines, (+)[3H]PN 200-110, (±)[3H]nitrendipine, and (±)[3H]Bay k 8644, showed that, for each combination tested, the labelled dihydropyridine could be displaced by the cold dihydropyridine. The binding reactions were markedly affected by temperature. The Kdvalues for most compounds were significantly higher (5-19 times) at 0° than at 37°C. In contrast, the affinity of (+)PN 200-110 was similar at 0° and 37°C, but slightly higher at 25°C. A thermodynamic analysis indicated that the binding of the two pure isomers that are Ca2+-channel activators (“agonists”), (-)Bay k 8644 and (+)202-791, was driven entirely by enthalpy and was associated with an unfavorable decrease in entropy. This was in marked contrast to the binding of the inhibitors (“antagonists”). The binding of (+)PN 200-110 and nitrendipine at low temperatures was driven largely or entirely by entropy. Other antagonist-binding reactions were driven mainly by enthalpy but were associated with favorable increases in entropy. The affinity of the three radiolabelled ligands for the dihydropyridine receptor differed 100 times and appeared to be due to large differences in dissociation rate constants for each of the ligands. The rates of dissociation of (+)[3H]PN 200-110 and (±)[3H]nitrendipine, but not of (±)[3H]Bay k 8644, were significantly slowed by diltiazem, a calcium-channel inhibitor that binds to another receptor on the calcium channel. The results show that there were marked differences in the binding of the various dihydropyridines and suggest that the energetics of binding of Ca2+-channel activators and inhibitors may be fundamentally different.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Endothelial cells (ECs) were isolated from bovine pulmonary artery and maintained in long-term culture. On reaching confluency, ECs formed a characteristic "cobblestone" monolayer. One hour after addition of 1 nM platelet-activating factor (PAF) to the growth medium, ECs underwent dramatic changes in shape from their normal polygonal morphology to more elongated spindle-shaped forms. More pronounced effects were evident in the presence of 0.1 nM phorbol-12-myristate-13-acetate (PMA), a potent activator of C kinase. It was found that at concentrations from 10<SUP>-11</SUP>-10<SUP>-7</SUP>M, PAF stimulates the phosphoinositide turnover in EC. The half-maximal activation in the release of inositol phosphates was at 10<SUP>-9</SUP>M. This finding suggested that an increase in intracellular Ca<SUP>2+</SUP>concentration and activation of protein kinase C were involved in the mechanism of action of PAF on EC. The metabolic responses of EC were evaluated by measuring the activity of β-adrenergic receptor-coupled adenylate cyclase (AC) in a crude membrane fraction and by assay of prostacyclin and thromboxane released by cultured EC. AC from control membranes was activated by isoproterenol in a dose-dependent manner (EC<SUB>50</SUB>= 30 nM) from 0.8–5.5 pmol cAMP/min/mg protein. If the membranes were isolated after preincubation of ECs with 1 nMPAF or 0.l nM PMA, the AC activity was decreased by 70 and 90%, respectively; in both cases, affinity for isoproterenol was lowered threefold (EC<SUB>50 </SUB>= 100 nM). Our data suggest that PAF interaction with EC leads to an apparent β-adrenergic receptor desensitization that probably acts via a phosphorylation mechanism involving C kinase. Incubation of EC for 30 minutes with 0.1–1.0 nM PAF caused inhibition of both prostacyclin and thromboxane production (55 and 75%, respectively) indicating that PAF acts at a level common to both pathways of arachidonate metabolism. Similar results were obtained using PMA (0.1 nM) but not with phorbol-12,13-didecanoate, an inactive analogue of PMA. Taken together, these data indicate that C kinase is involved in PAF-induced alteration in receptor sensitivity at the plasma membrane level as well as in intracellular enzymes responsible for prostacyclin and thromboxane synthesis by EC. This down-regulation of metabolic activity of EC is accompanied by concomitant shape changes.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Hamsters with either the dilated (BIO 53.58) or hypertrophic (BIO 14.6) form of cardiomyopathy and an inbred control strain of hamster (F1B) were treated for 6 months with high-dose L-carnitine (1 g/kg/day i.p.). After treatment, the animals were killed and their hearts perfused by the isolated working technique. Mechanical performance (as indicated by the double product of heart rate and left ventricular [LV] peak systolic pressure) of both carnitine-treated cardiomyopathic groups was increased significantly above their respective sham-treated groups. Associated with these increases in mechanical performance were significant increases in both peak-positive LV dP/dt (index of contractility) and peak negative dP/dt (index of relaxation) in both carnitine-treated myopathic groups. Serum carnitine levels were increased 10-15 times within 2 hours after injection of L-carnitine in all 3 groups. Myocardial free-carnitine levels were increased twofold in both control and dilated myopathic hearts above their respective sham-treated groups, restoring the level in the dilated hearts comparable to those of controls. Myocardial carnitine levels in the hypertrophic group were not significantly affected by treatment. Total high-energy phosphate stores, i.e., ATP plus creatine phosphate, were restored to control levels by L-carnitine treatment in both cardiomyopathic groups. Levels of the breakdown products of ATP were maintained primarily in the more readily convertible adenosine diphosphate and adenosine monophosphate forms in all three treated groups. These changes resulted in significantly higher ratios of (ATP)/(ADP + AMP + adenosine) and (creatine phosphate)/(creatine) in the treated hearts. This is the first study demonstrating that high-dose L-carnitine treatment results in improved cardiac performance and increased myocardial total high-energy phosphate stores in the Syrian hamster model with one of two distinct forms of cardiomyopathy, i.e., dilated or hypertrophic. The mechanisms for these effects of exogenous L-carnitine treatment cannot be totally explained by changes in oxidative energy metabolism.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID