Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug effects on myocardial contractile function are obviously of considerable practical importance for the toxicologist. The basic mechanism of such actions must reside at some point in the metabolism of cardiac muscle. Interference in the liberation of energy from the fuels that the heart uses may be implicated. It is possible that drugs may interfere with the storage (conservation) of that energy as the high energy phosphates (ATP and CP). Finally, the utilization of that stored energy by the contractile proteins themselves may be altered. The latter process is highly dependent on intracellular calcium ion kinetics. Anesthetic drugs, which produce reversible depression of myocardial contractile function is a dose-dependent fashion, have been shown to interfere to some extent with all three processes. However, the most important mechanism probably involves utilization of energy and intracellular calcium ion movement. A basic knowledge of the biochemistry of cardiac muscle is necessary for the understanding of drug action and toxicity at the subcellular level.
 ...
PMID:Myocardial metabolism for the toxicologist. 72 Mar 13

Trans-1,2-dichloroethylene (t-DCE), an industrial solvent, proved to be moderately toxic when studied in small laboratory animals. In adult female rats brief (8 h) and prolonged (8 h daily, on 5 consecutive days a week, for more than 16 weeks) inhalation of 200 ppm--the current TLV/MAC in various countries--produced histological evidence of slight to severe fatty degeneration of the liver lobules and Kupffer cells. In addition marked pulmonary hyperaemia and alveolar septal distention were noted. Fibrous swelling of the cardiac muscle (with striation) just barely maintained) and hyperaemia remained detectable for as long as 14 h post-exposure, but only occurred at 3000 ppm/8 h. A concentration of 1000 ppm/8 h was required to produce a fall in blood albumin, urea nitrogen, alkaline phosphatase activities and erythrocyte count. The cited concentrations failed to produce prenarcotic symptoms of narcosis (central nervous system (CNS) depression). The LD50 was found to be 6.0 ml/kg i.p. and 1.0 ml/kg p.o. for female rats, and 3.2 ml/kg i;p. for female mice. In some of the rats killed in these experiments the organ changes were found to be identical to those observed after inhalation.
 ...
PMID:Toxicity studies on trans-1,2-dichloroethylene. 85 30

In 100 consecutive patients with acute cerebrovascular accident, due to cerebral thrombosis in 72, cerebral hemorrhage in 12, embolus in 6, and subarachnoid hemorrhage in 10, there were 90 who had electrocardiographic abnormalities during the first three days after admission, compared to 50% in a control group. The patients with cerebrovascular accident had a 7- to 10-fold higher incidence of ST segment depression, prolonged Q-Tc interval and atrial fibrillation, and a 2- to 4-fold higher incidence of T wave inversion, conduction defects, premature ventricular beats and left ventricular hypetrophy. Patients who died had a 2-, 3- and 5-fold higher incidence of electrocardiographic evidence of recent myocardial infarction, atrial fibrillation and conduction defects than those who survived, but these changes occurred in only 5, 21 and 14% of all patients, and other electrocardiographic changes could not be correlated with mortality. During the first three days after admission 29 patients had elevation of serum enzymes which may be derived from cardiac muscle, particularly CPK, which was increased 6-fold, compared to 2-fold increases in HBDH, GOT, and LDH. Only 5 of these patients had electrocardiographic evidence of recent myocardial infarction. Patients with elevated serum CPK had a 2-fold higher incidence of ST segment depression, T wave inversion, conduction defects and atrial fibrillation than those with normal CPK, and a mortality of 66%, compared to 30%. Of 41 patients who died, 49% had elevated serum CPK, compared to 15% of 59 patients who survived. These differences were significant (P less than 0.01). Serum CPK was more frequently helpful than the electrocardiogram in evaluating the extent of cardiac damage and in predicting mortality. Patients with acute cerebrovascular accident should have repeated evaluation of serum CPK and the ECG, and be monitored for arrhythmias.
 ...
PMID:Electrocardiographic changes and myocardial damage in patients with acute cerebrovascular accidents. 89 40

In cardiac muscle, moderate degrees of hyperosmolality of the type encountered physiologically or clinically (i.e., less than 200 mosM above control) characteristically exert a positive inotropic effect, which presumably is mediated by increased Ca2+ availability for binding to troponin. In contrast, skeletal muscle displays significant contractile depression on exposure to hyperosmotic solutions, even at mild degrees of hypertonicity. To determine whether a similar potential for hyperosmolarity-induced depression also exists in cardiac muscle, right ventricular papillary muscles from cats were exposed to hypertonic solutions of mannitol or sucrose under circumstances in which positive inotropic effects were precluded by prior exposure to a bathing solution of 4.0 mM Ca2+ and paired electrical stimulation to maximize intracellular Ca2+ before addition of the hyperosmotic substances. In contrast to their usual positive inotropic effects, hypertonic solutions under these conditions caused cardiac depression at all osmolarities tested. Developed tension and its maximal rate of development (dT/dt) decreased by 18% at 50 mosM above control, by 30% at 100 mosM, by 36% at 150 mosM, and by 42% at 200 mosM (P less than 0.01 for all). Time to peak tension and resting tension were not changed significantly. When the muscles were returned to control solutions, tension development also returned toward normal. The data are compatible with the hypothesis that, within the range tested, all degrees of hyperosmolarity exert a significant negative inotropic influence on cardiac muscle, as is true in skeletal muscle; manifestation of this effect of increased tonicity normally would be obscured at low degrees of hyperosmolality, however, by an overriding positive influence that is absent in skeletal muscle.
 ...
PMID:Negative inotropic influence of hyperosmotic solutions on cardiac muscle. 121 82

The effects of insulin (In) on contractile activity of isolated cardiac muscle were studied in right ventricular moderator band (MB) of piglets and papillary muscle (PM) of cats and kittens. The muscles were bathed in modified Krebs solution containing 5.6 mM glucose at 30 degrees C and gassed with 95% O2 and 5% CO2. They were paced at 24 contractions per minute isometrically at Lmax. Addition of In (1 U/ml) to the bath induced a biphasic inotropic response to piglet MB. The initial negative effect was due to the preservative (0.2% phenol) in the regular commercial In solution. Following the transitory depression, both active isometric tension (AT) and maximal rate of tension development increased to a maximum (about 120% of control) within 15 min and then declined slightly toward control. Similar positive responses were observed in both cat and kitten PM, but without the initial negative effect. Maximal responses were not diminished by the absence of glucose in the bath. Increases in AT and dT/dt of both MB and PM in response to NE were significantly attenuated in the presence of In compared with untreated muscle. These findings demonstrate that In elicits a positive inotropic effect on mammalian cardiac muscle and that it impairs the inotropic action of NE.
 ...
PMID:Effects of insulin on cardiac muscle contraction and responsiveness to norepinephrine. 127 78

Addition of 10 mM citrate at constant free extracellular Ca concentration [( Ca]o; 2 mM) reduced contraction in rabbit ventricular muscle and isolated myocytes. We have recently shown that extracellular citrate decreases contraction and Ca current (ICa) in cardiac muscle by a direct effect on Ca channels rather than by Ca buffering per se [D. M. Bers, L. V. Hryshko, S. M. Harrison, and D. Dawson. Am. J. Physiol. 260 (Cell Physiol. 29): C900-C909, 1991]. Citrate rapidly depressed peak ICa and shifted both the peak ICa and the apparent reversal potential (Erev) to more negative potentials. When the impermeant cations, tetraethylammonium or N-methylglucamine were used instead of intracellular Cs, the citrate-induced shift in Erev was reduced or eliminated but depression of ICa was still observed. Thus citrate appears to alter the selectivity (PCa/PCs) of the Ca channel and reduce ICa. We also studied the effects of citrate on Na current through the Ca channel, observed when the divalent cation concentration is submicromolar. This current, termed INS for nonspecific, also exhibited leftward shifts in peak INS and smaller changes in Erev in the presence of citrate. However, neither peak INS nor single-channel conductance were affected by citrate. Thus the reduced PCa/PCs is due primarily to alteration of Ca permeation rather than monovalent cation permeation. Activation and inactivation curves for both ICa and INS were shifted toward more negative potentials by citrate. The shifts in gating and peak current to more negative membrane potentials would be consistent with a surface charge effect. The much larger shift in Erev for ICa (than for INS) is consistent with a reduction in Ca selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Citrate alters Ca channel gating and selectivity in rabbit ventricular myocytes. 131 Feb 10

Because the Na+ pump is considered to modulate the contractile force development by the cardiac muscle and depressed cardiac pump function is the hallmark of congestive heart failure, we characterized the sarcolemmal Na(+)-K(+)-ATPase activity in failing rat hearts after myocardial infarction. For this purpose, the left ventricular coronary artery was ligated, and hearts were examined 4, 8, and 16 wk later; sham-operated animals served as controls. Hemodynamic assessment revealed the presence of abnormal cardiac function at 4, 8, and 16 wk. Although accumulation of ascites in the abdominal cavity was present in experimental animals at 4 wk, other clinical signs of congestive heart failure in experimental rats including lung congestion and cardiac dilatation were evident 8 and 16 wk after induction of myocardial infarction. The depression in Na(+)-K(+)-ATPase activity in purified sarcolemmal membrane from the uninfarcted experimental left ventricle at 8 wk was associated with depressed Vmax without any changes in the affinities for Mg-ATP, Na+, and K+ or the pH optimum for the enzyme. The Kd values of both the high- and low-affinity binding sites for [3H]ouabain, which is believed to interact with Na(+)-K(+)-ATPase, were increased; however, no change in the density of either class of ouabain binding site was evident. The depression of Na(+)-K(+)-ATPase activity in failing hearts at 16 wk of myocardial infarction was not different from that observed at 8 wk but the enzyme activity was not altered at 4 wk of coronary occlusion. These data support the view that depression of Na(+)-K(+)-ATPase activity may serve as an adaptive mechanism during the development of congestive heart failure.
 ...
PMID:Sarcolemmal Na(+)-K(+)-ATPase activity in congestive heart failure due to myocardial infarction. 131 80

Among the mechanisms postulated to contribute to myocardial "stunning" is a depression of contractility by oxygen-derived free radicals. It has been suggested that these radicals might depress the calcium sensitivity of the contractile proteins. We have exposed the myofilaments (in chemically "skinned" rat cardiac muscle) to the superoxide anion and measured isometric force at controlled degrees of activation. Superoxide was generated by the xanthine/xanthine oxidase system: the effects to be described were shown to be specifically attributable to superoxide. Maximum calcium-activated force is reduced, or even completely abolished, in a dose-dependent fashion and without any alteration in calcium sensitivity. The myofilaments are highly sensitive to superoxide: significant force reduction has been shown to be caused by enzyme concentrations as low as 2 microunits/ml xanthine oxidase and with exposures of less than 1 minute to the generating system (at higher enzyme concentrations). Once force has been depressed, it cannot be recovered within the duration of the experiments described. When xanthine oxidase is applied during the calcium-induced contracture, tension falls steadily. However, a similar concentration is without immediate effect on the rigor contracture (evoked by applying ATP-free solutions). To account for the depression of maximum calcium-activated force, we conclude that some aspect of crossbridge behavior is particularly vulnerable to superoxide rather than that the radical has a nonspecific "proteolytic" effect. This action on the fundamental units of force production could contribute to myocardial stunning since the effects we report are consistent with many aspects of this phenomenon.
 ...
PMID:Depression of peak force without altering calcium sensitivity by the superoxide anion in chemically skinned cardiac muscle of rat. 131 36

Inhalational anesthetics and ventricular hypertrophy have adverse effects on cardiac muscle contraction. The effects of 1, 2, and 3% halothane on the contractile protein and sarcoplasmic reticulum, but not the sarcolemma, were examined in normal left ventricular tissue from rabbits that underwent a sham surgical procedure (n = 5) and in left ventricular hypertrophied tissue from surgically induced aortic coarctation (n = 7). Muscle samples were mechanically "skinned" to disrupt the sarcolemma. Fiber bundles were mounted in photodiode transducers and bathed in a series of solutions designed to examine the contractile protein [Ca2+]-tension responses or to examine Ca2+ storage by and release from the sarcoplasmic reticulum. Hill equation analysis of the [Ca2+]-tension relationship of the contractile protein was performed. Compared to normal muscle, hypertrophied muscle was associated with an 8.2% decrease in the [Ca2+] necessary for 50% maximum tension (more sensitive to Ca2+) (P less than 0.001) and an increase in the slope constant of 23% (P less than 0.001). In normal and hypertrophied tissue, each 1% of halothane incrementally decreased the contractile protein response to maximal [Ca2+] by 5% (P less than 0.01), increased the [Ca2+] at 50% maximum tension by 5% (P less than 0.01), and had no effect on the slope of the Hill equation. Halothane also inhibited Ca2+ storage by the sarcoplasmic reticulum. In normal muscle, 1, 2, and 3% halothane decreased the stored Ca2+ to 42, 22, and 9%, respectively, of Ca2+ storage without halothane (P less than 0.001). However, hypertrophied muscle demonstrated slightly less depression (P less than 0.05 by analysis of variance).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Left ventricular hypertrophy in rabbits does not exaggerate the effects of halothane on the intracellular components of cardiac contraction. 138 68

To examine the signals regulating cardiac growth and molecular structure of subcellular organelles, cardiac hypertrophy was induced in rats by constriction of the abdominal aorta for 12-13 wk or by treatment with a carnitine palmitoyltransferase I inhibitor, etomoxir (12-15 mg/kg body wt) for 12-13 wk. In contrast to pressure overload, etomoxir redistributed the myosin isozyme population from V3 to V1 and increased the sarcoplasmic reticulum (SR) Ca(2+)-stimulated ATPase activity. When rats with pressure-overloaded hearts were treated with etomoxir, the cardiac hypertrophy was increased whereas the shift in myosin isozymes from V1 to V3 was prevented and the depression in SR Ca(2+)-stimulated ATPase activity was reversed. Plasma thyroid hormone and insulin concentrations were not altered but triglyceride concentrations were reduced in etomoxir-treated rats with pressure overload. The data demonstrate a dissociation between cardiac muscle growth and changes in subcellular organelles and indicate that a shift in myocardial substrate utilization may represent an important signal for molecular remodeling of the heart.
 ...
PMID:Modification of subcellular organelles in pressure-overloaded heart by etomoxir, a carnitine palmitoyltransferase I inhibitor. 153 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>