Topic
Inotropism
About: Inotropism is a research topic. Over the lifetime, 162 publications have been published within this topic receiving 2807 citations.
Papers published on a yearly basis
Papers
TL;DR: Subcellular redox manipulations by pyruvate dissociated stimulated mitochondrial respiration and increased inotropism from low cytosolic phosphorylation potentials and was evidence against the extramitochondrial [ADP].[Pi]/[ATP] ratio being the primary factor in the control of mitochondria respiration.
Abstract: Bioenergetic and hemodynamic consequences of cellular redox manipulations by 0.2–20 mM pyruvate were compared with those due to adrenergic stess (0.7–1.1 μM norepinephrine) using isolated working guinea-pig hearts under the conditions of normoxia, low-flow ischemia, and reperfusion. 5 mM glucose (+ 5 U/I insulin) + 5 μM lactate were the basal energy-yielding substrates. To stabilize left ventricular enddiastolic pressure, ventricular filling pressure was held at 12 cmH2O under all conditions; this preload control minimized Frank-Starling effects on ventricular inotropism. Global low-flow ischemia was induced by reducing aortic pressure to levels (20–10 cmH2O) below the coronary autoregulatory reserve. Reactants of the creatine kinase, including H+ and other key metabolites, were measured by enzymatic, HPLC, and polarographic techniques.
In normoxic hearts, norepinephrine stimulations of inotropism, heart rate × pressure product, and oxygen consumption (MVO2) were associated with a fall in the cytosolic phosphorylation potential ([ATP]/([ADP] · [Pi])) as judged by the creatine kinase equilibrium. In contrast, infusion of excess pyruvate (5 mM) markedly increased [ATP]/([ADP] · [Pi]) and ventricular work output, while intracellular phosphate decreased; MVO2 remained constant under the same conditions. During reperfusion following ischemia, pyruvate effected strking and concentration-dependent increases in MVO2, phosphorylation potential, and inotropism. Pyruvate dehydrogenase flux was augmented during reperfusion hyperemia followed by near-complete recoveries of [ATP]/([ADP] · [Pi]), contractile force, heart rate × pressure product, and MVO2 in the presence of 5–10 mM pyruvate. Pyruvate also attenuated ischemic adenylate degradation. Omission of glucose from the perfusion medium rendered pyruvate ineffective in postischemic hearts. Similarly, excess lactate (5–15 mM) or acetate (5 mM) failed to reenergize reperfused hearts and severe depressions of MVO2 and inotropism developed despite the presence of glucose. Apparently, subcellular redox manipulations by pyruvate dissociated stimulated mitochondrial respiration and increased inotropism from low cytosolic phosphorylation potentials. This was evidence against the extramitochondrial [ADP] · [Pi]/[ATP] ratio being the primary factor in the control of mitochondrial respiration.
The mechanism of pyruvate enhancement of inotropism during normoxia and reperfusion is probably multifactorial. Thermodynamic effects on subcellular [NADH]/[NAD+] ratios are coupled with a rise in the cytosolic [ATP]/([ADP] · [Pi]) ratio at constant (normoxia) or increased (reperfusion) MVO2. In postischemic hearts the effect of pyruvate required the presence of glucose. It is proposed that pyruvate energization may improve ion pumping by the sarcoplasmic reticulum and hence Ca2+-handling by the latter which, in turn, might increase the contractile state; decreased intracellular [Pi] due to improved phosphate fixation may also be contributory. In addition, augmented pyruvate dehydrogenase flux during reperfusion seemed to expedite cellular reenergization and functional recovery in the postischemic hearts.
224 citations
TL;DR: The cardioinhibitory influence exerted on basal mechanical performance and the counterregulatory action against beta-adrenergic and endothelin-1 stimulations point to Cts as a novel cardiac modulator, able to protect the heart against excessive sympathochromaffin overactivation, e.g. hypertensive cardiomyopathy.
Abstract: Circulating levels of catestatin (Cts; human chromogranin A352-372) decrease in the plasma of patients with essential hypertension. Genetic ablation of the chromogranin A (Chga) gene in mice increases blood pressure and pretreatment of Chga-null mice with Cts prevents blood pressure elevation, indicating a direct role of Cts in preventing hypertension. This notable vasoreactivity prompted us to test the direct cardiovascular effects and mechanisms of action of wild-type (WT) Cts and naturally occurring human variants (G364S-Cts and P370L-Cts) on myocardial and coronary functions. The direct cardiovascular actions of WT-Cts and human variants were determined using the Langendorff-perfused rat heart. WT-Cts dose-dependently increased heart rate and coronary pressure and decreased left ventricular pressure, rate pressure product and both positive and negative LVdP/dt. WT-Cts not only inhibited phospholamban phosphorylation, but also the inotropic and lusitropic effects of WT-Cts were abolished by chemical inhibition of beta2-adrenergic receptors, Gi/o protein, nitric oxide or cGMP, indicating involvement of beta2-adrenergic receptors-Gi/o protein-nitric oxide-cGMP signaling mechanisms. In contrast, G364S-Cts did not affect basal cardiac performance but abolished isoproterenol-induced positive inotropism and lusitropism. P370L-Cts decreased rate pressure product and inhibited only isoproterenol-induced positive inotropism and lusitropism by 70%. Cts also inhibited endothelin-1-induced positive inotropism and coronary constriction. Taken together, the cardioinhibitory influence exerted on basal mechanical performance and the counterregulatory action against beta-adrenergic and endothelin-1 stimulations point to Cts as a novel cardiac modulator, able to protect the heart against excessive sympathochromaffin overactivation, e.g. hypertensive cardiomyopathy.
154 citations
TL;DR: The ability of these drugs to protect heart muscle against the deleterious effects of ischaemia and reperfusion may reflect their negative inotropism, with consequent maintenance of tissue ATP above the levels needed to maintain intracellular Ca2+ homeostasis.
Abstract: The term “calcium antagonist” has been used for more than a decade to describe a group of drugs whose negative inotropism is overcome by calcium. Because this term lacks specificity with respect to a precise mode of action, and implies a classical receptor-agonist-antagonist relationship, its continued use should be questioned. Drugs belonging to this group are verapamil, D600, nifedipine and diltiazem. They inhibit the slow inward current of the action potential and would more appropriately be called “slow channel inhibitors”. The group is heterogenous and may have to be subclassified. The negative inotropism of these drugs can be attributed to a reduction of the slow calcium current. The function of most intracellular organelles is unaffected. Studies with radioactively labelled verapamil show tight binding to glycolipids or glycoproteins in the sarcolemma. Consequent change in the conformational state of the cell membrane could inhibit the slow calcium current. The ability of these drugs to protect heart muscle against the deleterious effects of ischaemia and reperfusion may reflect their negative inotropism, with consequent maintenance of tissue ATP above the levels needed to maintain intracellular Ca2+ homeostasis, rather than a direct inhibitory effect on calcium influx during ischaemia or on reperfusion.
119 citations
TL;DR: Evidence for pyruvate enhancement of cardiac function may result from one or more of the following mechanisms: increased cytosolic ATP phosphorylation potential and Gibbs free energy of ATP hydrolysis, enhanced sarcoplasmic reticular calcium ion uptake and release, decreased cytOSolic inorganic phosphate concentration, oxyradical scavenging via direct neutralization of peroxides and/ or enhancement of the intracellular glutathione/NADPH antioxidant system, and/or closure
Abstract: Pyruvate, a metabolic product of glycolysis and an oxidizable fuel in myocardium, increases cardiac mechanical performance and energy reserves, especially when supplied at supraphysiological concentrations. The inotropic effects of pyruvate are most impressive in hearts that have been reversibly injured (stunned) by ischemia/reperfusion stress. Glucose appears to be an essential co-substrate for pyruvate's salutary effects in stunned hearts, but other fuels including lactate, acetate, fatty acids, and ketone bodies produce little or no improvement in postischemic function over glucose alone. In contrast to pharmacological inotropism by catecholamines, metabolic inotropism by pyruvate increases cardiac energy reserves and bolsters the endogenous glutathione antioxidant system. Pyruvate enhancement of cardiac function may result from one or more of the following mechanisms: increased cytosolic ATP phosphorylation potential and Gibbs free energy of ATP hydrolysis, enhanced sarcoplasmic reticular calcium ion uptake and release, decreased cytosolic inorganic phosphate concentration, oxyradical scavenging via direct neutralization of peroxides and/or enhancement of the intracellular glutathione/NADPH antioxidant system, and/or closure of mitochondrial permeability transition pores. This review aims to summarize evidence for each of these mechanisms and to consider the potential utility of pyruvate as a therapeutic intervention for clinical management of cardiac insufficiency.
115 citations
TL;DR: The results indicate that the maximum value of the ratio in systole is increased and the time course is shortened by positive inotropism (stimulation of the left stellate ganglion), but that the contour of the timecourse is approximately unchanged by positive Inotropism.
Abstract: Time course of pressure/volume ratio of the left ventricle in systole has been proposed as a good index of its pumping properties; the ratio is an approximately steady function of time with its time course almost un-altered by changes in left ventricular end-diastolic volume (preload) and arterial loading conditions (afterload). It is the purpose of the present investigation to compare the ratio in a positive inotropic state with a control in experiments on the dog. The results indicate that the maximum value of the ratio in systole is increased and the time course is shortened by positive inotropism (stimulation of the left stellate ganglion), but that the contour of the time course is approximately unchanged by positive inotropism.
84 citations
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Performance Metrics
| Year | Papers |
|---|---|
| 2022 | 1 |
| 2021 | 1 |
| 2018 | 1 |
| 2017 | 3 |
| 2016 | 3 |
| 2015 | 2 |