Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration.

TNF alpha mRNA and protein biosynthesis were examined in the adult feline heart after stimulation with endotoxin. When freshly isolated hearts were stimulated with endotoxin in vitro, de novo TNF alpha mRNA expression occurred within 30 min, and TNF alpha protein production was detected within 60-75 min; however, TNF alpha mRNA and protein production were not detected in diluent-treated hearts. Immunohistochemical studies localized TNF alpha to endothelial cells, smooth muscle cells, and cardiac myocytes in the endotoxin-treated hearts, whereas TNF alpha immunostaining was absent in the diluent-treated hearts. To determine whether the cardiac myocyte was a source for TNF alpha production, two studies were performed. First, in situ hybridization studies, using highly specific biotinylated probes, demonstrated TNF alpha mRNA in cardiac myocytes from endotoxin-stimulated hearts; in contrast, TNF alpha mRNA was not expressed in myocytes from diluent-treated hearts. Second, TNF alpha protein production was observed when cultured cardiac myocytes were stimulated with endotoxin, whereas TNF alpha protein production was not detected in the diluent-treated cells. The functional significance of the intramyocardial production of TNF alpha was determined by examining cell motion in isolated cardiac myocytes treated with superfusates from endotoxin- and diluent-stimulated hearts. These studies showed that cell motion was depressed in myocytes treated with superfusates from the endotoxin-treated hearts, but was normal with the superfusates from the diluent-treated hearts; moreover, the negative inotropic effects of the superfusates from the endotoxin-treated hearts could be abrogated completely by pretreatment with an anti-TNF alpha antibody. Finally, endotoxin stimulation was also shown to result in the intramyocardial production of TNF alpha mRNA and protein in vivo. Thus, this study shows for the first time that the adult mammalian myocardium synthesizes biologically active TNF alpha.     

Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation.

The Ca2+ ATPase of the sarcoplasmic reticulum (SERCA2) plays a dominant role in lowering cytoplasmic calcium levels during cardiac relaxation and reduction of its activity has been linked to delayed diastolic relaxation in hypothyroid and failing hearts. To determine the contractile alterations resulting from increased SERCA2 expression, we generated transgenic mice overexpressing a rat SERCA2 transgene. Characterization of a heterozygous transgenic mouse line (CJ5) showed that the amount of SERCA2 mRNA and protein increased 2. 6-fold and 1.2-fold, respectively, relative to control mice. Determination of the relative synthesis rate of SERCA2 protein showed an 82% increase. The mRNA levels of some of the other genes involved in calcium handling, such as the ryanodine receptor and calsequestrin, remained unchanged, but the mRNA levels of phospholamban and Na+/Ca2+ exchanger increased 1.4-fold and 1.8-fold, respectively. The increase in phospholamban or Na+/Ca2+ exchanger mRNAs did not, however, result in changes in protein levels. Functional analysis of calcium handling and contractile parameters in isolated cardiac myocytes indicated that the intracellular calcium decline (t1/2) and myocyte relengthening (t1/2) were accelerated by 23 and 22%, respectively. In addition, the rate of myocyte shortening was also significantly faster. In isolated papillary muscle from SERCA2 transgenic mice, the time to half maximum postrest potentiation was significantly shorter than in negative littermates. Furthermore, cardiac function measured in vivo, demonstrated significantly accelerated contraction and relaxation in SERCA2 transgenic mice that were further augmented in both groups with isoproterenol administration. Similar results were obtained for the contractile performance of myocytes isolated from a separate line (CJ2) of homozygous SERCA2 transgenic mice. Our findings suggest, for the first time, that increased SERCA2 expression is feasible in vivo and results in enhanced calcium transients, myocardial contractility, and relaxation that may have further therapeutic implications.     

The role of Ca++-sensitizers for the treatment of heart failure

For increasing myocardial contractility in patients with cardiac failure, catecholamines, phosphodiesterase-III (PDE) inhibitors, and calcium sensitizers are available. Improving myocardial performance with catecholamines and PDE inhibitors leads to increased intracellular calcium concentration as an unavoidable side effect. An increase in intracellular calcium can induce harmful arrhythmias and increases the energetic demands of the myocardium. Long-term trials with PDE inhibitors have raised concerns about the safety of positive inotropic treatment for cardiac failure. Calcium sensitizers are a new class of inotropic drugs. They improve myocardial performance by directly acting on contractile proteins without increasing intracellular calcium load. Thus, they avoid the undesired effects of an increased intracellular calcium load. Calcium sensitizers may enhance myocardial performance without increasing myocardial oxygen consumption and without provoking fatal arrhythmias. Two calcium sensitizers are available for the treatment of cardiac failure in men. Pimobendan is a drug with positive inotropic effects that additionally inhibits the production of proinflammatory cytokines. However, it exerts a significant inhibition of PDE at clinically relevant doses. Levosimendan is a calcium sensitizer with no major inhibition of PDE at clinically relevant doses. It opens ATP-dependent potassium channels and thus has vasodilating and cardioprotective effects. The most important studies of the long-term treatment of stable cardiac failure with pimobendan and on the short-term treatment of unstable cardiac failure with levosimendan are presented.     

Role of diastole in left ventricular function, I: Biochemical and biomechanical events.

Left ventricular diastolic function plays an important role in cardiac physiology. Lusitropy, the ability of the cardiac myocytes to relax, is affected by both biochemical events within the myocyte and biomechanical events in the left ventricle. Beta-adrenergic stimulation alters diastole by enhancing the phosphorylation of phospholamban, a substrate within the myocyte that increases the uptake of calcium ions into the sarcoplasmic reticulum, increasing the rate of relaxation. Troponin I, a regulatory protein involved in the coupling of excitation to contraction, is vital to maintaining the diastolic state; depletion of troponin I can produce diastolic dysfunction. Other biochemical events, such as defects in the voltage-sensitive release mechanism or in inositol triphosphate calcium release channels, have also been implicated in altering diastolic tone. Extracellular collagen determines myocardial stiffness; impaired glucose tolerance can induce an increase in collagen cross-linking and lead to higher end-diastolic pressures. The passive properties of the left ventricle are most accurately measured during the diastasis and atrial contraction phases of diastole. These phases of the cardiac cycle are the least affected by volume status, afterload, inherent viscoelasticity, and the inotropic state of the myocardium. Diastolic abnormalities can be conceptualized by using pressure-volume loops that illustrate myocardial work and both diastolic and systolic pressure-volume relationships. The pressure-volume model is an educational tool that can be used to demonstrate isolated changes in preload, afterload, inotropy, and lusitropy and their interaction.     

The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta.

Inducible nitric oxide (NO) produced by macrophages is cytotoxic to invading organisms and has an important role in host defense. Recent studies have demonstrated inducible NO production within the heart, and that cytokine-induced NO mediates alterations in cardiac contractility, but the cytotoxic potential of nitric oxide with respect to the heart has not been defined. To evaluate the role of inducible nitric oxide synthase (iNOS) on cardiac myocyte cytotoxicity, we exposed adult rat cardiac myocytes to either cytokines alone or to activated J774 macrophages in coculture. Increased expression of both iNOS message and protein was seen in J774 macrophages treated with IFN gamma and LPS and cardiac myocytes treated with TNF-alpha, IL-1 beta, and IFN gamma. Increased NO synthesis was confirmed in both the coculture and isolated myocyte preparations by increased nitrite production. Increased NO synthesis was associated with a parallel increase in myocyte death as measured by CPK release into the culture medium as well as by loss of membrane integrity, visualized by trypan blue staining. Addition of the competitive NO synthase inhibitor L-NMMA to the culture medium prevented both the increased nitrite production and the cytotoxicity observed after cytokine treatment in both the isolated myocyte and the coculture experiments. Because transforming growth-factor beta modulates iNOS expression in other cell types, we evaluated its effects on cardiac myocyte iNOS expression and NO-mediated myocyte cytotoxicity. TGF-beta reduced expression of cardiac myocyte iNOS message and protein, reduced nitrite production, and reduced NO-mediated cytotoxicity in parallel. Taken together, these experiments show the cytotoxic potential of endogenous NO production within the heart, and suggest a role for TGF-beta or NO synthase antagonists to mute these lethal effects. These findings may help explain the cardiac response to sepsis or allograft rejection, as well as the progression of dilated cardiomyopathies of diverse etiologies.     

Importance of intracellular calcium homeostasis for contraction and relaxation of the heart muscle]

The method of surface fluorometry with indo-1 allows the simultaneous quantitative recording of changes in free intracellular calcium ([Ca2+]i) transients during the cardiac cycle and haemodynamic parameters and ECG. Using this method, recent studies gave further insight into acute and chronic changes in [Ca2+]i during disease (e.g. heart failure, ischaemia, arrhythmias), as well as pharmacologic interventions. The failing myocyte is characterized by small calcium transients and elevated end-diastolic [Ca2+]i concentrations. Without an adequate delivery of substrate to the mitochondria (pyruvate, but not glucose) the cardiomyopathic heart muscle is no longer capable of maintaining its [Ca2+]i homeostasis. In healthy hearts, positive inotropic agents lead to an increase in developed pressure commensurately with the percentage changes in amplitude of the [Ca2+]i transients, while the end-diastolic [Ca2+]i levels seem to depend on the activation of cAMP. In failing hearts the latter finding may explain the different behaviour of end-diastolic [Ca2+]i and haemodynamics during perfusion with various catecholamines, more likely stimulating alpha- and/or beta-adrenoceptors. Further studies analysed [Ca2+]i during ischaemia or showed the importance of changes of [Ca2+]i in the genesis of premature beats and the initiation of tachyarrhythmias, in particular ventricular fibrillation. The present overview underlines the comprehensive role of calcium homeostasis in the pathophysiology of contraction and relaxation of the heart muscle.     

Endothelin enhances the contractile responsiveness of adult rat ventricular myocytes to calcium by a pertussis toxin-sensitive pathway.

It has long been assumed that the primary influences regulating cardiac contractility are the extent of mechanical loading of muscle fibers and the activity of the autonomic nervous system. However, the vasoactive peptide endothelin, initially found in vascular endothelium, is among the most potent positively inotropic agents yet described in mammalian myocardium. In isolated adult rat ventricular cells, endothelin's action was slow in onset but very long lasting with an EC50 of 50 pM that approximates the reported KD of the peptide for its receptor in rat heart. When the calcium activity of the buffer superfusing isolated single fura-2-loaded myocytes paced at 1.5 Hz was varied from 0.1 to 0.9 mM [Ca2+]o, 100 pM endothelin increased contractile amplitude with no significant change in diastolic or systolic [Ca2+]i, thus appearing to sensitize the myofilaments to intracellular calcium. Pertussis toxin, or prior exposure to a beta-adrenergic agonist, reduced or abolished the increase in myocyte contractility induced by endothelin. This novel and potent pharmacologic action of endothelin points to the potential importance of local, paracrine factors, perhaps derived from microvascular endothelium or endocardium, in the control of the contractile function of the heart.     

Electrocardiographic manifestations: electrolyte abnormalities

Because myocyte depolarization and repolarization depend on intra- and extracellular shifts in ion gradients, abnormal serum electrolyte levels can have profound effects on cardiac conduction and the electrocardiogram (EKG). Changes in extracellular potassium, calcium, and magnesium levels can change myocyte membrane potential gradients and alter the cardiac action potential. These changes can result in incidental findings on the 12-lead EKG or precipitate potentially life-threatening dysrhythmias. We will review the major electrocardiographic findings associated with abnormalities of the major cationic contributors to cardiac conduction-potassium, calcium and magnesium.     

The methylenedioxyindenes, a novel class of "intracellular calcium antagonists": effects on contractility and on processes involved in regulating intracellular calcium homeostasis

The 2-substituted methylenedioxyindenes are a novel class of "calcium antagonists" which have been characterized as acting intracellularly. In the present study, the effect of 2-propyl-methylenedioxyindene (p-MDI) on the contractility of isolated rabbit papillary muscles and aortic rings as well as on several metabolic processes believed to be important in regulating calcium movement within the cell was examined. p-MDI was found to exert a dose-dependent negative inotropic effect in the range of 1.0 X 10(-5) to 1.0 X 10(-3) M (1.0 X 10(-3) M p-MDI produced a total cessation of contractility). At a concentration of 1.0 X 10(-4) M p-MDI, this depressant effect could be partially reversed by increasing the level of calcium in the tissue bath. p-MDI also relaxed aortic rings previously contracted with 50 mM KCl or 10 microM norepinephrine, although the concentration of p-MDI required to relax norepinephrine-contracted rings was 3 times greater than that required to relax KCl-contracted rings. Such selectivity was also observed when the effects of verapamil on norepinephrine- and KCl-contracted rings were examined, but was not observed with papaverine. To determine whether the effects of p-MDI on cardiac and vascular smooth muscle were due to direct interference with any of the metabolic processes which regulate intracellular calcium homeostasis, the effects of p-MDI on isolated cardiac sarcoplasmic reticulum and mitochondria and on the intracellular calcium-binding protein calmodulin were examined. At concentrations which depressed cardiac contractility, p-MDI had no effect on 1) calcium transport, uptake or ethyleneglycol bis(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid-induced calcium release by sarcoplasmic reticulum, 2) calcium uptake by mitochondria or 3) calmodulin. p-MDI did, however, exert a biphasic effect of glutamate-supported mitochondrial respiration; stimulating oxygen consumption at concentrations of 1.0 X 10(-5) and 1.0 X 10(-4) M and inhibiting respiration at 1.0 X 10(-3) M. It is therefore concluded that p-MDI has no apparent direct effect on intracellular calcium movement per se and that the calcium antagonist effect of p-MDI may be due in part to calcium channel blockage. Inhibition of mitochondrial respiration may also contribute to the negative inotropic effect of high concentrations of p-MDI.     

Gentamicin blockade of slow Ca++ channels in atrial myocardium of guinea pigs.

Cardiac dysfunction is occasionally detected in patients undergoing treatment with amino-glycoside antibiotics, however, the mechanism responsible for the negative inotropic effect of these agents has not been identified. In the present investigation electrically driven left atria of guinea pigs were used to study the effects of gentamicin on calcium ion (Ca++)-dependent contractile events in heart muscle isolated from in vivo influences. When atria were first inactivated by excess potassium ion (K+; 22mM) and contractions were then restored by isoproterenol (an experimental model that accentuates the contractile dependence of myocardial fibers on influx of Ca++ through specific "slow channels" of the sarcolemma), the cardiac depressant activity of gentamicin (0.1 mM) was profoundly augmented. Conversely, the negative inotropic effect of tetrodotoxin (23.5 micron) was abolished by the same experimental conditions. Also, gentamicin (1 mM) and La+++ (0.5 mM) markedly decreased the positive inotropic response to increased frequency of stimulation; whereas, D600 (1.05 micron) converted the positive frequency-force relationship to a negative relationship. Present data indicate a direct cardiac depressant action of gentamicin, and suggest that this antibiotic adversely affects either the transport system responsible for Ca++ movement through slow channels of the sarcolemma, the availability of Ca++ for translocation to these sites, or both.     

Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis

OBJECTIVE: Changes in cardiac function due to sepsis have been widely reported. However, the underlying mechanisms remain poorly understood. In the mammalian heart, myocyte function and intracellular calcium homeostasis are closely coupled. In this study we tested the hypothesis that alterations in cardiac calcium homeostasis due to sepsis underlie the observed myocyte dysfunction. DESIGN: Randomized prospective animal study. SETTING: Research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 250-275 g. INTERVENTIONS: We induced sepsis by cecal ligation and puncture in the rat, which mimics the type of infection caused by perforation of the intestine in humans. MEASUREMENTS AND RESULTS: Forty-eight hours after cecal ligation and puncture, isolated cardiac ventricular cardiomyocytes demonstrated a 57% decreased peak systolic [Ca]. The time constant of the Ca transient increased 71% and 57% in myocytes obtained 24 hrs and 48 hrs after cecal ligation and puncture, respectively. The average shortening of cardiomyocytes 48 hrs after cecal ligation and puncture was significantly decreased. To investigate the cellular mechanisms of altered Ca transients and myocyte shortening, we measured Ca sparks, the spontaneous local Ca release events in cardiomyocytes at resting states. The Ca spark frequency progressively increased in myocytes 24 hrs and 48 hrs after cecal ligation and puncture. The total activity of sparks also increased compared with sham-operated animals. The overall leakage of sarcoplasmic reticulum Ca in resting states was increased in sepsis and resulted in reduced sarcoplasmic reticulum Ca content. CONCLUSIONS: Abnormal Ca leakage from the sarcoplasmic reticulum contributes significantly to the depressed myocyte shortening in sepsis. In the future, modalities that prevent this Ca leakage may prove beneficial in the treatment of sepsis-induced myocyte shortening.     

Negative inotropic effect of rapamycin on isolated human cardiomyocytes

Rapamycin is an increasingly important immunosuppressive drug and reduces restenosis after coronary stenting, but its effects on cardiac contractility are largely unknown. We investigated the acute inotropic effects of rapamycin on isolated human cardiomyocytes. Cardiomyocytes were enzymatically isolated from right atrial appendages obtained during routine coronary artery bypass surgery. Cell morphology was examined by confocal microscopy. Cell contraction was recorded after electrical stimulation. Rapamycin elicited a concentration-dependent decrease in fractional cell shortening ranging from 14.3 +/- 2.6% at 10(-8) M rapamycin to 26.4 +/- 4.2% at 10(-5) M. Rapamycin also caused a concentration-dependent decrease in diastolic cell length. Contractile performance of isolated cardiomyocytes was well preserved, as evidenced by the profound positive inotropic effects of high extracellular calcium concentration and the beta-adrenoreceptor agonist isoproterenol. The acute negative inotropic effect of rapamycin on human cardiomyocytes might be due to altered calcium homeostasis through the binding of rapamycin to FKBP12.6 and its regulatory function on the ryanodine receptor, with increased calcium leakage from the sarcoplasmic reticulum.     

Non-cyclic AMP-dependent, positive inotropic cyclodepsipeptides with negative chronotropy.

The effects of natural cyclodepsipeptides (CDPs) on isolated rat cardiac tissue preparations were examined in vitro. Destruxin A, destruxin B (DB), roseotoxin B (RB), and roseocardin (RC), a novel CDP, each caused a concentration-dependent increase in the contraction force of the right atrium and the papillary and trabecular muscles of the right ventricle at 0.6 to 600 microM. RB, destruxin A, and DB did not affect the half-decay time of relaxation of the papillary muscles, but RC slightly prolonged it, although to a much lesser extent than BA 41899, a calcium sensitizer. This inotropic effect is accompanied by a prolongation of the automatic atrial contraction intervals. The RB-induced increase in the contraction force of papillary muscle was not affected by phentolamine, propranolol, pyrilamine, or cimetidine. RB- and RC-induced increases in the contraction force of papillary muscles were not affected by 3-isobutyl-1-methylxanthine or carbachol. Neither peptide changed the cyclic AMP levels in trabecular muscles. Neither RB nor RC affected the activity of Na(+),K(+)-ATPase from rat kidney. Neither RB, RC, nor DB affected the resting membrane potential or the apparent input resistance of papillary muscles. These results suggest that these CDPs produce both non-cyclic AMP-dependent positive inotropic and negative chronotropic effects.     

Stretch-induced atriopeptin secretion in the isolated rat myocyte and its negative modulation by calcium.

Cellular mechanism(s) regulating atriopeptin secretion and processing by the atrial myocyte are currently unknown. Osmotic stretch of isolated atrial myocytes as well as potassium chloride depolarization were potent stimuli of atriopeptin secretion. Release was potentiated by buffering either extracellular calcium with EGTA or intracellular calcium with the intracellular chelator, BAPTA AM. Atrial release of atriopeptin was inhibited after administration of ionomycin which elevates intracellular calcium. Fetal or early neonatal ventricular myocytes actively synthesize atriopeptin. Atriopeptin secretion by ventricular myocytes was also markedly potentiated by osmotic stretch as well as KCl depolarization. Only the 126 amino acid prohormone was secreted by the stretch-stimulated atrial and ventricular myocyte. These data suggest that stretch of the myocyte plasma membrane is a major stimulus for atriopeptin secretion and that atriopeptin secretion is not stimulated by raising intracellular calcium and appears to be negatively modulated by this cation. Like the atrial myocyte, the ventricular myocyte possesses the cellular mechanism(s) necessary to secrete atriopeptin by a regulated mechanism.     

Influence of Calcium on the Inotropic Actions of Hyperosmotic Agents, Norepinephrine, Paired Electrical Stimulation, and Treppe

To analyze the interaction of calcium ion concentration with hypertonic agents and with other inotropic interventions, isolated right ventricular cat papillary muscles were studied under isometric conditions in Krebs-Ringer bicarbonate solution. Extracellular calcium concentrations were varied between 2.5 and 11.0 mM. Maximal inotropic effects occurred between 5 and 8.0 mM calcium and further elevation to 11.0 mM was without additional influence. The effect of hyperosmotic sucrose and mannitol on papillary muscle performance was compared with that of 10(-6) M norepinephrine at calcium concentrations of 2.5 and 10.0 mM and with paired electrical stimulation in 10.0 mM calcium. Both norepinephrine and the hyperosmotic agents produced significant increases in developed tension and in the maximal rate of tension rise (dT/dt) in Krebs-Ringer in 2.5 and 4.0 mM calcium. In 10 mM calcium norepinephrine increased developed tension and dT/dt, but sucrose and mannitol caused no change or small reductions in both. Paired electrical stimulation, like hyperosmolality, caused no increase in dT/dt in 10 mM calcium.The presence of a potent pharmacological inhibitor of systolic calcium transfer across the cell membrane (D600, 10(-6) M) reduced developed tension and dT/dt by 76+/-2.7 and 74+/-2.0%, respectively, and prevented and in fact reversed the expected increase in dT/dt associated with an increase in rate of stimulation (treppe). However, hypertonic mannitol and paired pacing persisted in causing marked increases in developed tension and dT/dt even in the presence of D600, suggesting that their inotropic effects are not dependent on increased intracellular transfer of calcium during systole through cell membrane channels in which D600 acts as a competitive inhibitor.The results of these studies suggest that apparent functional saturation of intracellular calcium receptor sites eliminates any additional inotropic effect of hyperosmolality or paired pacing. The data are compatible with the hypothesis that the inotropic effects of hyperosmolality and of paired pacing result from an increase in calcium concentration at the myofilaments during contraction. The increase induced by hyperosmolality might occur because of an increase in the total amount of calcium released into the cytosol with each action potential and/or as a passive consequence of cellular dehydration. Norepinephrine has the capacity to increase contractility even when intracellular calcium receptor sites appear to be functionally saturated, suggesting that it may act at least in part by a mechanism that is independent of changes in net intracellular calcium concentration.     

Ethanol, acetaldehyde, and myocardial protein synthesis

The cause of alcoholic myocardiopathy is unknown. The effects of acute exposure to ethanol or its metabolite acetaldehyde on protein synthesis in working, intact, guinea pig hearts in vitro were studied utilizing lysine-(14)C perfusion. Ethanol at 250 mg/100 ml, a level sufficient to markedly inhibit hepatic production of albumin, did not alter cardiac function, the equilibration of the intracellular free lysine pool in either ventricle, or the incorporation of lysine-(14)C into protein. Thus, in controls and ethanol-perfused hearts, the incorporation of lysine in 3 hr was 44.1+/-1.5 and 42.8+/-1.2 mumoles lysine/g protein N for the right ventricles and 25.6+/-1.0 and 24.3+/-0.8 for the left ventricles, respectively. Only at lethal levels, 1500 mg/100 ml ethanol, was protein synthesis depressed. Acetaldehyde 3.5 mg/100 ml (0.8 mM) effected a markedly positive chronotropic and inotropic effect on the perfused heart and slightly depressed equilibration of the intracellular free lysine pool. However, determinations of protein incorporation of lysine-(14)C based on intracellular lysine-(14)C specific activities showed a significant decrease from control right and left ventricle values, to 27.1+/-2.8 and 14.9+/-1.9. Propanalol, which abolished the chronotropic effect, did not prevent the inhibition of protein synthesis. The studies suggest that acetaldehyde, which inhibits cardiac protein synthesis in vitro, may play a role in alcoholic myocardiopathy by interfering with normal myocardial protein synthesis.     

Sex differences in the response of rat heart ventricle to calcium

Calcium (Ca2+) is a key mediator of myocardial function. Calcium regulates contraction, and disruption of myocellular Ca2+ handling plays a role in cardiac pathologies such as arrhythmias and heart failure. This investigation examines sex differences in sensitivity of the contractile proteins to Ca2+ and myofibrillar Ca2+ delivery in the ventricular myocardium. Sensitivity of contractile proteins to Ca2+ was measured in weight-matched male and female Sprague-Dawley rats using the skinned ventricular papillary muscle fiber and Ca(2+)-stimulated Mg(2+)-dependent adenosine triphosphatase (ATPase) activity methodologies. Calcium delivery was examined by measuring the contractile response to a range of extracellular Ca2+ concentrations in isolated ventricular myocytes, papillary muscle, and the isolated perfused whole heart. Findings from studies in the whole heart suggest that at a fixed preload, the male left ventricle generates more pressure than a female ventricle over a range of extracellular Ca2+ concentrations. In contrast, results from myocyte and papillary muscle studies suggest that females require less extracellular Ca2+ to elicit a similar contractile response. Results obtained from the 2 methods used to determine sex differences in Ca2+ sensitivity were equivocal. Further studies are required to elucidate sex differences in myocardial Ca2+ handling and the reasons for disparate results in different heart muscle preparations. The results of these studies will lead to the design of sex-optimized therapeutic interventions for cardiac disease.