Original ArticleCompensatory Asymmetry in Down-regulation and Inhibition of the Myocardial Ca2+ Cycle in Congestive Heart Failure Produced in Dogs by Idiopathic Dilated Cardiomyopathy and Rapid Ventricular Pacing
Abstract
In this study we used 2.5% myocardial homogenates to study sarcoplasmic reticulum (SR) activity of the Ca2+ pump and Ca2+ release channel (CRC) from dogs with congestive heart failure produced by either rapid ventricular pacing or idiopathic dilated cardiomyopathy. We used the florescent indicator dye and ratiometric spectrofluorometry to monitor Ca2+ uptake while the CRC was open and closed with ryanodine. We confirmed and extended conclusions derived from previous studies of the same dogs using isolated SR. Compared to controls, activities of dogs with either form of CHF were decreased by 36% for the Ca2+ pump (33.7 ± 7.3 and 21.6 ± 4.2 nM/s), 78% for the CRC (10.0 ± 2.8 and 1.4 ± 1.2 nM/s), 53% for total Ca2+-cycling (53.1 ± 8.5 and 24.8 ± 4.4 nM/s), and 17% for net Ca2+ uptake (23.7 ± 4.0 and 19.6 ± 4.0 nM/s). In the absence of SR and mitochondrial activity, ionized Ca2+ concentration in myocardial homogenates were 70% abnormally increased in dogs with CHF, probably due to decreased concentration of Ca2+-binding proteins. Comparison of homogenate and isolated SR activities indicated lower-than-normal membrane yields for dogs with CHF. This fractionation artefact previously resulted in up to 50% overestimation of the degree of downregulation of Ca2+-cycling activities in CHF. The CRC activity was found to be decreased due to decreased activity of the Ca2+-ATPase, decreased CRC content, and inhibition. Decreased CRC activity reversed most of the effect of down-regulation of the Ca2+-ATPase pump, which is proposed to conserve energy. Maintenance of net Ca2+-pump activity is expected to maintain the amplitude of the myocardial ionized Ca2+ transient whereas downregulation of the CRC and pump are predicted to reduce the total amount of Ca2+ cycled and slow the rise and fall of the Ca2+ transient.
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Canine Idiopathic Dilated Cardiomyopathy. Part I: Aetiology, Clinical Characteristics, Epidemiology and Pathology
2001, Veterinary JournalDilated cardiomyopathy (DCM), characterized by chamber dilatation and myocardial systolic and diastolic dysfunction, is one of the most common heart diseases in dogs. The aetiology of the myocardial hypokineis is seldom known in the individual case of DCM, although several theories concerning genetic, nutritional, metabolic, inflammatory, infectious, or drug- or toxin-induced myocardial disease have been discussed. DCM is often referred to as being breed-specific for Boxers, Doberman Pinschers, English Cocker Spaniels and other breeds. Review of reports on histopathologic findings in canine DCM reveals two histologically distinct forms of DCM; (1) cardiomyopathy of boxers and of Doberman pinschers, corresponding to the ‘fatty infiltration-degenerative’ type, and (2) the form seen in many giant, large- and medium-sized breeds, including some boxers and Doberman pinschers, which can be classified as the ‘attenuated wavy fiber’ type of DCM. The classification of canine idiopathic DCM according to histologic findigns seems superior to classification suggesting breed-specific syndromes, as some breeds (i.e. boxers and Doberman pinschers) may be affected by both diseases. However, ante mortem aetiological diagnosis of DCM is difficult. DCM carries a poor prognosis in dogs, and few prognostic indicators have been identified.
Calcium responsiveness in canine pacing-induced heart failure
1998, Journal of Molecular and Cellular CardiologyThe specific lesion(s) and potential compensatory alterations of excitation–contraction coupling in heart failure are not clear in detail. We therefore subjected five dogs to 2–5 weeks of rapid ventricular pacing until heart failure developed. Data obtained from these five dogs with pacing-induced heart failure were compared to data from six healthy controls. Under anesthesia,in situsteady state responses of regional contractile function to intracoronary calcium infusion were established. Maximal calcium-activated regional contractile function in dogs with heart failure was 46% less than in controls; calcium sensitivity was unchanged [pCa502.55±0.31v2.82±0.17 (±s.d.)]. Our data point to a decrease in maximal calcium-activated force and an unchanged calcium sensitivity if an unchanged calcium transient is assumed, or a compensatory increase in calcium sensitivity of failing myocardium if a decreased calcium transient is assumed.
Cardiac calcium release channel (ryanodine receptor) in control and cardiomyopathic human hearts: MRNA and protein contents are differentially regulated
1997, Journal of Molecular and Cellular CardiologyAbnormal intracellular calcium handling in cardiomyopathic human hearts has been associated with an impaired function of the sarcoplasmic reticulum, but previous reports on the gene expression of the ryanodine receptors (Ry2) are contradictory. We measured the mRNA levels, the protein levels and the number of high affinity [3H]ryanodine binding sites in the left ventricle of non-failing (n=9) and failing human hearts [idiopathic dilated (IDCMn=16), ischemic (ICMn=7) or mixed (MCMn=8) cardiomyopathies]. Ry2 mRNA levels were significantly reduced in IDCM (−30%) and unchanged in MCM and ICM and Ry2 protein levels were similar. In contrast, we observed a two-fold increase in the number of high affinity Ry2 (Bmax=0.43±0.11v0.22±0.13 pmol/mg protein, respectively;P<0.01) and an unchanged Kd. Furthermore, levels of myosin heavy chain mRNA and protein per g of tissue were similar in failing and non-failing hearts, suggesting that the observed differences in Ry2 are not caused by the increase in fibrosis in failing heart. Therefore, the dissociation between the two-fold increase in the number of high affinity ryanodine receptors observed in all failing hearts and the slightly decreased mRNA level or unchanged protein level suggests that the ryanodine binding properties are affected in failing myocardium and that such modifications rather than a change in gene expression alter the channel activity and could contribute to abnormalities in intracellular Ca2+handling.
Electrophysiology of rabbit ventricular myocytes following sustained rapid ventricular pacing
1997, Journal of Molecular and Cellular CardiologyThe present study examined changes in electrophysiological properties of ventricular myocytes isolated from rabbit hearts after 2–3 weeks of rapid ventricular pacing. Left ventricular end-diastolic pressure at completion of the pacing period was nearly four-fold greater than in age-matched controls, although there was no significant change in heart weight/body weight ratio. Action potentials recorded in current-clamp mode at low stimulation frequencies were significantly longer in duration and phase 1 diminished in isolated myocytes from paced hearts compared with control. In voltage-clamp experiments,l-type Ca2+current (ICa) density was not different between groups of myocytes, but the maximum current (at+10 mV) elicited by 10μmisoproterenol was approximately 40% less in myocytes from paced hearts. In contrast, maximum ICaelicited by 10μmforskolin was similar in both groups. The 4-aminopyridine-sensitive, transient outward current (Ito) was 65% less (at+60 mV) in myocytes from paced hearts than from control. However, after approximately 24 h in culture, Itodensity in these myocytes returned toward control values. Despite marked reduction in Itodensity, the inward rectifier current (IK1) was not different between groups. These data demonstrate that Itois significantly and reversibly decreased in myocytes from rapidly paced hearts, which may partly account for marked changes in action potential morphology. Although basal ICawas not altered in this group of myocytes compared with control, its modulation byβ-agonists was markedly blunted, probably through a decrease in receptor density or coupling to adenylyl cyclase. These changes in myocyte K+and Ca2+channel behavior in paced hearts may relate to impaired contractility and arrhythmogenesis that is characteristic of the intact failing heart.
Isoform Diversity and Regulation of Organellar-Type Ca<sup>2+</sup>-Transport ATPases
1997, Advances in Molecular and Cell BiologyThis chapter discusses differential expression and the physiological meaning of the Ca2+-transport ATPase isoforms involved in intracellular Ca2+ accumulation. The chapter describes the diversity of the eukaryotic Ca2+-transport ATPases in intracellular Ca2+–storage sites. Data on vertebrates, as well as on invertebrates and non-animal species is also included in the chapter. Since alternative processing of primary gene transcripts contributes to the isoform diversity and focuses to alternative transcript processing in Ca2+–transport ATPases and to the mechanisms controlling them. The chapter deals with the regulatory proteins of the Ca2+-transport ATPases, through which the different signal-transduction pathways control the ATPase activity. The chapter discusses various factors controlling tissue-dependent expression of Ca2+-transport ATPases in both health and disease. Both in excitable and inexcitable cells, intracellular Ca2+ stores play a central role in cellular Ca2+ signaling, and in the maturation and targeting of secreted and membrane proteins. Multiple isoforms of Ca2+-transport ATPases accumulate Ca2+ in the stores. The first class of these enzymes is represented by the sarcoen doplasmic reticulum Ca2+–ATPases (SERCA) family. This chapter discusses the different P-type Ca2+–transport ATPases in non-vertebrate species. The mechanisms controlling alternative splicing underlying SERCA2a/b isoform diversity and the functional meaning of the diversity are more extensively explored the chapter.
Experimental heart failure produced by rapid ventricular pacing in the dog
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