|
1. |
Introduction. Emerging concepts underlying drug discovery in congestive heart failure |
|
Drug Development Research,
Volume 18,
Issue 4,
1989,
Page 263-264
George B. Weiss,
Edmund J. Sybertz,
Preview
|
PDF (96KB)
|
|
ISSN:0272-4391
DOI:10.1002/ddr.430180402
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1989
数据来源: WILEY
|
2. |
Novel approaches to study myocardial hypertrophy towards development of anti‐hypertensive drugs: Expression of myosin light chain genes during cardiac hypertrophy |
|
Drug Development Research,
Volume 18,
Issue 4,
1989,
Page 265-277
C. Chandra Kumar,
Preview
|
PDF (928KB)
|
|
摘要:
AbstractMyocardial hypertrophy as an adaptive response to various physiological and pathological conditions is characterized by major alterations in the cellular restructuring of the heart as well as by many biochemical and genetic alterations. Hence, the development of hypertrophy provides a unique opportunity to study the various mechanisms underlying the functions of the normal and diseased heart, as well as to understand the molecular mechanisms that operate to regulate cardiac specific gene expression. Both the spontaneously hypertensive rat strain (SHR) and the myocardial cell culture system developed by Paul Simpson have been used as model systems to study cardiac specific gene expression. We have isolated and characterized in detail the rat ventricular specific myosin light chain (MLC)‐1 and MLC‐2 cDNA clones. Using a sensitives S1 nuclease analysis we have shown that while no MLC‐1 mRNA of the ventricular type is detectable in the normal and SHR atrial muscle, there is a selective increase in ventricular MLC‐2 mRNa in both 6 week old (prehypertensive stage) and 18 week old (hypertensive) SHR heart atria. The myocardial cell culture system has been used to examine the effects of α‐adrenergic stimulation on the accumulation of contractile units and the expression of MLC‐2 gene. Stimulation of α‐adrenergic receptors with norepinephrine results in an increase in cellular MLC‐2 protein content as well as an increase in steady‐state level of MLC‐2 mRNA. This increase in MLC‐2 mRNA is mediated in part by an increase in transcription of the MLC‐2 gene. In order to characterize the regulatory elements of the MLC‐2 gene, we have characterized in detail the genomic clone corresponding to rat cardiac MLC‐2 cDNA. The results show a complete conservation of exon and intron organizations between cardiac and skeletal MLC‐2 genes. There is also a strong conservation of DNA sequence elements upstream to the transcription initiation site between rat cardiac and chicken cardiac MLC‐2 genes. Analysis of thecis‐ andtrans‐acting factors that regulate MLC‐2 gene expression during cardiac hypertrophy should prove very useful in understanding the molecular mech
ISSN:0272-4391
DOI:10.1002/ddr.430180403
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1989
数据来源: WILEY
|
3. |
Physiological and pharmacological modulation of cardiac contractile proteins |
|
Drug Development Research,
Volume 18,
Issue 4,
1989,
Page 279-293
Edward D. Pagani,
Paul J. Silver,
Preview
|
PDF (1010KB)
|
|
摘要:
AbstractThe contractile‐relaxation cycle of cardiac muscle is dependent upon the coordination of a variety of membrane and cytosolic events. The functional activities of the structures responsible for these events can be altered by endogenous modulators, on both a beat‐to‐beat or a long‐term basis, in order to optimize cardiac performance and meet the circulatory and nutritional needs of the body. This review focuses on the force‐generating structures, or myofibrils, of cardiac muscle, its activation by intracellular calcium, and the ways that activation of the myofibrillar proteins can be modulated by physiological and pharmacological mechanisms. Activation of the myofibrillar proteins is regulated by the troponin‐tropomyosin system of the actin (thin) filament; when troponin C binds calcium, sites along the thin filament are made available for myosin (thick) filament interaction. There are a number of physiological mechanisms that influence the affinity of troponin C for calcium, three of which include troponin I phosphorylation, intracellular pH, and muscle length. The relative affinity of troponin C for calcium decreases in parallel with a reduction in muscle length and intracellular pH and in parallel with an increase in troponin I phosphorylation. The type of myosin (isozyme) present in cardiac tissue also regulates myofibrillar activity. Ventricular muscle can contain up to three isozymes of myosin (V1, V2, and V3). Myofibrils containing only the V1 myosin isozyme can have an ATPase activity two to threefold hight than myofibrils containing only the V3 myosin isozyme. The type of myosin isozyme present in cardiac tissue is determined by a variety of factors; thyrotoxicosis and strenuous exercise tend to increase the relative amount of the V1 isozyme, whereas insulin and thyroxine insufficiency as well as aortic and pulmonary stenosis tend to decrease the relative amount of the V1 isozyme. Besides these physiologicall mechanisms, there are a variety of pharmacological agents that have been shown to alter the calcium activation (sensitize or desensitize) and/or maximal activity (potentiate or attenuate) of the cardiac contractile proteins. Some cardiotonic agents which increase the calcium sensitivity of the contractile proteins are AR‐L 115BS (Sulmazole), AR‐L 57, pimobendan, APP 201‐533, DPI 201‐106, and MCI‐154. However, some of these compounds are not selective and have ancillary activities, such as inhibiting cyclic nucleotide phosphodiesterase, so a single direct link to cardiotonic activity cannot be made. In addition to this class of agents, some calmodulin antagonists also can modulate cardiac contractile protein activity via modulation of calcium binding to troponin C. Some of the calcium‐binding protein modulators, such as calmidazolium, trifluoperazine, perhexiline, and bepridil are several times more potent in increasing myofibrillar ATPase activity than either AR‐L 115BS or APP 201‐533. The effect of these agents on altering calcium activation of the contractile proteins is also dependent upon the species and cardiovascular condition of the animal from which myofibrils are obtained. For example, calmidazolium increased basal and decreased maximal myofibrillar ATPase activity in both normal and myopathic hamster hearts but only increased the calcium sensitivity of myofibrils prepared from normal canine hearts. Studies are ongoing to evaluate the effect of these types of agents on ATPase activity of myofibrils from normal human hearts and hearts of patients with end‐stage failure. The relative advantages/disadvantages of using these types of agents to alter cardiac performance await future synthesis and identification of nanomolar potent compounds that selectively and specificaally alter the activity of
ISSN:0272-4391
DOI:10.1002/ddr.430180404
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1989
数据来源: WILEY
|
4. |
Sodium‐Calcium exchange: A possible target for drug development |
|
Drug Development Research,
Volume 18,
Issue 4,
1989,
Page 295-304
John P. Reeves,
Preview
|
PDF (687KB)
|
|
摘要:
AbstractThe Na+‐Ca2+exchange system is a carrier‐mediated transport process which couples the transmembrane movement of Ca2+ions to the movement of Na+ions in the opposite direction. It functions primarily as a Ca2+extrusion process in cardiac cells and is thought to be an important mechanism for altering myocardial contractility through changes in intracellular [Na+]. We khave investigated the properties of the cardiac Na+‐Ca2+exchange system using a subcellular preparation of membrane vesicles derived from the cardiac sarcolemma. Vesicle studies have been useful in investigating the kinetics of Na+‐Ca2+exchange activity and in establishin the stoichiometry of the exchange process as 3 Na+per Ca2+. The kinetec results are most easily interpreted in terms of a model for the Na+‐Ca2+exchange carrier which features two types of cation binding sites: a divalent site for which Ca2+and 1‐2 Na+ions compete and a second, monovalent site which binds the third Na+involved in Na+‐Ca2+exchange. Na+‐Ca2+exchange activity in vesicles is stimulated by a variety of agents or treatments, including limited proteolysis, phospholipase treatment, redox reagents, anionic amphiphiles, and intravesicular Ca2+, all of which lower the apparent Kmfor Ca2+. The physiological significance of these modes of regulation of exchange activity is at present uncertain. Progress in identifying and purifying the exchange carrier has been hampered by the lack of specific high‐affinity probes that could be used in labelling studies. Indirect estimates of the number of exchange carriers in sarcolemmal vesicles suggest that there are 10‐20 pmol of exchanger per mg of membrane protein and that the exchange system has a maximal turnover of approximately 103sec−1. Studies are under way in several laboratories to clone a cDNA for the exchange carrier using oocytes ofXenopus laevisas
ISSN:0272-4391
DOI:10.1002/ddr.430180405
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1989
数据来源: WILEY
|
5. |
Simultaneous31P nuclear magnetic resonance spectroscopy and mechanical function in working heart models affected by drugs |
|
Drug Development Research,
Volume 18,
Issue 4,
1989,
Page 305-325
Sheila M. Cohen,
Jeffrey G. Werrmann,
Brian W. King,
Preview
|
PDF (1194KB)
|
|
摘要:
AbstractA working heart model was designed which enabled simultaneous measurement of the physiological function of the heart and the levels of high‐energy phosphates and inorganic phosphate, as well as intracellular pH, by high‐resolution31P NMR spectroscopy. Careful control of conditions, such as temperature and metallic ions, produced rabbit heart preparations that had stable work output, heart rate, and ATP levels for more than 7 hr. Rat hearts were stable for at least 3 hr. As an example of the utility of the model, the effect of ischemia and two drugs were studied. Global ischemia of a rabbit heart at 36.2°C resulted in almost complete loss of phosphocreatine (PCr) wth 7 min and slower loss of ATP, which reached a plateau at 40% of its initial concentration with 12 min. ntracellular pH fell form 7.01 to 6.03 during 21 min of ischemia. Post‐ischemia, the heart's power output and ATP concentration both returned to about 70% of pre‐ischemia levels, whereas PCr overshot its initial value by 33%. BRL 34915, a K+channel activator, produced an age‐ and species‐dependent negative inotropic effect in non‐ischemic hearts, with only minor changes in ATP, PCr or pH. In hearts obtained from rats pretreated for 2 days with enalapril, an inhibitor of the angiotensin‐converting enzyme, post‐ischemia power output returned to 74 ± 7% of preischemia levels, compared with 33 ± 11% in hearts from sham‐treated rats (N = 6). Enalapril also lessened the decline of ATP during 20 min of global ischemia and enhanced the recovery of ATP in post‐ischemic hearts (both about 30% greater than control).31P NMR of working heart preparations enable the effect of drugs and/or ischemia on intracellular energy levels to be determined concurrently with function of the heart. A reproducible method in inducing global ischemia in working hearts facilitates the study of drug effects on functiona
ISSN:0272-4391
DOI:10.1002/ddr.430180406
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1989
数据来源: WILEY
|
6. |
Cardiocirculatory dynamics during heart failure in the rat: Effects of prototypic drugs |
|
Drug Development Research,
Volume 18,
Issue 4,
1989,
Page 327-354
Stephen F. Flaim,
Preview
|
PDF (1466KB)
|
|
摘要:
AbstractThe goal of these studies was to evaluate the effects of congestive heart failure on the peripheral circulations, looking specifically for the regions responsible for the rise in peripheral resistance observed in patients with this disease condition. During the course of these experiments, we evaluated the effects of different modes of exercise on cardiocirculatory dynamics and cardiac output distribution in normal animals in order to determine the most appropriate mode to induce an adequate exercise stess. Based on these studies, we chose treadmill exercise for use in animal models of heart failure. The animal species chosen for these studies was the rat. This choice was based on the availability of novel techniques which allowed for repetitive and accurate hemodynamic and regional blood flow determinations in rodents which provided a cost‐effective approach to the study of heart disease. Once appropriate models for congestive failure and for exercise were adequately characterized and studied, additional experiments designed to evaluate the acute effects of appropriate therapeutic agents such as calcium blockers, nitro‐vasodilators, and angiotensinconverting enzyme inhibitors were conducted. In order to determine the scope of the therapeutic efficacy of some of these compounds, studies were also conducted on models of hypertensive dise
ISSN:0272-4391
DOI:10.1002/ddr.430180407
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1989
数据来源: WILEY
|
7. |
Masthead |
|
Drug Development Research,
Volume 18,
Issue 4,
1989,
Page -
Preview
|
PDF (85KB)
|
|
ISSN:0272-4391
DOI:10.1002/ddr.430180401
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1989
数据来源: WILEY
|
|