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LIST OF CONTRIBUTORS Lloyd Barr Department of ygoloisyhP University of Illinois Urbana, Illinois Nancy .J Boerth Department of ygolohtaP University of Alabama at Birmingharr Birmingham, Alabama reteP Brink stnemtrapeD of ygoloisyhP dna scisyhpoiB etatS University of New York---Stony Brook Stony Brook, New kroY kiR sleetsaC Laboratorium voor eigoloisyF Katholieke Universiteit de nevueL ,grebsiuhtsaG Bruxelles, Belgium Samuel .K Chacko Pathobiology Department University of ainavlysnneP loohcS of Veterinary Medicine Philadelphia, ainavlysnneP egroeG .J Christ Departent of Urology Albert nietsniE College of Medicine Bronx, New kroY Odile Cl~ment-Chomienne Department of ygolocamrahP University of yraglaC ,yraglaC Alberta, adanaC Wilfiam .C Cole Department of ygolocamrahP University of yraglaC ,yraglaC Alberta, adanaC iiv iiiv TSIL FO SROTUBIRTNOC Michael DiSanto Division of Urology ytisrevinU of ainavlysnneP Philadelphia, ainavlysnneP Robert .E Garfield Department of ygolocenyG/scirtetsbO ytisrevinU of saxeT Medical hcnarB ,notsevlaG saxeT William .£- Gerthoffer Department of ygolocamrahP ytisrevinU of adaveN loohcS of Medicine ,oneR adaveN ellebasI Gorrene Department of Molecular ygoloisyhP ytisrevinU of Virginia ,ellivsettolrahC Virginia Bernard Himpens Laboratorium voor eigoloisyF Katholieke Universiteit de nevueL ,grebsiuhtsaG ,sellexurB Belgium ikaasaM Ito ehT tsriF Department of Internal Medicine Mie University School of Medicine ,usT napaJ Department of ygolocenyG/scirtetsbO uneV niaJ ytisrevinU of saxeT Medical hcnarB ,notsevlaG saxeT ehT tsriF Department of ygoloisyhP ieS ihsayaboK ihcugamaY University loohcS of Medicine Ube, napaJ Padmini salivalamoK Department of ygolohtaP ytisrevinU of Alabama at Birmingham Birmingham, Alabama The tsriF Department of Internal okusaY Kureishi Medicine Mie University School of Medicine ,usT napaJ tsiL of Contributors xi Janice .K Larsen tnemtrapeD of Molecular dna evitargetnI ygoloisyhP ytisrevinU of Illinois ,anabrU Illinois samohT .M nlocniL tnemtrapeD of ygolohtaP ytisrevinU of amabalA ta mahgnimriB ,mahgnimriB amabalA drahciR .A ssieM tnemtrapeD of scisyhpoiB/ygoloisyhP anaidnI University loohcS of Medicine ,silopanaidnI anaidnI giwduL neaissiM muirotarobaL voor eigoloisyF ekeilohtaK Universiteit ed nevueL ,grebsiuhtsaG ,sellexurB muigleB okimiK imagoM ehT tsriF Department of ygoloisyhP ihcugamaY ytisrevinU loohcS of Medicine ,ebU napaJ treboR .S Moreland tnemtrapeD of ygolocamrahP dna ygoloisyhP PCM nnamenhaH ytisrevinU ,aihpledalihP ainavlysnneP ihsekaT onakaN ehT tsriF Department of lanretnI Medicine Mie University loohcS of Medicine ,usT napaJ Masato Ohmura ehT tsriF Department of ygoloisyhP ihcugamaY ytisrevinU loohcS of Medicine ,ebU napaJ egroeG .R edaaS tnemtrapeD of ygolocenyG/scirtetsbO ytisrevinU of saxeT Medical hcnarB ,notsevlaG saxeT TSIL FO SROTUBIRTNOC X nehpetS .M smiS tnemtrapeD of ygoloisyhP ehT University of nretseW Ontario ,nodnoL Ontario, adanaC okustaN adekl-ikorodoT ehT tsriF Department of ygoloisyhP ihcugamaY ytisrevinU loohcS of Medicine ,ebU napaJ yrogerG .R edaW tnemtrapeD of ygoloisyhP ehT University of nretseW Ontario ,nodnoL Ontario, adanaC nalA .J nieW noisiviD of ygolorU ytisrevinU of ainavlysnneP ,aihpledalihP ainavlysnneP ironusaY otomihsoY ehT tsriF Department of ygoloisyhP ihcugamaY ytisrevinU loohcS of Medicine ,ebU napaJ umgnoY gnehZ tnemtrapeD of ygoloibohtaP ytisrevinU of ainavlysnneP ,aihpledalihP ainavlysnneP ECAFERP The idea of this volume was to provide for advanced graduate students, medical students, and postdoctorals who are beginning to do research related to smooth muscle a sampling of the orienting ideas of the researchers working on problems in smooth muscle physiology and pathophysiology. Therefore, an essential goal of the volume is to identify the lines of investigation that are currently being pursued by investigators whose concerns are with smooth muscle or with organs with parenchymal tissues consisting of smooth muscle. Various types of smooth muscle constitute the parenchyma or characteristic tis- sues of a large number of organs or regions of organs. In each case, the phenotype is distinctly different and, while smooth muscles do not exhibit the diversity of epithelia, they nevertheless span a great range of physiological responsiveness. Undoubtedly, the variations in the characteristic responses of different smooth muscles result from the expression of sets of transduction subserving proteins. However, it is what the sets are and how they work and are regulated that fascinates the physiologist. In this book, the contrast between sameness and diversity will recur as a theme. How do smooth muscles differ? Some are tonic and others are phasic. Some are sparsely innervated and others are innervated nearly one to one. Some are sponta- neously active, rhythmically or tonically, while others are normally contracted or relaxed. While some smooth muscle myocytes generate action potentials, others never do. Some are activated by norepinepherine and inhibited by acetylcholine, while others are activated by acetylcholine and inhibited by norepinepherine. Even ix xii ECAFERP though myocytes in all smooth muscle tissues are interconnected by way of gap junctions, the degree to which they are coupled is quite variable and they subserve different physiological functions in different smooth muscles. There are hypothe- ses galore, but the testing of them remains to be done. Each smooth muscle has a set of characteristics that determine its behavior and although other smooth muscles may share these attributes, the patterns of their expression leads to distinctiveness in the smooth muscle tissue physiology. Some of these characteristics are more useful than others for categorization purposes and one of the goals of this book is to help identify those qualities that provide better ways to describe the diversity of smooth muscle. A common way to explain the diversity of smooth muscle is to say that, in smooth muscle, we have an example of a great variation in the expression of signal transduction pathways. Of course the expression of the terminal effector (i.e., the contractile) pathways remain rel- atively constant and define the tissue. The definition of a smooth muscle myocyte might be as follows: fusiform interconnected by gap junctions and by nonaligned actin and myosin filaments. This would correspond to the microscopic observation that smooth muscle myocytes are identifiable because of both their shape and the clear expression of a contractible apparatus devoid of the sarcomeric apparatus found in straited skeletal and cardiac muscles. Another relevant question is to what extent can various smooth muscle charac- teristics be grouped together to allow the definition of classes? In current terms, how many instances of smooth muscle are there? Instead, perhaps we need to dis- tinguish between more levels of differentiation than we have in the past. Perhaps we should we decide that each of the organs have different smooth muscle tissues and should concentrate on new functional and molecular parameters to define cat- egories. The following might be examples: A. Receptors: Which kinds of receptors are there for the different kinds of transmitter, neurohumor, or neuromodulator and what are their associated signal transduction pathways? Innervation, receptor type, and second-mes- senger cascade seem to correlate. B. Connectivity: How well and by which isoforms of connexin are cells con- nected? C. Mechanically there is a trade off between those properties that lead to faster, more transient contractions as opposed to those that lead to slower, more energetically efficient contractions. Among smooth muscles, some have a more obvious specialization toward the "latch" mode of contracting. Will contractile protein isoforms correlate with these functionalities or are there other determinant proteins? There is an easy division of smooth muscles into those which are spontaneously active and those which are completely dependent on innervation for activation. ecaferP xiii The channel proteins that are expressed must be the material substrate for these kinds of differences. A recurrent cluster of questions swirl around the issue of regulation of the con- tractile process itself. By analogy to striated muscles, steps other than attachment may be expected to play important roles in the kinetics of the cross bridge cycle. What steps other than attachment might be regulated and are important in deter- mining the mechanical output? Examples include bridge cycle influencing steps, particularly those that might alter the force per active cross bridge. The bottom line issue is to determine what is the overall rate at which a muscle can transduce bond energy into mechanical energy as a function of load. Endurance of the contractile activity, speed of shortening, and dependence on oxygen are among the other functions we can begin to identify on a molecular basis. The primary determinant of force in the present consensus paradigm seems to be to the number of cross bridges activated. The fraction of time each bridge is engaged during cycling or the force exerted while being engaged does not seem to vary so much, so more bridges means more mechanical output. As will be dis- cussed, mechanisms for the activation of cross bridges include (1) phosphoryla- tion of myosin, (2) actin-based mechanisms, including those involving caldesmon and calponin, and (3) other regulatory mechanisms, especially those that occur downstream from the phosphorylation of myosin. Thus, it is a near consensus that the primary activating event is the phosphorylation of myosin and the P-myosin/ myosin ratio is expected to be perhaps the most important regulatory parameter. This ratio is influenced by the relative activity of myosin light chain kinase (MLCK) and the activities of the several myosin light chain phosphatases. The possibility also exists that there are other enzymes that either affect the ratio or activate or deactivate myosin in another ways. Suffice therefore to say that the extent of smooth muscle diversity and the underlying mechanisms of action remain interesting open areas of questioning. Lloyd Barr and George J. Christ Guest Editors MECHANICS OF SMOOTH MUSCLE drahciR A. Meiss I. Introduction ............................................... 3 A. The Role of Mechanical Studies in Smooth Muscle Research .... 3 B. Special Mechanical Properties Unique to Smooth Muscle ....... 3 C. The Aims and Scope of This Chapter ....................... 4 II. The Basics of Muscle Mechanics ............................... 4 A. Contributions from Classical Muscle Mechanics and Their Use in the Smooth Muscle Context .................... 4 B. Terms that Describe and Quantify Fundamental Properties ....... 4 C. Terms that Describe the Mechanical Conditions of Contraction... 8 D. Standard Measures of Mechanical Function ................. 12 E. Conceptual Models of Muscle Components and Their Arrangements .................................... 17 F. Adapting the Classical (Skeletal) Muscle Paradigm to Smooth Muscle Problems ............................... 18 III. Technical Aspects of Mechanical Measurements ................. 18 A. Establishing Satisfactory Conditions for Measurement ......... 18 B. Instrument and Equipment Considerations .................. 18 C. Choice of Preparations .................................. 22 Advances in Organ Biology, Volume 8, pages 1-48. Copyright © 2000 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0613-0 2 RICHARD A. SSIEM D. Specialized Mechanical Preparations and Measurements ....... 23 IV. The Mechanics of Smooth Muscle ............................. 24 A. Passive Mechanical Properties ............................ 25 B. Early Mechanical Events in Activation ..................... 25 C. Isometric Contraction and Relaxation ...................... 26 D. Isotonic Contraction and Relaxation ....................... 27 E. Characterization of Smooth Muscle Stiffness ................. 29 F. Response to Externally Imposed Changes in Mechanical Conditions .................................. 32 V. Mechanical Differences between Smooth and Skeletal Muscle ....... 34 A. Special Mechanical States--The "Latch Bridge" Phenomenon... 34 B. Length Dependence of Force and Shortening ................. 36 C. Functional Adaptations of Mechanical Properties ............. 38 D. Structural Constraints on Smooth Muscle Function ............ 40 VI. Current Understanding and Future Trends in Smooth Muscle Mechanics ................................ 42 A. Current Knowledge of the Mechanism of Contraction .......... 42 B. Trends for the Future ................................... 43 Acknowledgments ......................................... 44 References ............................................... 44 ABSTRACT The function of smooth muscle, in its wide variety of physiological roles in the body, requires the changing of metabolic energy into mechanical effects. The study of the means by which smooth muscle cells and tissues interact physically with the internal and external environments is the field of muscle mechanics. Although the mechanical roles of smooth muscle are many and varied, their study can be organized, guided, and simplified by using the paradigm provided by years of study of skeletal muscle. This chapter first presents the terminology, functional relationships, and standard experimental approaches that have arisen largely through the study of skeletal muscle. After treating the technical requirements for making reliable and adequate mechanical measurements of smooth muscle func- tion, specific features of the mechanics of smooth muscle are discussed, compar- ing and contrasting them with the mechanical properties of skeletal muscle and pointing out the special features unique to smooth muscle. The current state of knowledge in the field is briefly surveyed, and areas of current concern and importance are highlighted. scinahceM of htoomS elcsuM 3 I. INTRODUCTION A. The Role of Mechanical Studies in Smooth Muscle Research Mechanical studies of contraction have been a part of smooth muscle research for the better part of a century. Most of these studies have been done on largely intact visceral organs of which smooth muscle is a major and integral part, and smooth muscle as a contractile system per se was not the primary object of study. It is within the past 35 years that smooth muscle has come into its own as a subject for physiological and biophysical studies focused on its specialized contractile and control mechanisms. To be sure, much smooth muscle research is still carried on at the organ and system level; these studies now have the additional advantage of a much more complete understanding of the unique properties of the smooth mus- cle contraction and control mechanisms, particularly at the molecular level. While this new knowledge has led to a further appreciation of the similarities and differ- ences among the many types of smooth muscle, it is still the case that many organ- and tissue-level studies could benefit from further and more practical application of specific knowledge of the mechanical properties of smooth muscle. .B Special Mechanical Properties Unique to Smooth Muscle Studies of the mechanical properties of skeletal muscle, dating back to the nine- teenth century, have provided a highly useful framework for the design and anal- ysis of smooth muscle contraction, and this framework that will be used as an organizing principle in this chapter. However, although many similarities between the two muscle types have long been apparent, the growing knowledge of the marked differences in structure has led to a divergence the paths of muscle mechanics research, and mechanical studies in skeletal muscle have been pursued at a high level of biophysical and technical refinement. Many of the methods and techniques used for the detailed study of skeletal muscle are uniquely related to its specialized structure (particularly to its regular striation pattern) and cannot be directly related to smooth muscle function. Nevertheless, they have provided for an orderly and consistent empirical approach to smooth muscle study. As a result, the literature of smooth muscle mechanics contains many reports of smooth mechanical properties that appear quite similar to those of skeletal muscle. In many cases, however, it is not at all clear that the molecular, cellular, and tissue-based mechanisms underlying smooth muscle contractile phenomena are specifically related to those responsible for similar behavior in skeletal muscle. Modern research has shown significant similarities between smooth and skeletal muscle at the fundamental molecular level (Harris and Warshaw, 1993; Guilford et al., 1997; Harris et al., 1994). From a mechanical standpoint, however, there are a number of critical differences between smooth and skeletal muscle. The most important of these relate to cellular and tissue structure and modes of the control

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Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.