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tension on response to stimulation Part I. Review
SMOOTH BLADDER
MUSCLE
PHYSIOLOGY
AND URETHRA
ON RESPONSE
AND EFFECT
MUSCLE
OF
LENGTH/TENSION
TO STIMULATION
Part I. Review NABIL
K. BISSADA,
ALEX
E. FINKBEINER.
M.D. M.D.
From the Department of Urology, University Medical Sciences, Little Rock, Arkansas
ABSTRACT - With particular reference to the lower urinary physiology of smooth muscle is presented. The relationship macologic stimulation is discussed.
With increasing interest in lower urinary tract function and dysfunction, a better understanding of the neuroanatomy and neuropharmacology of the bladder and bladder outlet has been achieved. Yet, little work on the basic physiology of the detrusor smooth muscle and the relation of stretch and tension of detrusor smooth muscle fibers to its response to drugs or electric stimulation has been done. The value of this information both scientifically and clinically is apparent. Herein, we review smooth muscle physiology, the effect of muscle length-tension alterations on bladder and urethral function, and the effect of these alterations on the response of the bladder to drugs and electric stimulation.
of Arkansas
for
tract, a review of basic anatomy and as altered by electrical and phar-
Smooth or plain muscle consists of spindleshaped fibers which are held tightly together by connective tissue. These muscle fibers lack the cross-banded pattern observed in striated muscle. Each smooth muscle fiber contains a single nucleus located near the center of the cell and cystoplasm, or sarcoplasm. The sarcoplasm is homogeneous and contains many fibrils that run the length of the cell and are presumed to be the contractile elements. The sarcoplasmic reticulum is poorly developed in comparison to
that of skeletal muscles. l-3 Although the exact contractile mechanism in most smooth muscles is not known, it is believed to be similar to that involved in skeletal muscle contractility. In intestinal smooth muscle, there is evidence that the contractile units are made up of small bundles of interdigitating thick and thin filaments that are irregularly shaped and randomly arranged. When the muscle contracts, the thick and thin filaments are thought to slide on each other (v.i.). Smooth muscle cells exhibit considerable variations in their length (from 500 U in pregnant uterus, 200 U in intestine, and 20 U in blood vessels). Likewise, they exhibit a wide variety of functional roles in the body, and their responses to pharmacologic and other stimuli is quite diverse so that it is sometimes difficult to describe the general physiology of smooth muscle.2*4 For convenience, smooth muscles are classified into visceral and multiunit smooth muscles although a spectrum exists between these two extremes. Multiunit smooth muscle are composed of individual cellular units arranged loosely. No intracellular bridges have been demonstrated. Examples of the multiunit smooth muscle include the ciliary muscle (intrinsic muscle of the eye), nictitating membrane and iris, pilomotor
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muscle, and muscles of some of the larger blood vessels.3 In some respects these muscles resemble skeletal muscle in that nerve impulses are generally required to initiate contraction; they are not sensitive to quick stretch; they are not spontaneously rhythmic; and contraction is generally more rapid than in visceral smooth muscle. Contractions are more discrete, fine, and localized than in unitary muscles. Unitary or viceral smooth muscle: Most hollow viscera such as the stomach, intestine, bile ducts, ureters, uterus, and bladder have sheets of unitary muscles in their walls. The individual fibers are closely packed in a roughly parallel fashion. Low electric resistance bridges are present among the individual cells; these probably represent areas in which the cell wall consists of plasma membrane alone and lacks a basement membrane (“intermediate junctions”). 5,6 Despite differences among different visceral muscles, most are spontaneously active, show interfiber conduction, and are stimulated to contract by quick stretch. Although capable of independent activity, they may be regulated by intrinsic and extrinsic nerves. The bladder and the vas deferens combine some properties of both unitary (visceral) and multiunit muscles. Thus, they resemble visceral muscle in terms of morphology and their responses to mechanical stretch. On the other hand, they resemble multiunit muscles in respect to activation and control. In a sense, the bladder is a neurogenic not a myogenic organ inasmuch as it performs useful work only under the influence of its motor innervation. Bioelectric
Events
As stated previously, despite lack of definite knowledge about the exact mechanisms involved in the function of various types of smooth muscle, they all contain actin and myosin, the same contractile proteins found in muscle fibers generally. Consequently, it is assumed that contraction of smooth muscle occurs in a manner similar to that in skeletal muscle. The electrical properties of all excitable tissues are dependent on the distribution of ions on the inside and outside of the cell membranes and the relative permeability of the cell membranes to these ions.? Resting
membrane
potential
In the resting state, potassium ion (K+) concentration is greater on the inside than on the outside of the cell membrane. Conversely,
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sodium ion (Na+) concentration is greater on outside of cell membrane than on inside. A mechanism of extruding Na+ from within to outside the cell membrane against a concentration gradient (sodium pump) has been demonstrated in smooth muscle.* As in skeletal muscles, this process requires energy expenditure which is provided by dephosphorylation of ATP. An inward movement of K+ is coupled with the outward movement of Na+. When a smooth muscle cell is in a nonexcited state, the electric potential difference across the cell membrane (transmembrane potential) is called the “resting membrane potential” or “RMP.” The RMP is determined primarily by the distribution of potassium ions (K+) across the cell membrane and the relative permeability of the cell membrane to K+.’ Since in the resting state the K+ concentration on the inside of the cell is greater than on the outside, there is a tendency for the positively charged K+ to diffuse from inside to outside the cell. An electric gradient thus develops with the inside of the cell membrane becoming more negative than the outside of the cell membrane. This electric gradient tends to oppose further movement of K+ from inside to outside the cell. An equilibrium is thus reached in which K+ concentration is greater inside the cell than outside the cell membrane; thus, the inside of the cell membrane becomes electronegative with respect to the outside of the cell membrane. The RMP of smooth muscle is generally low, on the order of about - 50 mv.2 The maintenance of a relatively low range of the RMP in smooth muscle (in comparison to striated muscle) is probably due to the relative permeability of resting smooth muscle cell membrane to Na+ thus permitting some movement of Na+ to the inside of the cell membrane. Regular and irregular fluctuations in the membrane potential of several millivolts often are present, and these are superimposed upon the basic resting potential (v.i.). Action potential If the cell membrane is depolarized rapidly enough to reach a certain level or threshold (the threshold potential), an action potential develops. The ionic fluxes during excitation of smooth muscle are rather poorly understood. It involves alterations in the concentration of Na+ and mediation of Ca++ whose intracellular concentration increases following depolarization. The ATP-ADP system provides energy for the contractile process. It appears that when a cell is
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excited,
it loses its preferential
permeability
to
The process by which depolarization of the muscle fiber initates contraction is called “excitation-contraction coupling.” Excitation contraction coupling in smooth muscle is not fully understood. It appears to be similar to that involved in the contraction of skeletal muscle and to be mediated by calcium ions, whose intracellular concentration increases following de-
the ATP-ADP system providing energy for the contractile process.* The contractile process in muscles is brought about by the interaction of the contractile proteins actin and myosin. In the relaxed state, a regulator system, consisting of the proteins troponin and tropomyosin (relaxing proteins), prevents the interaction between actin and myosin. 11,12 In the resting muscle troponin is tighly bound to actin, and tropomyosin covers the sites where myosin heads bind to actin. When Ca++ binds to troponin, the binding of troponin to actin is presumably weakened allowing displacement of the tropomyosin. This, in turn, uncovers binding sites on the myosin heads and binding of actin and myosin occurs resulting in muscle contraction.13 In smooth muscle, the sarcoplasmic reticulum and T-system are poorly developed; therefore, the interstitial fluid is probably a major source of Ca+ + necessary to activate the contractile system. As stated earlier, extracellular Ca+ + move into the inside of the cells during the action potential leading to an increase in Ca++ in the region of the contractile proteins with subsequent development of a contraction. l4 There is some evidence, however, that a portion of calcium ions required for the activation of smooth muscle may be obtained from intracellular calcium pools, in particular the mitochondria and microsomes. The relative portions of Ca++ contributed by the intracellular organelles vary considerably among smooth muscle fibers derived from different tissues. Relaxation occurs in a reverse manner to that described for contraction. It is initiated by a decrease in the amount of free Ca++ in the sarcoplasm available to the contractile proteins. This may involve the uptake of Ca++ by intracellular storage sites or its extrusion to the extracellular fluid. Recently, it has been suggested that cyclic nucleotides may play an important role in smooth muscle function. 15-17For instance, cyclic AMP is believed to mediate the beta-adrenergic relaxing effect in a variety of smooth muscles including the bladder. The contractile properties of smooth muscle fibers differ from those of striated muscle in several aspects. Contraction of smooth muscle is a relatively slow process compared to that of striated muscle. However, smooth muscle is capable of sustaining forceful contractions for long periods of time with a very low concomitant expenditure of energy. Similarly, the relaxation of smooth muscle is a prolonged one. Second, in
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K+ and becomes permeable to Na+ and Ca+ + which move inward across the cell membrane. The inward movement of positively charged ions makes the inside of the cell less negative with respect to the outside than is present in the resting state; this results in depolarization. ‘O The action potentials recorded from a particular smooth muscle are subject to considerable variation as may be anticipated from the various functional types of smooth muscle encountered in the body. Action potentials developed by smooth muscles belong to three classes: (1) typical rapid spike action potentials (similar to that encountered in skeletal muscles) e.g., in uterine muscle fibers treated with estrogenic hormones; (2) action potentials with a prolonged depolarization plateau (like that encountered in cardiac muscle) in which the contractile activity persists throughout the duration of the entire action potential; and (3) the resting potential of smooth muscle often consisting of small waves, spikes, or nipples. These electric oscillations may occur at subthreshold voltages or eventually develop sufficient magnitude so that they reach threshold value, in which case an action potential develops. Typical pacemaker potentials also commonly occur in many types of visceral although in these the smooth muscle, pacemaker loci are found at multiple sites within the tissue. These pacemaker loci can shift from one area to another rather than remain fixed in one area. The latent period (time from onset of an action potential to the contractile response) of smooth muscle is quite long compared with that of skeletal muscle. Visceral muscle starts to contract approximately 200 msec. following the onset of the spike, and continues until about 150 msec. after the spike is over. Sometimes the peak of contraction is reached up to 500 msec. following development of the spike (compared with a latent period of less than 10 msec. in skeletal and cardiac muscle). Excitation-Contraction Muscle
Coupling Contractions
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polarization;
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marked contrast to skeletal muscle which can shorten to between 25 and 35 per cent of its resting length during a maximal isotonic contraction, smooth muscle is able to contract through much greater distances. This characteristic is of considerable physiologic importance in hollow viscera such as the bladder, uterus, and stomach. The property of stressrelaxation, to be discussed later, is also important in this regard since it allows the bladder during filling and distention to increase the length of the muscle fibers gradually without an increase in tension, Automaticity
of Smooth
Muscle
Many smooth muscle fibers exhibit spontaneous rhythmic oscillations of their membrane potential that leads to automaticity of the mechanical contractions when the threshold oscillations are of sufficient magnitude to depolarize the cells to its threshold for firing. Mechanical stretch or distention (v.i.) is an extremely potent stimulus to noninnervated visceral smooth muscle, and is followed by a decline in the resting membrane potential to threshold and development of an action potential. Furthermore, stretch augments the tone of visceral smooth muscle. A threshold stretch stimulus of about 1 mm. for each 10 mm. length of smooth muscle is usually needed to elicit a response, but more sensitive muscles respond more readily (rabbit detrusor ratio is 1:15). All visceral smooth muscle examined actively contract in response to a quick stretch of 1 mm./ sec. A response to slow stretch is seen only rarely and only with the most excitable muscles such as taenia coli and bladder. I8 The inherent rhythmic pattern of some smooth muscle such as the intestine can be modified not only by the degree of applied stretch, but also by chemical agents (neurotransmitters) which augment or depress the firing rate by depolarizing or hyperpolarizing the membrane respectively. Tone Tone in smooth msucle is not reflex in nature. It does not depend on intact innervation, although nerves can modify it. It is best described as maintained contraction which is capable of being inhibited.” As stated earlier, spontaneous rhythmic contractions may be superimposed on the fundamental tonic contraction pattern of smooth muscle.2 In isolated human detrusor strips, basic tone may be inhibited (reduced) by
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epinephrine, norepinephrine, or isoprenaline, but it is not affected by physostigmine, atropine, or hexamethonium.” However, De Sy20 found that catecholamines had little or no effect on the basal tension of isolated guinea pig detrusor strips. Metabolism Qualitatively the metabolism of smooth muscle fibers is the same as that in other types of muscle. The immediate source of energy for muscle contraction is ATP. Hydrolysis of the bonds between the phosphate residues of ATP is associated with the release of large amounts of energy. The hydrolysis of ATP to ADP is catalyzed by myosin. Compared with skeletal muscle, the capacity of anaerobic glycolysis is highly developed in smooth muscle. Furthermore, the relatively low energy consumption seen during extended periods of tonic contraction in smooth muscle probably is related to the formation of large numbers of low-energy state actomyosin cross bridges within the myofilaments themselves so that little energy is required to maintain the tonic state. Relation
of Length to Tension in Smooth Muscle
(Plasticity)
Stretching smooth muscle alters two of its important characteristics, namely, its membrane potential and its response to contractile stimuli.21 Smooth muscle can exert variable tension at any particular length. If a strip of visceral smooth muscle is stretched, it first exerts increased tension. However, if the muscle is held at the greater length after stretching, the tension gradually decreases. Sometimes the tension falls to or below the level exerted before the muscle was stretched. This makes it impossible to correlate length and developed tension accurately. is2 This phenomenon is called the stressrelaxation of smooth muscle. In this respect, smooth muscle behaves similarly to a viscous amorphous mass, a property called plasticity of smooth muscle. As stated previously this property is important in the storage phase of the urinary bladder since it allows the bladder to accommodate increasing amounts of urine without an increase in tension. Muscle
Length/Tension Relationship in Detrusor and Urethra
Detrusor Compared with other visceral smooth muscle, bladder muscle has a short latency period (time
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from stretch to initiation of contraction) and a slow contraction time. Its magnitude of response (height of contraction) to stretch is intermediate. l8 In guinea pig detrusor strips (2 x 10 mm.) gradual stretching (2 mm./5 min.) resulted in increase in tension. At first the increase in length resulted in only moderate elevation of tension; further stretching caused a progressive sharper increase in tension. In all preparations the increase in rest tension resulted in the occurrence of spontaneous activity, which reached a maximum (range 0.5 to 2 Cm.) at approximately 200-250 per cent of initial length.20 This experiment illustrates the distensibility of the bladder wall. Distention resulted not only in a slowly progressive passive increase in tension of the strips but also had a marked influence on the spontaneous contractions and the reactivity Therefore, all the further of the preparations. experiments were performed on strips at the optimal point of their length-tension relation, in order to obtain standardized conditions of optimal activity. In detrusor strips from dogs, the tension was increased as the strips were stretched. The tension changed relatively little until the muscle was stretched to about 140 per cent of its resting length.‘l In rabbit detrusor stripsz2 resting (baseline) tension changes began developing at about 134 per cent of the muscle’s equilibrium length (starting length). A s resting tension developed at increasing stretch increments, spontaneous activity became more apparent. The contractile force of these spontaneous contractions became maximal at a mean of 191 per cent equilibrium length. The frequency of spontaneous contractions increased in a sigmoid curve manner as the muscle was lengthened. The maximum rate occurred near the breaking point or decreased slightly before the breaking point. In rats the bladder in vitro was filled via a catheter.23 The resting pressure in the bladder increased progressively as the organ was filled with successive increments of fluid. However, these pressure elevations fell slowly, reaching a constant value within five minutes. As the fluid volume within the bladder increases, the muscle fibers undergo a uniform elongation. The mean fiber length is clearly a function of the radius of the bladder. Muscle fibers increase in length nearly twofold when the bladder is filled to its physiological capacity, i.e., volume at which micturition usually occurs.
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Urethra In urethral strips from dogs,24 muscle length was minimally increased until enough tension was developed to record spontaneous activity. This occurred at 110 to 120 per cent of resting length. All strips contracted when norepinephrine (NEp) was added to the bath. As the strips were increased in length, the magnitude of the contraction elicited by NEp increased in proportion to increased muscle length up to 180 per cent resting length. The urethral strips exhibited a much greater increase in contractile response to increasing length than did strips from the anterior base or trigone. In a bladder-urethra preparation from dogs in vitro, urethral pressure profile was recorded with different degrees of stretching. Progressive increase in stretch of the urethra resulted in an increase in both profile pressure and functional length. Maximum tension was achieved at the muscle tension that most closely approximates normal length (natural length). Bruschini, Schmidt, and Tanagho25 suggested that a decrease in activity of urethral musculature accompanies the slackening in urethral length that occurs in stress incontinence patients. Muscle Electric
Length/Tension and Response to Stimulation (E.S.) in Bladder and Urethra
In detrusor strip experiments from guinea pigs,2o an identical electrical stimulus (20 cps, 5 sec.) was applied to each strip at different degrees of distention (length). The reactivity of the strips (contractile response) increased rapidly to reach a maximum at about 200 to 250 per cent of the initial length. After that the strips were kept at the point of optimal length, and their response to different frequencies of electric stimulation was recorded. The contractile response of the strips increased with increasing frequency of E. S. and reached a maximum at a frequency of 30 to 40 cps. The response to E. S. was then tested in the presence of blocking agents in the bath. Atropine (lop6 Gm./ml.) depressed reactivity to blocking E.S. by 50 per cent. 20,26 Ganglionic drugs did not influence the response to E. S. Phentolamine at increasing doses had little effect on the response to E. S. (none at lo-’ Gm. /ml., 5 per cent at 10e6 Gm‘./ml., and 25 per at 10e5 Gm./ml.). Propranolol cent potentiation depressed the reactivity to (10-j Gm./ml.) E.S.20
3
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In detrusor strips from rabbits, the contractile response to E.S. was recorded at different muscle strip lengths. The maximum contractile response was elicited at a muscle length that was 272 per cent of the equilibrium (resting or baseline) length. Beyond that point the contractile response began to decline. The maximum contractile response to E. S. was 2.9 times greater than the maximum spontaneous contraction.22 It was concluded that the bladder may respond to external stimulation with more efficient contraction when it is full rather than slightly or moderately full. In the rat bladder in vitro, the contractile reat low stimulation sponses to E.S., elicited rates, were increased more by stretch than those elicited by stimuli applied at the optimal rate.s Carpenter’ also found that maximum intravesical pressure in response to electrical stimulation occurred at low intravesical volumes, and with progressive filling of the bladder, intravesical pressure manifested during the contractile response from electrical stimulation varied inversely with the volume in the bladder. By converting pressure to tension using Laplace’s law, he found that the maximum force generated by electrical stimulation occurred at mid-volumes and mid-muscle fiber lengths. He concluded that in the low volume range, the force generated by the contracting bladder appears to be diminished by its viscous-elastic properties. Otherwise, at rest and during stimulation the bladder smooth muscle displays a length-tension relation similar to that found in cardiac and skeletal muscle. He suggests that a minimum state of stretch of bladder musculature is essential for the production of a maximum contractile response. Wintonz7 also concluded the isometric tension developed in response to electrical or chemical stimulation of smooth muscle increases with length up to a maximum value and then decreases. Muscle Length/Tension Drugs in Bladder
and Response and Urethra
to
Detrusor De Syzo found that catecholamines have little or no effect on spontaneous activity of isolated guinea pig detrusor strips. Electric stimulation was maximal at a length about 200 to 250 per cent of initial lengths (see above). Spontaneous activity was unaffected by NEp or isoproterenol (1O-7-1O-j Gm./ml.) but was markedly increased by ACh (10-7-10-5 Gm./ml.). The effect of ACh was abolished by atropine.26 The re-
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sponse to E. S., however, was blocked only partially by atropine. 20,26 The effect of adrenergic drugs on the contractile response to electric stimulation (20 cps for 5 sec. every 2.5 min.) was recorded. Isoproterenol (lo-’ Gm./ml.) decreased the reaction to a standard E. S. to an average of 76 per cent of control. In a concentration of 10V6 Gm./ml., isoproterenol depressed the response to 72 per cent of control. Propranolol (10e6-10m5 Gm./ml.) abolished this effect of isoproterenol. Phentolamine had no effect on the depressed response to E. S. caused by the presence of isoproterenol in the bath. NEp (lo-’ Gm./ml.) depressed the contractile response to E. S. to an average of 83.3 per cent of control. In higher doses of NEp (lop6 Gm./ml.), the response to E.S. was 69.8 per cent of control. Propranolol (lop6 Gm./ml.) only partially inhibited the effect of NEp (10m6 GmJml.) in some strips, and phentolamine (lop6 GmJml.) partially inhibited this NEp effect in some strips. Complete inhibition of this effect of NEp was obtained when the two blockers were present in the bathsz6 De Syzo explained these results by stating that it is possible that both alpha and beta receptors in the guinea pig bladder react to stimulation in the same direction, i.e., relaxation, as has been observed on other smooth muscles of the guinea pig. Utilizing detrusor strips from cat and rabbit, De Syz6 observed more significant rest tonus than in strips from guinea pigs. These strips (from cat and rabbit) responded to norepinephrine (NEp) and isoproterenol by relaxing. 26 In detrusor strips from dogs, the effect of NEp (10-6-10-5 Gm./ml.) on spontaneous (rhythmic) activity of the strips at different lengths was investigated. At lengths near the resting length, NEp invariably caused a reduction in spontaneous activity and a decrease in baseline tension (beta response). This response was unaltered by pretreatment with phentolamine or atropine, but was blocked by propranolol. At times, an increase in baseline tension was seen with NEp when the alpha effect was unmasked following pretreatment with propranolol. ” These results were similar to those elicited in experiments utilizing detrusor strips from cats and rabbits2* In these later experiments (cats and rabbits) the detrusor strips responded to epinephrine, NEp and isoprenaline (10e7 Gm./ml.) by relaxing; this effect was blocked by propranolol indicating that beta receptors are involved. The responses to
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epinephrine and NEp were reversed by propranolol indicating that the strips also possessed alpha receptors. The excitatory responses (to epinephrine and NEp in the presence of propranolol) were blocked by phenoxybenzamine. The detrusor strips from dogs which relaxed in response to NEp (10-6-10-5 Gm./ml.) at the lower lengths were then stretched and tested for their response to NEP.~~ As the length was increased, NEp at the same concentration caused an increase in baseline tension and amplitude of contractions in 70 per cent of the strips tested (28 to 40 strips). This change from beta to alpha response occurred at an average of 180 per cent of the resting length. The 12 strips which did not respond had minimal spontaneous activity and reacted minimally, if at all, to any adrenergic stimulation. *’ Increasing the concentration of NEp at a given length increased the magnitude of the alpha or beta response, but in no instance was a beta response converted to an alpha response by increasing the concentration of NEp. The contractile response to NEp at high length was unaffected by atropine or propranolol. Following pretreatment with phentolamine, no alpha response was seen and a decrease in baseline tension (beta response) occurred.21 Benson et aZ.*l suggested that the net effect of stimulation of both alpha and beta receptors by NEp may be dependent on the initial state of the membrane potential which in turn is dependent on the length of the muscle; stretch partially depolarizes the muscle cell membrane rendering it more capable to respond to contractile stimulation. They also suggested that the alpha contractile effect of NEp (and sympathetic nervous system) at high muscle lengths may work synergistically with the cholinergic system in bladder emptying. In guinea pig detrusor strips, variable responses to prostaglandins El, E2, FI, F2 were noted when the strips were kept at 1 Gm. tension. However, the responses to all four prostaglandins correlated with muscle length. The maximum response to prostaglandins occurred at a length of about 190 per cent of resting at lengths greater than length. Furthermore, I40 per cent of resting length a contractile response was always elicited in response to any of the four prostaglandins at all doses. With detrusor strip lengths of 140 per cent or less of resting length, variable responses occurred including many that responded by a relaxation or biphasic response. 2g Like NEp, the direction of the response to prostaglandin was determined
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more by the degree of stretch of the detrusor rather than by the dose of prostaglandin; prostaglandins always elicited a contractile response at high degrees of distention, a factor that may be important in emptying of full bladders.
Urethra Urethral strips from dogs were suspended in the bath at approximately 110 to 120 per cent of resting length. They responded to norepinephrine (10e6 Gm./ml.) by a contraction in the magnitude of 0.2 to 1 Gm. The length of the strips was then increased to 150 to 180 per cent of the resting length, and the contractile response to NEp was much greater and exceeded 1 Gm. The response to NEp was blocked by phentolamine (10d6 Gm./m1.).24 Similar observations were noted from the bladder base. Benson et al. 24 suggested that operations designed to restore continence by increasing urethral length may, in part, achieve their success by making the urethral musculature more responsive to alpha-adrenergic stimulation. 4301 West Markham Little Rock, Arkansas 72201 (DR. FINKBEINER) References 1. Ganong WF: Excitable tissue muscle, in: Review of Medical Physiology, Lang Medical Publishers, Los Altos, California, 1977, chap. 3, pp. 32-37. 2. Jenson D: The physiology of contractile cells and tissues, in: The Principles of Physiology, Appleton-Century-Crofts, New York, 1976, chap. 4, pp. 113-155. 3. Posser CL: Electrical and mechanical properties of visceral smooth muscle, in Boyarski S, Ed: Neurogenic Bladder, William & Wilkins, Co., Baltimore, 1967, chap. 5,pp. 51-55. 4. Sheuard RS: Smooth muscles. in: Human Phvsiolow, 1. P. Lippincoit, Philadelphia, 1971, chap. 9, pp. 148-162. c” . 5. Dewey MM, and Barr L: Intercellular connection between smooth muscle cells: the nexus, Science 137: 670 (1962). 6. Weiss RM: Ureteral function, Urology 12: 114 (1978). 7. Hodgkin AL: Ionic movements and electrical activity in giant nerve fibers, Proc. R. Sot. Lond. (Biol.) 148: 1 (1958). 8. Carpenter FG: Motor responses of bladder smooth muscle in relation to elasticity and fiber length, Invest. Ural. 6: 273 (1968). 9. Bennett MR, and Bumstock G: Application of the sucrosegap method to determine the ionic basis of the membrane potential of smooth muscle, J. Physiol. (London) 183: 637 (1966). 10. Bennett MR, Bumstock G, Holman ME, and Walker JW: The effects of Ca2+ on plateau-type action potentials in smooth muscle, ihid. 161: 47P (1962). 11. Ebashi S, and Endo M: Calcium ion and muscle contraction, Prog. Biophsy. 18: 123 (1968). 12. Greaser ML, and Gergley J: Reconstitution of troponin activity from three protein components, J. Biol. Chem. 246: 4226 (1971). 13. Entman ML: The role of cyclic AMP in the modulation of cardiac contractilitv. in Greengard P. and Robinson GA, Eds: Advances in Cyclic Nucleotide Research, New York, Raven Press, 1974, vol. 4, pp. 163-193. 14. Ax&son J: Mechanical properties of smooth muscle, and the relationship between mechanical and electrical activity, in
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Bulbring E, Brading AF, Jones AW, and Tomita T, Eds: Smooth Muscle, William & Wilkins, Co., Baltimore, 1970, pp. 289-315. 15. Anderson RGG: Cyclic AMP and calcium ions in mechanical and metabolic responses of smooth muscle, influence of some hormones and drugs, Acta Physiol. Stand. (Suppl.) 5382: 1 (1972). 16. Kroeger EA, and Marshall JM: Beta-adrenergic effects on rat myometrium: role of cyclic AMP, Am. J. Physiol. 226: 1298 (1974). 17. Triner L, ct al: Cyclic AMP and smooth muscle function, Ann. N.Y. Acad. Sci. 185: 458 (1971). 18. Bumstock G, and Prosser CL: Responses of smooth muscles to quick stretch; relation to stretch to conduction, Am. J. Physiol. 198: 921 (1960). 19. Todd JD, and Mack AJ: A study of human bladder detrusor muscle, Br. J. Ural. 41: 448 (1969). 20. De Sy W: The reactivity of isolated urinary bladder strips of the guinea pig toward electric stimulation, Arch. Int. Physiol. Biochem. 79: 459 (1971). 21. Benson GS, Raezer DM, Wein AJ, and Corriere JN: Effect of muscle length on adrenergic stimulation of canine detrusor, Urology 5: 769 (1975). 22. Anderson GF, Pierce JM, Jr, and Blair LL: Tension
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changes in rabbit bladder muscle: effect of stretch, Invest. Ural. 6: 267 (1968). 23. Csapo AI: Smooth muscle as a contractile unit, Physiol. Rev. (suppl. 5) 42: 7 (1962). 24. Benson GS, et al: Adrenergic innervation and stimulation of canine urethra, Urology 7: 337 (1976). 25. Brucshini H, Schmidt RA, and Tanagho EA: Effect of urethral stretch on urethral pressure profile, Invest. Ural. 15: 107 (1977). 26. De Sy W: Receptor responses in isolated smooth muscle of the urinary bladder, Arch. Int. Pharmacodyn. Ther. 186: 188 (1970). 27. Winton FR: The influence of length on the responses of unstriated muscle to electrical and chemical stimulation and stretching, J. Physiol. 61: 368 (1926). 28. Edvardsen P, and Setekleiv J: Distribution of adrenergic receptors in the urinary bladder of cats, rabbits and guinea pigs, Acta Pharmacol. Toxicol. 26: 437 (1968). 29. Finkbeiner AE, and Bissada NK: In vitro effects of prostaglandins on guinea pig detrusor and bladder outlet, Presented at the American Urological Association Annual Meeting, Chicago (1977).
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MUSCLE
PHYSIOLOGY
AND URETHRA
ON RESPONSE
AND EFFECT
MUSCLE
OF
LENGTH/TENSION
TO STIMULATION
Part I. Review NABIL
K. BISSADA,
ALEX
E. FINKBEINER.
M.D. M.D.
From the Department of Urology, University Medical Sciences, Little Rock, Arkansas
ABSTRACT - With particular reference to the lower urinary physiology of smooth muscle is presented. The relationship macologic stimulation is discussed.
With increasing interest in lower urinary tract function and dysfunction, a better understanding of the neuroanatomy and neuropharmacology of the bladder and bladder outlet has been achieved. Yet, little work on the basic physiology of the detrusor smooth muscle and the relation of stretch and tension of detrusor smooth muscle fibers to its response to drugs or electric stimulation has been done. The value of this information both scientifically and clinically is apparent. Herein, we review smooth muscle physiology, the effect of muscle length-tension alterations on bladder and urethral function, and the effect of these alterations on the response of the bladder to drugs and electric stimulation.
of Arkansas
for
tract, a review of basic anatomy and as altered by electrical and phar-
Smooth or plain muscle consists of spindleshaped fibers which are held tightly together by connective tissue. These muscle fibers lack the cross-banded pattern observed in striated muscle. Each smooth muscle fiber contains a single nucleus located near the center of the cell and cystoplasm, or sarcoplasm. The sarcoplasm is homogeneous and contains many fibrils that run the length of the cell and are presumed to be the contractile elements. The sarcoplasmic reticulum is poorly developed in comparison to
that of skeletal muscles. l-3 Although the exact contractile mechanism in most smooth muscles is not known, it is believed to be similar to that involved in skeletal muscle contractility. In intestinal smooth muscle, there is evidence that the contractile units are made up of small bundles of interdigitating thick and thin filaments that are irregularly shaped and randomly arranged. When the muscle contracts, the thick and thin filaments are thought to slide on each other (v.i.). Smooth muscle cells exhibit considerable variations in their length (from 500 U in pregnant uterus, 200 U in intestine, and 20 U in blood vessels). Likewise, they exhibit a wide variety of functional roles in the body, and their responses to pharmacologic and other stimuli is quite diverse so that it is sometimes difficult to describe the general physiology of smooth muscle.2*4 For convenience, smooth muscles are classified into visceral and multiunit smooth muscles although a spectrum exists between these two extremes. Multiunit smooth muscle are composed of individual cellular units arranged loosely. No intracellular bridges have been demonstrated. Examples of the multiunit smooth muscle include the ciliary muscle (intrinsic muscle of the eye), nictitating membrane and iris, pilomotor
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muscle, and muscles of some of the larger blood vessels.3 In some respects these muscles resemble skeletal muscle in that nerve impulses are generally required to initiate contraction; they are not sensitive to quick stretch; they are not spontaneously rhythmic; and contraction is generally more rapid than in visceral smooth muscle. Contractions are more discrete, fine, and localized than in unitary muscles. Unitary or viceral smooth muscle: Most hollow viscera such as the stomach, intestine, bile ducts, ureters, uterus, and bladder have sheets of unitary muscles in their walls. The individual fibers are closely packed in a roughly parallel fashion. Low electric resistance bridges are present among the individual cells; these probably represent areas in which the cell wall consists of plasma membrane alone and lacks a basement membrane (“intermediate junctions”). 5,6 Despite differences among different visceral muscles, most are spontaneously active, show interfiber conduction, and are stimulated to contract by quick stretch. Although capable of independent activity, they may be regulated by intrinsic and extrinsic nerves. The bladder and the vas deferens combine some properties of both unitary (visceral) and multiunit muscles. Thus, they resemble visceral muscle in terms of morphology and their responses to mechanical stretch. On the other hand, they resemble multiunit muscles in respect to activation and control. In a sense, the bladder is a neurogenic not a myogenic organ inasmuch as it performs useful work only under the influence of its motor innervation. Bioelectric
Events
As stated previously, despite lack of definite knowledge about the exact mechanisms involved in the function of various types of smooth muscle, they all contain actin and myosin, the same contractile proteins found in muscle fibers generally. Consequently, it is assumed that contraction of smooth muscle occurs in a manner similar to that in skeletal muscle. The electrical properties of all excitable tissues are dependent on the distribution of ions on the inside and outside of the cell membranes and the relative permeability of the cell membranes to these ions.? Resting
membrane
potential
In the resting state, potassium ion (K+) concentration is greater on the inside than on the outside of the cell membrane. Conversely,
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sodium ion (Na+) concentration is greater on outside of cell membrane than on inside. A mechanism of extruding Na+ from within to outside the cell membrane against a concentration gradient (sodium pump) has been demonstrated in smooth muscle.* As in skeletal muscles, this process requires energy expenditure which is provided by dephosphorylation of ATP. An inward movement of K+ is coupled with the outward movement of Na+. When a smooth muscle cell is in a nonexcited state, the electric potential difference across the cell membrane (transmembrane potential) is called the “resting membrane potential” or “RMP.” The RMP is determined primarily by the distribution of potassium ions (K+) across the cell membrane and the relative permeability of the cell membrane to K+.’ Since in the resting state the K+ concentration on the inside of the cell is greater than on the outside, there is a tendency for the positively charged K+ to diffuse from inside to outside the cell. An electric gradient thus develops with the inside of the cell membrane becoming more negative than the outside of the cell membrane. This electric gradient tends to oppose further movement of K+ from inside to outside the cell. An equilibrium is thus reached in which K+ concentration is greater inside the cell than outside the cell membrane; thus, the inside of the cell membrane becomes electronegative with respect to the outside of the cell membrane. The RMP of smooth muscle is generally low, on the order of about - 50 mv.2 The maintenance of a relatively low range of the RMP in smooth muscle (in comparison to striated muscle) is probably due to the relative permeability of resting smooth muscle cell membrane to Na+ thus permitting some movement of Na+ to the inside of the cell membrane. Regular and irregular fluctuations in the membrane potential of several millivolts often are present, and these are superimposed upon the basic resting potential (v.i.). Action potential If the cell membrane is depolarized rapidly enough to reach a certain level or threshold (the threshold potential), an action potential develops. The ionic fluxes during excitation of smooth muscle are rather poorly understood. It involves alterations in the concentration of Na+ and mediation of Ca++ whose intracellular concentration increases following depolarization. The ATP-ADP system provides energy for the contractile process. It appears that when a cell is
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excited,
it loses its preferential
permeability
to
The process by which depolarization of the muscle fiber initates contraction is called “excitation-contraction coupling.” Excitation contraction coupling in smooth muscle is not fully understood. It appears to be similar to that involved in the contraction of skeletal muscle and to be mediated by calcium ions, whose intracellular concentration increases following de-
the ATP-ADP system providing energy for the contractile process.* The contractile process in muscles is brought about by the interaction of the contractile proteins actin and myosin. In the relaxed state, a regulator system, consisting of the proteins troponin and tropomyosin (relaxing proteins), prevents the interaction between actin and myosin. 11,12 In the resting muscle troponin is tighly bound to actin, and tropomyosin covers the sites where myosin heads bind to actin. When Ca++ binds to troponin, the binding of troponin to actin is presumably weakened allowing displacement of the tropomyosin. This, in turn, uncovers binding sites on the myosin heads and binding of actin and myosin occurs resulting in muscle contraction.13 In smooth muscle, the sarcoplasmic reticulum and T-system are poorly developed; therefore, the interstitial fluid is probably a major source of Ca+ + necessary to activate the contractile system. As stated earlier, extracellular Ca+ + move into the inside of the cells during the action potential leading to an increase in Ca++ in the region of the contractile proteins with subsequent development of a contraction. l4 There is some evidence, however, that a portion of calcium ions required for the activation of smooth muscle may be obtained from intracellular calcium pools, in particular the mitochondria and microsomes. The relative portions of Ca++ contributed by the intracellular organelles vary considerably among smooth muscle fibers derived from different tissues. Relaxation occurs in a reverse manner to that described for contraction. It is initiated by a decrease in the amount of free Ca++ in the sarcoplasm available to the contractile proteins. This may involve the uptake of Ca++ by intracellular storage sites or its extrusion to the extracellular fluid. Recently, it has been suggested that cyclic nucleotides may play an important role in smooth muscle function. 15-17For instance, cyclic AMP is believed to mediate the beta-adrenergic relaxing effect in a variety of smooth muscles including the bladder. The contractile properties of smooth muscle fibers differ from those of striated muscle in several aspects. Contraction of smooth muscle is a relatively slow process compared to that of striated muscle. However, smooth muscle is capable of sustaining forceful contractions for long periods of time with a very low concomitant expenditure of energy. Similarly, the relaxation of smooth muscle is a prolonged one. Second, in
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K+ and becomes permeable to Na+ and Ca+ + which move inward across the cell membrane. The inward movement of positively charged ions makes the inside of the cell less negative with respect to the outside than is present in the resting state; this results in depolarization. ‘O The action potentials recorded from a particular smooth muscle are subject to considerable variation as may be anticipated from the various functional types of smooth muscle encountered in the body. Action potentials developed by smooth muscles belong to three classes: (1) typical rapid spike action potentials (similar to that encountered in skeletal muscles) e.g., in uterine muscle fibers treated with estrogenic hormones; (2) action potentials with a prolonged depolarization plateau (like that encountered in cardiac muscle) in which the contractile activity persists throughout the duration of the entire action potential; and (3) the resting potential of smooth muscle often consisting of small waves, spikes, or nipples. These electric oscillations may occur at subthreshold voltages or eventually develop sufficient magnitude so that they reach threshold value, in which case an action potential develops. Typical pacemaker potentials also commonly occur in many types of visceral although in these the smooth muscle, pacemaker loci are found at multiple sites within the tissue. These pacemaker loci can shift from one area to another rather than remain fixed in one area. The latent period (time from onset of an action potential to the contractile response) of smooth muscle is quite long compared with that of skeletal muscle. Visceral muscle starts to contract approximately 200 msec. following the onset of the spike, and continues until about 150 msec. after the spike is over. Sometimes the peak of contraction is reached up to 500 msec. following development of the spike (compared with a latent period of less than 10 msec. in skeletal and cardiac muscle). Excitation-Contraction Muscle
Coupling Contractions
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polarization;
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marked contrast to skeletal muscle which can shorten to between 25 and 35 per cent of its resting length during a maximal isotonic contraction, smooth muscle is able to contract through much greater distances. This characteristic is of considerable physiologic importance in hollow viscera such as the bladder, uterus, and stomach. The property of stressrelaxation, to be discussed later, is also important in this regard since it allows the bladder during filling and distention to increase the length of the muscle fibers gradually without an increase in tension, Automaticity
of Smooth
Muscle
Many smooth muscle fibers exhibit spontaneous rhythmic oscillations of their membrane potential that leads to automaticity of the mechanical contractions when the threshold oscillations are of sufficient magnitude to depolarize the cells to its threshold for firing. Mechanical stretch or distention (v.i.) is an extremely potent stimulus to noninnervated visceral smooth muscle, and is followed by a decline in the resting membrane potential to threshold and development of an action potential. Furthermore, stretch augments the tone of visceral smooth muscle. A threshold stretch stimulus of about 1 mm. for each 10 mm. length of smooth muscle is usually needed to elicit a response, but more sensitive muscles respond more readily (rabbit detrusor ratio is 1:15). All visceral smooth muscle examined actively contract in response to a quick stretch of 1 mm./ sec. A response to slow stretch is seen only rarely and only with the most excitable muscles such as taenia coli and bladder. I8 The inherent rhythmic pattern of some smooth muscle such as the intestine can be modified not only by the degree of applied stretch, but also by chemical agents (neurotransmitters) which augment or depress the firing rate by depolarizing or hyperpolarizing the membrane respectively. Tone Tone in smooth msucle is not reflex in nature. It does not depend on intact innervation, although nerves can modify it. It is best described as maintained contraction which is capable of being inhibited.” As stated earlier, spontaneous rhythmic contractions may be superimposed on the fundamental tonic contraction pattern of smooth muscle.2 In isolated human detrusor strips, basic tone may be inhibited (reduced) by
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epinephrine, norepinephrine, or isoprenaline, but it is not affected by physostigmine, atropine, or hexamethonium.” However, De Sy20 found that catecholamines had little or no effect on the basal tension of isolated guinea pig detrusor strips. Metabolism Qualitatively the metabolism of smooth muscle fibers is the same as that in other types of muscle. The immediate source of energy for muscle contraction is ATP. Hydrolysis of the bonds between the phosphate residues of ATP is associated with the release of large amounts of energy. The hydrolysis of ATP to ADP is catalyzed by myosin. Compared with skeletal muscle, the capacity of anaerobic glycolysis is highly developed in smooth muscle. Furthermore, the relatively low energy consumption seen during extended periods of tonic contraction in smooth muscle probably is related to the formation of large numbers of low-energy state actomyosin cross bridges within the myofilaments themselves so that little energy is required to maintain the tonic state. Relation
of Length to Tension in Smooth Muscle
(Plasticity)
Stretching smooth muscle alters two of its important characteristics, namely, its membrane potential and its response to contractile stimuli.21 Smooth muscle can exert variable tension at any particular length. If a strip of visceral smooth muscle is stretched, it first exerts increased tension. However, if the muscle is held at the greater length after stretching, the tension gradually decreases. Sometimes the tension falls to or below the level exerted before the muscle was stretched. This makes it impossible to correlate length and developed tension accurately. is2 This phenomenon is called the stressrelaxation of smooth muscle. In this respect, smooth muscle behaves similarly to a viscous amorphous mass, a property called plasticity of smooth muscle. As stated previously this property is important in the storage phase of the urinary bladder since it allows the bladder to accommodate increasing amounts of urine without an increase in tension. Muscle
Length/Tension Relationship in Detrusor and Urethra
Detrusor Compared with other visceral smooth muscle, bladder muscle has a short latency period (time
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from stretch to initiation of contraction) and a slow contraction time. Its magnitude of response (height of contraction) to stretch is intermediate. l8 In guinea pig detrusor strips (2 x 10 mm.) gradual stretching (2 mm./5 min.) resulted in increase in tension. At first the increase in length resulted in only moderate elevation of tension; further stretching caused a progressive sharper increase in tension. In all preparations the increase in rest tension resulted in the occurrence of spontaneous activity, which reached a maximum (range 0.5 to 2 Cm.) at approximately 200-250 per cent of initial length.20 This experiment illustrates the distensibility of the bladder wall. Distention resulted not only in a slowly progressive passive increase in tension of the strips but also had a marked influence on the spontaneous contractions and the reactivity Therefore, all the further of the preparations. experiments were performed on strips at the optimal point of their length-tension relation, in order to obtain standardized conditions of optimal activity. In detrusor strips from dogs, the tension was increased as the strips were stretched. The tension changed relatively little until the muscle was stretched to about 140 per cent of its resting length.‘l In rabbit detrusor stripsz2 resting (baseline) tension changes began developing at about 134 per cent of the muscle’s equilibrium length (starting length). A s resting tension developed at increasing stretch increments, spontaneous activity became more apparent. The contractile force of these spontaneous contractions became maximal at a mean of 191 per cent equilibrium length. The frequency of spontaneous contractions increased in a sigmoid curve manner as the muscle was lengthened. The maximum rate occurred near the breaking point or decreased slightly before the breaking point. In rats the bladder in vitro was filled via a catheter.23 The resting pressure in the bladder increased progressively as the organ was filled with successive increments of fluid. However, these pressure elevations fell slowly, reaching a constant value within five minutes. As the fluid volume within the bladder increases, the muscle fibers undergo a uniform elongation. The mean fiber length is clearly a function of the radius of the bladder. Muscle fibers increase in length nearly twofold when the bladder is filled to its physiological capacity, i.e., volume at which micturition usually occurs.
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Urethra In urethral strips from dogs,24 muscle length was minimally increased until enough tension was developed to record spontaneous activity. This occurred at 110 to 120 per cent of resting length. All strips contracted when norepinephrine (NEp) was added to the bath. As the strips were increased in length, the magnitude of the contraction elicited by NEp increased in proportion to increased muscle length up to 180 per cent resting length. The urethral strips exhibited a much greater increase in contractile response to increasing length than did strips from the anterior base or trigone. In a bladder-urethra preparation from dogs in vitro, urethral pressure profile was recorded with different degrees of stretching. Progressive increase in stretch of the urethra resulted in an increase in both profile pressure and functional length. Maximum tension was achieved at the muscle tension that most closely approximates normal length (natural length). Bruschini, Schmidt, and Tanagho25 suggested that a decrease in activity of urethral musculature accompanies the slackening in urethral length that occurs in stress incontinence patients. Muscle Electric
Length/Tension and Response to Stimulation (E.S.) in Bladder and Urethra
In detrusor strip experiments from guinea pigs,2o an identical electrical stimulus (20 cps, 5 sec.) was applied to each strip at different degrees of distention (length). The reactivity of the strips (contractile response) increased rapidly to reach a maximum at about 200 to 250 per cent of the initial length. After that the strips were kept at the point of optimal length, and their response to different frequencies of electric stimulation was recorded. The contractile response of the strips increased with increasing frequency of E. S. and reached a maximum at a frequency of 30 to 40 cps. The response to E. S. was then tested in the presence of blocking agents in the bath. Atropine (lop6 Gm./ml.) depressed reactivity to blocking E.S. by 50 per cent. 20,26 Ganglionic drugs did not influence the response to E. S. Phentolamine at increasing doses had little effect on the response to E. S. (none at lo-’ Gm. /ml., 5 per cent at 10e6 Gm‘./ml., and 25 per at 10e5 Gm./ml.). Propranolol cent potentiation depressed the reactivity to (10-j Gm./ml.) E.S.20
3
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In detrusor strips from rabbits, the contractile response to E.S. was recorded at different muscle strip lengths. The maximum contractile response was elicited at a muscle length that was 272 per cent of the equilibrium (resting or baseline) length. Beyond that point the contractile response began to decline. The maximum contractile response to E. S. was 2.9 times greater than the maximum spontaneous contraction.22 It was concluded that the bladder may respond to external stimulation with more efficient contraction when it is full rather than slightly or moderately full. In the rat bladder in vitro, the contractile reat low stimulation sponses to E.S., elicited rates, were increased more by stretch than those elicited by stimuli applied at the optimal rate.s Carpenter’ also found that maximum intravesical pressure in response to electrical stimulation occurred at low intravesical volumes, and with progressive filling of the bladder, intravesical pressure manifested during the contractile response from electrical stimulation varied inversely with the volume in the bladder. By converting pressure to tension using Laplace’s law, he found that the maximum force generated by electrical stimulation occurred at mid-volumes and mid-muscle fiber lengths. He concluded that in the low volume range, the force generated by the contracting bladder appears to be diminished by its viscous-elastic properties. Otherwise, at rest and during stimulation the bladder smooth muscle displays a length-tension relation similar to that found in cardiac and skeletal muscle. He suggests that a minimum state of stretch of bladder musculature is essential for the production of a maximum contractile response. Wintonz7 also concluded the isometric tension developed in response to electrical or chemical stimulation of smooth muscle increases with length up to a maximum value and then decreases. Muscle Length/Tension Drugs in Bladder
and Response and Urethra
to
Detrusor De Syzo found that catecholamines have little or no effect on spontaneous activity of isolated guinea pig detrusor strips. Electric stimulation was maximal at a length about 200 to 250 per cent of initial lengths (see above). Spontaneous activity was unaffected by NEp or isoproterenol (1O-7-1O-j Gm./ml.) but was markedly increased by ACh (10-7-10-5 Gm./ml.). The effect of ACh was abolished by atropine.26 The re-
328
sponse to E. S., however, was blocked only partially by atropine. 20,26 The effect of adrenergic drugs on the contractile response to electric stimulation (20 cps for 5 sec. every 2.5 min.) was recorded. Isoproterenol (lo-’ Gm./ml.) decreased the reaction to a standard E. S. to an average of 76 per cent of control. In a concentration of 10V6 Gm./ml., isoproterenol depressed the response to 72 per cent of control. Propranolol (10e6-10m5 Gm./ml.) abolished this effect of isoproterenol. Phentolamine had no effect on the depressed response to E. S. caused by the presence of isoproterenol in the bath. NEp (lo-’ Gm./ml.) depressed the contractile response to E. S. to an average of 83.3 per cent of control. In higher doses of NEp (lop6 Gm./ml.), the response to E.S. was 69.8 per cent of control. Propranolol (lop6 Gm./ml.) only partially inhibited the effect of NEp (10m6 GmJml.) in some strips, and phentolamine (lop6 GmJml.) partially inhibited this NEp effect in some strips. Complete inhibition of this effect of NEp was obtained when the two blockers were present in the bathsz6 De Syzo explained these results by stating that it is possible that both alpha and beta receptors in the guinea pig bladder react to stimulation in the same direction, i.e., relaxation, as has been observed on other smooth muscles of the guinea pig. Utilizing detrusor strips from cat and rabbit, De Syz6 observed more significant rest tonus than in strips from guinea pigs. These strips (from cat and rabbit) responded to norepinephrine (NEp) and isoproterenol by relaxing. 26 In detrusor strips from dogs, the effect of NEp (10-6-10-5 Gm./ml.) on spontaneous (rhythmic) activity of the strips at different lengths was investigated. At lengths near the resting length, NEp invariably caused a reduction in spontaneous activity and a decrease in baseline tension (beta response). This response was unaltered by pretreatment with phentolamine or atropine, but was blocked by propranolol. At times, an increase in baseline tension was seen with NEp when the alpha effect was unmasked following pretreatment with propranolol. ” These results were similar to those elicited in experiments utilizing detrusor strips from cats and rabbits2* In these later experiments (cats and rabbits) the detrusor strips responded to epinephrine, NEp and isoprenaline (10e7 Gm./ml.) by relaxing; this effect was blocked by propranolol indicating that beta receptors are involved. The responses to
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epinephrine and NEp were reversed by propranolol indicating that the strips also possessed alpha receptors. The excitatory responses (to epinephrine and NEp in the presence of propranolol) were blocked by phenoxybenzamine. The detrusor strips from dogs which relaxed in response to NEp (10-6-10-5 Gm./ml.) at the lower lengths were then stretched and tested for their response to NEP.~~ As the length was increased, NEp at the same concentration caused an increase in baseline tension and amplitude of contractions in 70 per cent of the strips tested (28 to 40 strips). This change from beta to alpha response occurred at an average of 180 per cent of the resting length. The 12 strips which did not respond had minimal spontaneous activity and reacted minimally, if at all, to any adrenergic stimulation. *’ Increasing the concentration of NEp at a given length increased the magnitude of the alpha or beta response, but in no instance was a beta response converted to an alpha response by increasing the concentration of NEp. The contractile response to NEp at high length was unaffected by atropine or propranolol. Following pretreatment with phentolamine, no alpha response was seen and a decrease in baseline tension (beta response) occurred.21 Benson et aZ.*l suggested that the net effect of stimulation of both alpha and beta receptors by NEp may be dependent on the initial state of the membrane potential which in turn is dependent on the length of the muscle; stretch partially depolarizes the muscle cell membrane rendering it more capable to respond to contractile stimulation. They also suggested that the alpha contractile effect of NEp (and sympathetic nervous system) at high muscle lengths may work synergistically with the cholinergic system in bladder emptying. In guinea pig detrusor strips, variable responses to prostaglandins El, E2, FI, F2 were noted when the strips were kept at 1 Gm. tension. However, the responses to all four prostaglandins correlated with muscle length. The maximum response to prostaglandins occurred at a length of about 190 per cent of resting at lengths greater than length. Furthermore, I40 per cent of resting length a contractile response was always elicited in response to any of the four prostaglandins at all doses. With detrusor strip lengths of 140 per cent or less of resting length, variable responses occurred including many that responded by a relaxation or biphasic response. 2g Like NEp, the direction of the response to prostaglandin was determined
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more by the degree of stretch of the detrusor rather than by the dose of prostaglandin; prostaglandins always elicited a contractile response at high degrees of distention, a factor that may be important in emptying of full bladders.
Urethra Urethral strips from dogs were suspended in the bath at approximately 110 to 120 per cent of resting length. They responded to norepinephrine (10e6 Gm./ml.) by a contraction in the magnitude of 0.2 to 1 Gm. The length of the strips was then increased to 150 to 180 per cent of the resting length, and the contractile response to NEp was much greater and exceeded 1 Gm. The response to NEp was blocked by phentolamine (10d6 Gm./m1.).24 Similar observations were noted from the bladder base. Benson et al. 24 suggested that operations designed to restore continence by increasing urethral length may, in part, achieve their success by making the urethral musculature more responsive to alpha-adrenergic stimulation. 4301 West Markham Little Rock, Arkansas 72201 (DR. FINKBEINER) References 1. Ganong WF: Excitable tissue muscle, in: Review of Medical Physiology, Lang Medical Publishers, Los Altos, California, 1977, chap. 3, pp. 32-37. 2. Jenson D: The physiology of contractile cells and tissues, in: The Principles of Physiology, Appleton-Century-Crofts, New York, 1976, chap. 4, pp. 113-155. 3. Posser CL: Electrical and mechanical properties of visceral smooth muscle, in Boyarski S, Ed: Neurogenic Bladder, William & Wilkins, Co., Baltimore, 1967, chap. 5,pp. 51-55. 4. Sheuard RS: Smooth muscles. in: Human Phvsiolow, 1. P. Lippincoit, Philadelphia, 1971, chap. 9, pp. 148-162. c” . 5. Dewey MM, and Barr L: Intercellular connection between smooth muscle cells: the nexus, Science 137: 670 (1962). 6. Weiss RM: Ureteral function, Urology 12: 114 (1978). 7. Hodgkin AL: Ionic movements and electrical activity in giant nerve fibers, Proc. R. Sot. Lond. (Biol.) 148: 1 (1958). 8. Carpenter FG: Motor responses of bladder smooth muscle in relation to elasticity and fiber length, Invest. Ural. 6: 273 (1968). 9. Bennett MR, and Bumstock G: Application of the sucrosegap method to determine the ionic basis of the membrane potential of smooth muscle, J. Physiol. (London) 183: 637 (1966). 10. Bennett MR, Bumstock G, Holman ME, and Walker JW: The effects of Ca2+ on plateau-type action potentials in smooth muscle, ihid. 161: 47P (1962). 11. Ebashi S, and Endo M: Calcium ion and muscle contraction, Prog. Biophsy. 18: 123 (1968). 12. Greaser ML, and Gergley J: Reconstitution of troponin activity from three protein components, J. Biol. Chem. 246: 4226 (1971). 13. Entman ML: The role of cyclic AMP in the modulation of cardiac contractilitv. in Greengard P. and Robinson GA, Eds: Advances in Cyclic Nucleotide Research, New York, Raven Press, 1974, vol. 4, pp. 163-193. 14. Ax&son J: Mechanical properties of smooth muscle, and the relationship between mechanical and electrical activity, in
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Bulbring E, Brading AF, Jones AW, and Tomita T, Eds: Smooth Muscle, William & Wilkins, Co., Baltimore, 1970, pp. 289-315. 15. Anderson RGG: Cyclic AMP and calcium ions in mechanical and metabolic responses of smooth muscle, influence of some hormones and drugs, Acta Physiol. Stand. (Suppl.) 5382: 1 (1972). 16. Kroeger EA, and Marshall JM: Beta-adrenergic effects on rat myometrium: role of cyclic AMP, Am. J. Physiol. 226: 1298 (1974). 17. Triner L, ct al: Cyclic AMP and smooth muscle function, Ann. N.Y. Acad. Sci. 185: 458 (1971). 18. Bumstock G, and Prosser CL: Responses of smooth muscles to quick stretch; relation to stretch to conduction, Am. J. Physiol. 198: 921 (1960). 19. Todd JD, and Mack AJ: A study of human bladder detrusor muscle, Br. J. Ural. 41: 448 (1969). 20. De Sy W: The reactivity of isolated urinary bladder strips of the guinea pig toward electric stimulation, Arch. Int. Physiol. Biochem. 79: 459 (1971). 21. Benson GS, Raezer DM, Wein AJ, and Corriere JN: Effect of muscle length on adrenergic stimulation of canine detrusor, Urology 5: 769 (1975). 22. Anderson GF, Pierce JM, Jr, and Blair LL: Tension
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changes in rabbit bladder muscle: effect of stretch, Invest. Ural. 6: 267 (1968). 23. Csapo AI: Smooth muscle as a contractile unit, Physiol. Rev. (suppl. 5) 42: 7 (1962). 24. Benson GS, et al: Adrenergic innervation and stimulation of canine urethra, Urology 7: 337 (1976). 25. Brucshini H, Schmidt RA, and Tanagho EA: Effect of urethral stretch on urethral pressure profile, Invest. Ural. 15: 107 (1977). 26. De Sy W: Receptor responses in isolated smooth muscle of the urinary bladder, Arch. Int. Pharmacodyn. Ther. 186: 188 (1970). 27. Winton FR: The influence of length on the responses of unstriated muscle to electrical and chemical stimulation and stretching, J. Physiol. 61: 368 (1926). 28. Edvardsen P, and Setekleiv J: Distribution of adrenergic receptors in the urinary bladder of cats, rabbits and guinea pigs, Acta Pharmacol. Toxicol. 26: 437 (1968). 29. Finkbeiner AE, and Bissada NK: In vitro effects of prostaglandins on guinea pig detrusor and bladder outlet, Presented at the American Urological Association Annual Meeting, Chicago (1977).
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