SECTION I CELLULAR PHYSIOLOGY Raynaud's Disease A 32-year-old woman sees her family physician because of episodes of severe pain in her hands,associated with skin color changes and coldness of the hands.These attacks usually occurred during the winter and after exposure of the hands to cold. The physician precipitated one of these attacks by having the patient put her hands in a basin of cold water.At first the hands turned white,and this was associated with increasing pain of the fingers.Then the hands turned slightly cyanotic, followed rapidly by redness and throbbing discomfort.Gradually the pain disappeared, and the hands returned to normal color.The patient was told that she had Raynaud's disease and that she should avoid exposure of her hands to cold. 1.The ability of any muscle to generate force decreases with shortening below the optimum length for force generation.How can vascular smooth muscle contraction occlude an artery when the blood pressure opposing shortening remains at normal levels? 2.Do the mechanisms that regulate vascular smooth muscle activation precisely match blood flow to that needed to provide oxygen and substrates to the muscles of the fingers? 3.Would cooling affect muscle function in the fingers? 4.Is there anything about smooth muscle that would make it more temperature-sensitive than skeletal muscle? 5.Is an impaired ATP synthetic capacity and a form of rigor mortis a reasonable explanation for cooling-induced vasospasm? 6.Why is Raynaud's disease usually an inconvenience rather than a condition that precipitates ulceration and gangrene? 7.What is responsible for the color(s)of the affected fingers? 8.In what sense is the term vasospasm misleading?
SECTION I CELLULAR PHYSIOLOGY Raynaud's Disease A 32-year-old woman sees her family physician because of episodes of severe pain in her hands, associated with skin color changes and coldness of the hands. These attacks usually occurred during the winter and after exposure of the hands to cold. The physician precipitated one of these attacks by having the patient put her hands in a basin of cold water. At first the hands turned white, and this was associated with increasing pain of the fingers. Then the hands turned slightly cyanotic, followed rapidly by redness and throbbing discomfort. Gradually the pain disappeared, and the hands returned to normal color. The patient was told that she had Raynaud's disease and that she should avoid exposure of her hands to cold. 1. The ability of any muscle to generate force decreases with shortening below the optimum length for force generation. How can vascular smooth muscle contraction occlude an artery when the blood pressure opposing shortening remains at normal levels? 2. Do the mechanisms that regulate vascular smooth muscle activation precisely match blood flow to that needed to provide oxygen and substrates to the muscles of the fingers? 3. Would cooling affect muscle function in the fingers? 4. Is there anything about smooth muscle that would make it more temperature-sensitive than skeletal muscle? 5. Is an impaired ATP synthetic capacity and a form of rigor mortis a reasonable explanation for cooling-induced vasospasm? 6. Why is Raynaud's disease usually an inconvenience rather than a condition that precipitates ulceration and gangrene? 7. What is responsible for the color(s) of the affected fingers? 8. In what sense is the term vasospasm misleading?
9.What is responsible for the bright red color of the affected fingers after an attack? 10.What is the normal response of cutaneous blood vessels in the hand to warming or cooling? 11.What normally mediates the response of the cutaneous blood vessels to temperature? 12.Is it significant that individuals with Raynaud's disease often are susceptible to migraine headaches or angina? 13.What would be the effect of denervation of the cutaneous blood vessels of the hand? 14.Denervated cutaneous blood vessels slowly regain spontaneous tone.Is this attributable to reinnervation by sympathetic fibers? 15.Could vasospasm be caused by a loss of normal inactivation or vasodilator function rather than an enhanced constrictor response? ANSWER 1.Two principal factors make this possible.(1)The load on the smooth muscle is the tangential wall stress,and this falls as the radius decreases.(2)The vascular wall is essentially incompressible;hence,constriction leads to increased wall thickness and decreased lumen diameter. 2.No.Blood flow to the digits is important in temperature regulation and the cutaneous fraction of the total hand blood flow is relatively high.The vessels constrict rhythmically in the digits and the frequency decreases as the environment warms.The vascular system will shift blood flow to tissues with increased needs, such as working muscle.For example,blood flow to the leg muscles is increased during bicycle exercise but blood flow to the fingers is reduced. 3.Although core temperature is maintained during cold exposure,the temperature of the extremities will fall below 37 C.Enzymatic activity is highly temperature dependent;therefore all aspects of muscle function will be depressed
9. What is responsible for the bright red color of the affected fingers after an attack? 10. What is the normal response of cutaneous blood vessels in the hand to warming or cooling? 11. What normally mediates the response of the cutaneous blood vessels to temperature? 12. Is it significant that individuals with Raynaud's disease often are susceptible to migraine headaches or angina? 13. What would be the effect of denervation of the cutaneous blood vessels of the hand? 14. Denervated cutaneous blood vessels slowly regain spontaneous tone. Is this attributable to reinnervation by sympathetic fibers? 15. Could vasospasm be caused by a loss of normal inactivation or vasodilator function rather than an enhanced constrictor response? ANSWER 1. Two principal factors make this possible. (1) The load on the smooth muscle is the tangential wall stress, and this falls as the radius decreases. (2) The vascular wall is essentially incompressible; hence, constriction leads to increased wall thickness and decreased lumen diameter. 2. No. Blood flow to the digits is important in temperature regulation and the cutaneous fraction of the total hand blood flow is relatively high. The vessels constrict rhythmically in the digits and the frequency decreases as the environment warms. The vascular system will shift blood flow to tissues with increased needs, such as working muscle. For example, blood flow to the leg muscles is increased during bicycle exercise but blood flow to the fingers is reduced. 3. Although core temperature is maintained during cold exposure, the temperature of the extremities will fall below 37°C. Enzymatic activity is highly temperature dependent; therefore all aspects of muscle function will be depressed
4.Because crossbridge regulation by phosphorylation depends on the enzymes myosin kinase and myosin phosphatase,the events that link activation and contraction are potentially more temperature dependent in smooth muscle.Some smooth muscles (piloerector and cutaneous vascular smooth muscle)may be exposed to reduced temperatures because of their superficial location. 5.Lower temperatures would reduce the rates of ATP synthesis,but this would be offset by reduced rates of ATP consumption.Rigor mortis does not occur physiologically,and fatigue processes inhibit muscle contraction before ATP levels are reduced.Furthermore,the extraordinary high economy of force maintenance by vascular smooth muscle makes it comparatively insensitive to metabolic limitations. 6.The specific answer is uncertain,although glycolysis can provide ATP during a period of anoxia.However,sufficient circulation must be maintained to prevent cell death over longer periods.Intermittent or collateral circulation must meet the minimum requirements of the cooled tissues for survival. 7.Apart from skin pigments the color is mainly a function of the amount of blood in the cutaneous venous plexus.Coloration from red to blue is attributable to the degree of saturation of hemoglobin by oxygen in the red blood cells. 8.A spasm usually refers to a sudden,violent,involuntary and painful contraction of a muscle.However,a vasospasm is neither violent nor painful (although the downstream loss of flow may induce intense pain,as in a coronary vasospasm).In the absence of a skeleton,the muscle shortens to a length that occludes the vessel while it reduces the forces generated. 9.Interruption of flow is followed by reactive hyperemia:an elevation of flow above preocclusion levels,caused by accumulated vasodilator metabolites that relax vascular smooth muscle.Many vasodilators elevate cyclic nucleotide levels in smooth muscle cells. 10.As part of the body's thermoregulation mechanism,warming normally induces vasodilation,whereas cooling induces vasoconstriction.However,prolonged,severe cold leads to a secondary vasodilation
4. Because crossbridge regulation by phosphorylation depends on the enzymes myosin kinase and myosin phosphatase, the events that link activation and contraction are potentially more temperature dependent in smooth muscle. Some smooth muscles (piloerector and cutaneous vascular smooth muscle) may be exposed to reduced temperatures because of their superficial location. 5. Lower temperatures would reduce the rates of ATP synthesis, but this would be offset by reduced rates of ATP consumption. Rigor mortis does not occur physiologically, and fatigue processes inhibit muscle contraction before ATP levels are reduced. Furthermore, the extraordinary high economy of force maintenance by vascular smooth muscle makes it comparatively insensitive to metabolic limitations. 6. The specific answer is uncertain, although glycolysis can provide ATP during a period of anoxia. However, sufficient circulation must be maintained to prevent cell death over longer periods. Intermittent or collateral circulation must meet the minimum requirements of the cooled tissues for survival. 7. Apart from skin pigments the color is mainly a function of the amount of blood in the cutaneous venous plexus. Coloration from red to blue is attributable to the degree of saturation of hemoglobin by oxygen in the red blood cells. 8. A spasm usually refers to a sudden, violent, involuntary and painful contraction of a muscle. However, a vasospasm is neither violent nor painful (although the downstream loss of flow may induce intense pain, as in a coronary vasospasm). In the absence of a skeleton, the muscle shortens to a length that occludes the vessel while it reduces the forces generated. 9. Interruption of flow is followed by reactive hyperemia: an elevation of flow above preocclusion levels, caused by accumulated vasodilator metabolites that relax vascular smooth muscle. Many vasodilators elevate cyclic nucleotide levels in smooth muscle cells. 10. As part of the body's thermoregulation mechanism, warming normally induces vasodilation, whereas cooling induces vasoconstriction. However, prolonged, severe cold leads to a secondary vasodilation
11.Peripheral temperature receptors and the sympathetic nervous system mediate the response of cutaneous blood vessels to temperature.Also,cooled blood that reaches the anterior hypothalamus will produce reflex cutaneous vasoconstriction. Constriction of blood vessels is typically caused by increases in sympathetic nerve activity,whereas reduced sympathetic nerve activity is associated with vasodilation.The arteriovenous anastomoses prominent in the fingers and toes are entirely under neural control. 12.Because a precipitating cause of the three conditions is digital,cerebral, and coronary vasospasm,respectively,this "coincidence"suggests that there may be some generalized vascular abnormality.However,the digital vasculature has strong neural control,the coronary vessels less so,and the cerebral vessels negligible neural regulation.Hence a common factor is not obvious. 13.An acute vasodilation would be expected,because these vessels have an extensive sympathetic innervation and lack parasympathetic vasodilator fibers. Unlike skeletal muscle,smooth muscle can survive and maintain function after denervation. 14.Unlike denervated skeletal muscle,in which the motor nerve bodies remain intact and can grow from the severed axon and reinnervate cells,the cell bodies of fibers in the sympathetic ganglia would be destroyed by denervation procedures. The return of tone is probably caused by denervation hypersensitivity or supersensitivity to circulating catecholamines.These changes in sensitivity result from an increase in the number of receptors on the smooth muscle cells. Supersensitivity also occurs in denervated skeletal muscle cells,as receptors for acetylcholine are no longer limited to the motor end plate. 15.Yes.Tone is the balance between mechanisms that tend to increase myoplasmic Ca++and those that tend to reduce it.A loss of the latter would lead to vasospasm. Although cutaneous blood vessels do not have vasodilator nerves,they relax in response to circulating or locally produced metabolites or other vasodilators
11. Peripheral temperature receptors and the sympathetic nervous system mediate the response of cutaneous blood vessels to temperature. Also, cooled blood that reaches the anterior hypothalamus will produce reflex cutaneous vasoconstriction. Constriction of blood vessels is typically caused by increases in sympathetic nerve activity, whereas reduced sympathetic nerve activity is associated with vasodilation. The arteriovenous anastomoses prominent in the fingers and toes are entirely under neural control. 12. Because a precipitating cause of the three conditions is digital, cerebral, and coronary vasospasm, respectively, this "coincidence" suggests that there may be some generalized vascular abnormality. However, the digital vasculature has strong neural control, the coronary vessels less so, and the cerebral vessels negligible neural regulation. Hence a common factor is not obvious. 13. An acute vasodilation would be expected, because these vessels have an extensive sympathetic innervation and lack parasympathetic vasodilator fibers. Unlike skeletal muscle, smooth muscle can survive and maintain function after denervation. 14. Unlike denervated skeletal muscle, in which the motor nerve bodies remain intact and can grow from the severed axon and reinnervate cells, the cell bodies of fibers in the sympathetic ganglia would be destroyed by denervation procedures. The return of tone is probably caused by denervation hypersensitivity or supersensitivity to circulating catecholamines. These changes in sensitivity result from an increase in the number of receptors on the smooth muscle cells. Supersensitivity also occurs in denervated skeletal muscle cells, as receptors for acetylcholine are no longer limited to the motor end plate. 15. Yes. Tone is the balance between mechanisms that tend to increase myoplasmic Ca++ and those that tend to reduce it. A loss of the latter would lead to vasospasm. Although cutaneous blood vessels do not have vasodilator nerves, they relax in response to circulating or locally produced metabolites or other vasodilators