SECTION I CELLULAR PHYSIOLOGY A8thms A 20-year-old woman with a long history of asthmatic attacks was rushed to the hospital emergency room because of severe respiratory distress.The current asthnatic attack failed to respond to the usual antihistanine drug that was self-administered.When seen by the emergency room physician.the woman was sitting up,obviously amxious,and desperately trying to breathe.She was slightly cyanotic, sweat ing.wheezing.and had a heart rate of 120 beats/min.She was given oxygen and epinephrine,and her symptons subsided considerably,although wheezing and crackling sounds were still audible by auscultation,and she was extremely fatigued. 1.What is the physical cause of the dyspnea (difficulty in breathing)and fatigue? 2.What factors might contribute to airway narrowing? 3.What causes the characteristic wheezing with inspiration and expiration? 4.Why is wheezing first observed during expiration at the onset of an asthmatic attack? 5.What are the kinds of stimuli that can influence airway smooth ruscle acti￥ation7 6.Why is spooth muscle an important component of the airways? 7.List the types of muscle involved in asthmatic attacks. 8.Does fatigue occur in all of the muscles imvolved in an asthmatic attack? 9.Would a drug that relaxes airway smooth muscle relieve an asthmatic attack if the drug was properly formulated as an inhalant? 10.Would a drug that was effective in reducing airway resistance by relaxing airway smooth muscle decrease pulmonary blood pressure? 11.Why would an asthmatic attack be associated with hyperinflated lungs?
SECTION I CELLULAR PHYSIOLOGY Asthma A 20-year-old woman with a long history of asthmatic attacks was rushed to the hospital emergency room because of severe respiratory distress. The current asthmatic attack failed to respond to the usual antihistamine drug that was self-administered. When seen by the emergency room physician, the woman was sitting up, obviously anxious, and desperately trying to breathe. She was slightly cyanotic, sweating, wheezing, and had a heart rate of 120 beats/min. She was given oxygen and epinephrine, and her symptoms subsided considerably, although wheezing and crackling sounds were still audible by auscultation, and she was extremely fatigued. 1. What is the physical cause of the dyspnea (difficulty in breathing) and fatigue? 2. What factors might contribute to airway narrowing? 3. What causes the characteristic wheezing with inspiration and expiration? 4. Why is wheezing first observed during expiration at the onset of an asthmatic attack? 5. What are the kinds of stimuli that can influence airway smooth muscle activation? 6. Why is smooth muscle an important component of the airways? 7. List the types of muscle involved in asthmatic attacks. 8. Does fatigue occur in all of the muscles involved in an asthmatic attack? 9. Would a drug that relaxes airway smooth muscle relieve an asthmatic attack if the drug was properly formulated as an inhalant? 10. Would a drug that was effective in reducing airway resistance by relaxing airway smooth muscle decrease pulmonary blood pressure? 11. Why would an asthmatic attack be associated with hyperinflated lungs?
12.In what ways can a drug or physiologic regulator acting on the sarcolemma of an airway smooth muscle bring about relaxation? ANSVER 1.Narrowing of the lumen of the airways inereases the resistance to air flow in and out of the lungs.and therefore increases the effort of the skeletal muscles involved in respiration. 2.Factors that contribute to airvay narrowing include the following: constriction of the smooth musele encireling the airvays,increased intrathoracic pressure that tends to compress the airvays.abnormal secretion of rucus,or an inflamatory response that increases capillary permeability and thus leads to mucosal edena. 3.Just as restricting the stem of a balloon causes turbulent air flow and the generation of sounds,airway narrowing is offset by respiratory efforts that increase the velocity of air flow and thus induce turbulence and wheezing. 4.Airvay lumen diameter is a balance betveen the force exerted by the airway smooth musele against a load and of the pressure gradient between the inside and outside of the airway.On inspiration the thorax is enlarged:this reduces the pressure on the outside of the airways and causes air to flow into the lungs.This also increases airway diameter somewhat and thus reduces the air flow resistance, turbulence.and wheezing.The pressure gradient across the wall reverses on expiration and narrows the airways.ligher flow rates result,and they cause turbulence and wheezing. 5.Smooth muscle contraction reflects a balance between excitatory (constrictor) and inhibitory (dilator)agents,including neurotransnitters,circulating hornones, locally produced hormomes,and drugs.These inputs may act directly on smooth musele cells or indirectly via actions on nerves or other cells associated with the snooth muscle.Of special inportance to the airways are airborne irritants or antigens, such as pollen,that aet on the airsay epithelia and can trigger asthmatic attacks
12. In what ways can a drug or physiologic regulator acting on the sarcolemma of an airway smooth muscle bring about relaxation? ANSWER 1. Narrowing of the lumen of the airways increases the resistance to air flow in and out of the lungs, and therefore increases the effort of the skeletal muscles involved in respiration. 2. Factors that contribute to airway narrowing include the following: constriction of the smooth muscle encircling the airways, increased intrathoracic pressure that tends to compress the airways, abnormal secretion of mucus, or an inflammatory response that increases capillary permeability and thus leads to mucosal edema. 3. Just as restricting the stem of a balloon causes turbulent air flow and the generation of sounds, airway narrowing is offset by respiratory efforts that increase the velocity of air flow and thus induce turbulence and wheezing. 4. Airway lumen diameter is a balance between the force exerted by the airway smooth muscle against a load and of the pressure gradient between the inside and outside of the airway. On inspiration the thorax is enlarged; this reduces the pressure on the outside of the airways and causes air to flow into the lungs. This also increases airway diameter somewhat and thus reduces the air flow resistance, turbulence, and wheezing. The pressure gradient across the wall reverses on expiration and narrows the airways. Higher flow rates result, and they cause turbulence and wheezing. 5. Smooth muscle contraction reflects a balance between excitatory (constrictor) and inhibitory (dilator) agents, including neurotransmitters, circulating hormones, locally produced hormones, and drugs. These inputs may act directly on smooth muscle cells or indirectly via actions on nerves or other cells associated with the smooth muscle. Of special importance to the airways are airborne irritants or antigens, such as pollen, that act on the airway epithelia and can trigger asthmatic attacks
6.Like the vascular systen,the airways comstitute an enornous network of connected tubes of various sizes.Smooth muscle is the effector cell that regulates airway dianeter and thus promotes the optimum flow of air to each part of the lung. Smooth ruscle constriction is also part of cough reflexes,as the increased velocity of air flow through narrowed airvays helps expel mcus or irritants. 7.Airway snooth muscle.the skeletal ruscles involved in inspiration and expiration (diaphragm and intercostal muscles).and the heart and vascular smooth muscle are all involved in transporting oxygen from the lungs to the working skeletal ruscles. 8 Fatigue occurs only in the skeletal muscles involved in inspiration and expiration.because their ATP comsumption rates,attr ibuted to erossbridge cycling. are very high because of the effort expended to overcome increased airvay resistance. The mscle fatigue can prevent sufficient ventilation to meet the increased oxygen need.The resulting fall in blood oxygen and increase in carbon dioxide can lead to respiratory failure.The ATP comsunption rates of srooth muscle are so ruch lover than those of skeletal muscle that fatigue does not occur. 9.Not necessarily.The airway epitheliu presents a barrier between the air and the smooth musele.Hence the drug would not be effective unless it can cross the barrier.A drug that acted on the epithelial cells to cause the production and release of a relaxing agent might be more offective.In practice an asthaatie attack is usually relieved in a few ninutes by drugs that are delivered in the inspired gas or intravenously and that directly or indirectly relax afrvay smooth muscle. 10.Assuming that the drug crosses the alveolar-capillary merbranes and reaches the vascular smooth muasele,the effect will depend on (1)the presence and density of receptors for the drug.and (2)whether receptor activation is inhibi tory (as in the airway smooth muscle)or excitatory.In the latter case the pulmonary blood pressure would increase,and the systenic hypoxemia may worsen.Side effects are common,and their occurrence and nature vill vary with the mode of administration of the drug
6. Like the vascular system, the airways constitute an enormous network of connected tubes of various sizes. Smooth muscle is the effector cell that regulates airway diameter and thus promotes the optimum flow of air to each part of the lung. Smooth muscle constriction is also part of cough reflexes, as the increased velocity of air flow through narrowed airways helps expel mucus or irritants. 7. Airway smooth muscle, the skeletal muscles involved in inspiration and expiration (diaphragm and intercostal muscles), and the heart and vascular smooth muscle are all involved in transporting oxygen from the lungs to the working skeletal muscles. 8. Fatigue occurs only in the skeletal muscles involved in inspiration and expiration, because their ATP consumption rates, attributed to crossbridge cycling, are very high because of the effort expended to overcome increased airway resistance. The muscle fatigue can prevent sufficient ventilation to meet the increased oxygen need. The resulting fall in blood oxygen and increase in carbon dioxide can lead to respiratory failure. The ATP consumption rates of smooth muscle are so much lower than those of skeletal muscle that fatigue does not occur. 9. Not necessarily. The airway epithelium presents a barrier between the air and the smooth muscle. Hence the drug would not be effective unless it can cross the barrier. A drug that acted on the epithelial cells to cause the production and release of a relaxing agent might be more effective. In practice an asthmatic attack is usually relieved in a few minutes by drugs that are delivered in the inspired gas or intravenously and that directly or indirectly relax airway smooth muscle. 10. Assuming that the drug crosses the alveolar-capillary membranes and reaches the vascular smooth muscle, the effect will depend on (1) the presence and density of receptors for the drug, and (2) whether receptor activation is inhibitory (as in the airway smooth muscle) or excitatory. In the latter case the pulmonary blood pressure would increase, and the systemic hypoxemia may worsen. Side effects are common, and their occurrence and nature will vary with the mode of administration of the drug
11.Because the resistance to air flow in expiration is greater than in inspiration (see answer to question 4),not all of the inspired air is exhaled in the initial phase of the attack.This further compromises ventilation and contributes to the dyspnea. 12.It might block and thereby inactivate the receptor site for one of the agemts that induce the contraction.Alternatively,the agent might activate a receptor that brings about relaxation by enhancing Cat+extrusion or sequestration.Sone drugs block sarcolemn Catt
11. Because the resistance to air flow in expiration is greater than in inspiration (see answer to question 4), not all of the inspired air is exhaled in the initial phase of the attack. This further compromises ventilation and contributes to the dyspnea. 12. It might block and thereby inactivate the receptor site for one of the agents that induce the contraction. Alternatively, the agent might activate a receptor that brings about relaxation by enhancing Ca++ extrusion or sequestration. Some drugs block sarcolemma Ca++