Cardiologic Principles II: Hemodynamics




INTRODUCTION



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Adequate tissue perfusion depends on maintenance of volume status, vascular resistance, cardiac contractility, and cardiac rhythm. All of these components of the hemodynamic system are vulnerable to the effects of xenobiotics. Cardiovascular toxicity is manifested by the development of hemodynamic instability, heart failure, cardiac conduction abnormalities, or dysrhythmias. The presence of a specific pattern of cardiovascular anomalies (toxicologic syndrome or “toxidrome”) often suggests a particular class or type of xenobiotic.



In addition, an alteration in hemodynamic functioning is frequently the indirect result of metabolic abnormalities. Poisoning with a xenobiotic often leads to development of acid–base disturbances, hypoxia, or electrolyte abnormalities with secondary hemodynamic changes. In these patients, supportive care with ventilation, oxygenation, and fluid and electrolyte repletion can dramatically improve the cardiovascular status.




PHYSIOLOGY OF THE CARDIOVASCULAR SYSTEM



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Maintaining cardiac contractility, heart rate and rhythm, and vascular resistance requires complex modulation of the cardiac and vascular systems. Xenobiotics cause hemodynamic abnormalities as a result of direct effects on the myocardial cells, the cardiac conduction system, or on the arteriolar smooth muscle cells. These effects are frequently mediated by interactions with cellular ion channels or cell membrane neurohormonal receptors. These complex cellular systems provide multiple sites for xenobiotics to demonstrate their toxicologic effects. Xenobiotics and xenobiotic metabolites interact with the cellular receptors, intracellular signal mechanisms, effector enzymes, or intracellular organelles.



Toxic effects of xenobiotics can be due to direct poisoning from excessive amounts of a xenobiotic that follow an overdose. Slower accumulation of the xenobiotic or active metabolites (due to alterations in metabolism) also leads to adverse effects. Additionally, the toxic effects of a xenobiotic can be altered by the characteristics of the host subject. Underlying medical conditions, presence of other xenobiotics, electrolyte abnormalities, concurrent acid–base, and hydration status contribute to the potential adverse hemodynamic effects of a xenobiotic. Even with a small concentration of a xenobiotic, hemodynamic toxicity may occur due entirely to underlying genetic differences in the cellular receptors or the intracellular signal transducers in the particular patient.



This complex interaction between the xenobiotic and patient’s physiology and genetic diversity is exemplified by the Brugada syndrome. This congenital cardiac channelopathy (Chaps. 15 and 57) predisposes to sudden cardiac death due to polymorphic ventricular tachycardia or ventricular fibrillation. Brugada syndrome is characterized by an atypical right bundle branch pattern with a characteristic cove-shaped ST segment elevation in leads V1 to V3 of the electrocardiogram (ECG) in the absence or structural heart disease, ischemia, or electrolyte disturbances).10,83 This typical type 1 Brugada ECG pattern is shown in Fig. 15-12. However, this distinctive ECG pattern can be covert30 and only unmasked by sleep, fever, bradycardia, or by xenobiotics such as vagotonic medications or class I antidysrhythmics (sodium channel blockers).4,59 The reason for this variable and dynamic response to xenobiotics is the heterogeneous genetic basis of the disorder. Mutations in each of 10 different genes have been linked to the Brugada syndrome; more than 300 different mutations have been identified in the SCN5A gene alone which encodes the α subunit of the cardiac sodium channel. Brugada syndrome is also associated with mutations in other cardiac ion channels and with mutations of the glycerol-3-phosphate 1-like (GDP1L) gene, which interacts with the cardiac sodium channel subunits at the cell membrane.5 The complexity of the potential xenobiotic interactions and variable potential for toxicity has lead to the establishment of a Web page (www.brugadadrugs.org) to provide up-to-date classification of xenobiotics into those to avoid, those to preferably avoid, and those to potentially use for treatment.11,59




AUTONOMIC NERVOUS SYSTEM AND HEMODYNAMICS



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In addition to the voltage-dependent ion channels, the cell membrane contains channels that open in response to receptor binding of neurotransmitters or neurohormones.60,61 The hemodynamic effects of many xenobiotics are mediated by interactions with membrane receptors and by changes in the autonomic nervous system. The autonomic nervous system is functionally divided into the sympathetic (ie, adrenergic) and parasympathetic (ie, cholinergic) systems. The 2 systems, which share certain common features, function semi-independently of each other. The sympathetic nervous system is primarily responsible for the maintenance of arteriolar tone and cardiac inotropy and chronotropy through the release of norepinephrine and epinephrine. The parasympathetic nervous system opposes the sympathetic nervous system and reduces overall cardiovascular response such as through vagal nerve innervation of the heart, resulting in reduced heart rate. Through complex feedback, the 2 systems provide the balance needed for existence under changing external conditions.



Adrenergic Receptors



Cellular Physiology of Adrenergic Receptors



The effects of adrenergic xenobiotics on the cell are primarily mediated through a secondary messenger system of cyclic adenosine monophosphate (cAMP). The intracellular cAMP concentration is regulated by the membrane interaction of 3 components: the adrenergic receptor, a G-protein complex, and adenylate cyclase, the (enzyme that synthesizes cAMP in the cell.)13,27,76,77 These receptors are described in detail in Chapter 13.



The G proteins serve as “signal transducers” between the receptor molecule in the cell membrane and the effector enzyme, adenylate cyclase, in the cytosol. The G proteins consist of 3 subunits: α, β, and γ.17,54,55 The α subunit of a G protein complex binds to the adrenergic receptor in the cell membrane and to the adenylate cyclase enzyme. The G protein complex exists in several isomeric forms, depending on their interactions with adenylate cyclase. These forms, Gs, Gi, and Gq, have different functions in the regulation of cellular activity. The Gs protein complexes contain αs subunits that stimulate adenylate cyclase when “activated” by adrenergic receptor interaction. These Gs complexes are primarily responsible for the stimulatory activity of β-adrenergic agonist agents. β1– and β2-adrenergic receptors interact primarily with βs subunits in stimulatory Gs protein complexes. The αi subunits of Gs proteins inhibit the activity of adenylate cyclase. Some β2-adrenergic receptors and the α2-adrenergic receptors interact with inhibitory Gi proteins to decrease the activity of adenylate cyclase. A third form, Gq, interacts with the α1-adrenergic receptors but does not interact directly with adenylate cyclase. Instead, the Gq interacts with phospholipase C to mediate the cell response to α1-adrenergic stimulation.



The G protein complex is composed of the cellular receptor and the 3 subunits, α, β, and γ, which are involved in the cellular response to catecholamines. In the absence of a catecholamine at the receptor site, the receptor protein is bound to the β and β-γ–dimer of the G protein, and guanosine diphosphate (GDP) is bound to the α subunit. Catecholamine binding to the receptor causes a conformational change in the α subunit; GDP dissociates and guanosine triphosphate (GTP) binds to the α subunit. The α subunit (with GTP bound) then dissociates from the receptor and from the β-γ–dimer. This “activated” α subunit then interacts with adenylate cyclase or other effector enzymes. Interaction of the αs subunit with adenylate cyclase increases the activity of the enzyme, resulting in a rapid increase in the intracellular cAMP (Fig. 16–1).13,17,45,54




FIGURE 16–1.


Binding of the β-adrenergic agonist to the β receptor of a myocardial cell causes the Gs protein to activate AC to produce cAMP. The cAMP interacts with and activates PKA. Subsequent phosphorylation by PKA changes the activity of multiple other various cellular proteins, including phospholamban, calcium channels, and troponin, all of which increase the activity of the myocardial cell. Refer to the text for more details. AC = adenylate cyclase; cAMP = cyclic adenosine monophosphate; Cav-L = L-type voltage-dependent calcium channel; PKA = protein kinase A; RyR = ryanodine receptor; SR = sarcoplasmic reticulum.





Cyclic AMP acts as a secondary messenger in the cell. Cyclic AMP interacts with protein kinase A (PKA) and other cAMP-dependent protein kinases to increase their protein phosphorylating activity.44 In the absence of cAMP, PKA is a tetramer of 2 regulatory and 2 catalytic subunits. Cyclic AMP binds to the regulatory subunits to release the active enzymatic units from the tetramer (Fig. 16–1). The activated protein kinases then transfer phosphate groups from ATP to serine (as well as to threonine and tyrosine amino acid groups) on enzymes that are involved in intracellular regulation and activities. Phosphorylation increases or decreases the activity of specific enzymes, and specific protein kinases are highly selective in the proteins that they phosphorylate.73,74



Protein kinase A phosphorylates a variety of cellular proteins involved in Ca2+ regulation, including the voltage-sensitive Ca2+ channel, phospholamban, and troponin,31,32,72 which are involved in the regulation and control of cellular muscle fiber contraction. Phosphorylation of the L-type calcium channel increases the entry of Ca2+ ions into the cell during membrane depolarization.58 Phosphorylation of phospholamban decreases its ability to inhibit the calcium ATPase pump on the sarcoplasmic reticulum (SR). Decreased inhibition of the calcium ATPase pump on the SR increases the efficiency of Ca2+ storage in the SR, which enhances both the cellular contractility as the Ca2+ is released into the cell cytosol and the relaxation of muscle fibers as the Ca2+ is pumped back into the SR.58



Physiologic Effects of Adrenergic Receptor Subclasses



The existence of 2 types of adrenergic receptors, α and β, was first proposed in 1948 to explain both the excitatory and the inhibitory effects of catecholamines on different smooth muscle tissue.1 The α receptor was subsequently subdivided into α1 and α2 when norepinephrine and other α-adrenergic agonists were found to inhibit the release of additional norepinephrine from neurons into the synapse. The α1-adrenergic receptors are located on postsynaptic cells outside the central nervous system, primarily on blood vessels, and mediate arteriolar constriction. The “autoregulatory” α2-adrenergic receptors are primarily located on the presynaptic neuronal membrane and, when stimulated, decrease release of additional norepinephrine into the synapse. Additionally, some α2-adrenergic receptors are also found on the postsynaptic membrane in the central nervous system. Activation of these postsynaptic α2-receptors in the cardiovascular control center in the medulla and elsewhere in the central nervous system decreases sympathetic outflow from the brain. Thus, α2-adrenergic agonists generally decrease peripheral vascular resistance, decrease heart rate, and decrease blood pressure. The α1– and α2-adrenergic receptors also interact with circulating catecholamines and other sympathomimetics. The effects of sympathomimetics vary in the different organ systems as a result of differences in the adrenergic receptors and in the cellular responses to the receptor interactions.



The β-adrenergic receptors are subclassified into 3 subtypes: β1, β2, and β3 (Table 16–1). The most prevalent β-adrenergic subtype in the heart is β1 (80%), although β2 (20%) and β3 (few) receptors are also present.9,20,26,60 Stimulation of the β1-adrenergic receptors increases heart rate, contractility, conduction velocity, and automaticity. The β2-adrenergic receptors primarily cause relaxation of smooth muscle with resulting bronchodilation and arteriolar dilation. The β3 receptors are located primarily on adipocytes, where they play a role in lipolysis and thermogenesis.14 With normal aging and in the setting of heart failure, a decline in β-adrenergic responsiveness referred to as “β-adrenergic desensitization” occurs. This process is believed to be due to a decrease in β1-adrenergic receptor density in cardiac myocytes, alterations in signaling of G-proteins and kinase activity, and an increase in baseline circulating plasma norepinephrine and epinephrine levels.22,81




TABLE 16–1Types and Function of the β-Adrenergic Receptors



The β1– and β2-receptors interact with Gs proteins and stimulate the adenylate cyclase enzyme. Differences in the resultant clinical effects are primarily related to the location and number of the different receptors in different tissues and to differences in the specificity of the tissue protein kinases activated by cAMP. Stimulation of the β1-adrenergic receptor results in increased heart rate and increased contractility. β2-Adrenergic receptor stimulation causes relaxation, as opposed to contraction, of smooth muscle. Because both β-adrenergic receptor subtypes interact with stimulatory Gs proteins, their clinical effects would appear to be paradoxical. However, there are 2 primary reasons for their different effects when Gs complexes are stimulated by β1– or β2-adrenergic agonists. First, PKA is not a single enzyme, but a group of related enzymes variably expressed in different tissues.8,35,56 The actions and the substrates of the varied protein kinase enzymes differs between β1– and β2-adrenergic responsive tissues. Second, whereas β1-adrenergic stimulation results in cAMP-mediated effects throughout the cytoplasm, β2-adrenergic stimulation is compartmentalized within the cell. The effect of β2-adrenergic stimulation of Gs-type receptors is primarily localized phosphorylation of the L-type calcium channels, increasing their activity.16,39,84,85 Additionally, some β2-adrenergic receptors are also coupled to Gi-type receptors that inhibit adenylate cyclase and prevent the diffuse cytoplasmic increases in cAMP.69,70,85 Also, β2-adrenergic receptor stimulation does not result in phosphorylation of phospholamban42 or troponins.16



The α2-adrenergic receptor interacts with a Gi protein that has an inhibitory interaction with adenylate cyclase. Binding of α2-adrenergic agonists to the receptor inhibits (not stimulates) adenylate cyclase and decreases intracellular cAMP.



The α1-adrenergic receptors also are associated with G proteins. However, rather than being associated with Gs proteins and adenylate cyclase, the α1-adrenergic receptors are associated with Gq proteins that are linked to phospholipase C.75 Agonist binding to the receptor activates the hydrolysis of phosphatidyl inositol 4,5-bisphosphate (PIP2) to 1,2-diacylglycerol (DAG) and inositol triphosphate (IP3).29 The IP3 acts as an intracellular messenger, binds to receptors on the SR, and initiates the release of calcium ion.6 1,2-Diacylglycerol activates protein kinase C, which phosphorylates slow Ca2+ channels and other intracellular proteins, and increases the influx of Ca2+ ion into the cell (Fig. 16–2).62,68,87




FIGURE 16–2.


Binding of the α-adrenergic agonist to the α1-adrenergic receptor causes the Gq protein to activate PLC. PLC catalyzes the hydrolysis of PIP to produce DAG and IP3. IP3 interacts with the RyR on the sarcoplasmic reticulum to enhance release of Ca2+ from this cellular store. The Ca2+ and DAG activate protein kinase C, which phosphorylates and changes the activity of various cellular proteins, including phospholamban. Refer to the text for more details. Cav-L = L-type voltage-dependent Ca2+ channel; DAG = 1,2-diacylglycerol; IP3 = inositol triphosphate PIP = 4,5-bisphosphate; PLC = phospholipase C; RyR = ryanodine receptor.





Many xenobiotics interact with G-protein membrane receptors and alter the intracellular cAMP or Ca2+ concentration. β-Adrenergic antagonist overdose results in decreased stimulation of adenylate cyclase by Gs proteins, decreased production of cAMP, decreased activation of the cAMP-dependent kinases, and decreased Ca2+ release (Chap. 59). Similarly, by different mechanisms, Ca2+ channel blocker overdose results in decreased cytoplasmic [Ca2+] concentration (Chap. 60).



Glucagon receptors, which resemble β-adrenergic receptors, are coupled to the same Gs proteins as β-adrenergic receptors and thus stimulate adenylate cyclase activity.28,86 The ability of glucagon to increase cAMP is further enhanced by its inhibitory activity on phosphodiesterase (preventing cAMP breakdown).21,51 Phosphodiesterase inhibitors, such as amrinone, milrinone, and enoximone, exert at least some of their inotropic activity by preventing the degradation of cAMP and enhancing calcium cycling.46,79,82 In a canine model of propranolol poisoning, amrinone significantly increased inotropy, stroke volume, and cardiac output.46




INTRACELLULAR CALCIUM, CALCIUM CHANNELS, AND MYOCYTE CONTRACTILITY



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The contraction and relaxation cycle of the myocyte is controlled by the flux of Ca2+ into and out of the SR into the cytoplasm of the cell.18,43,63 Only a small proportion of the Ca2+ involved in myofibril contraction actually enters the cell through the exterior cell membrane during the action potential and membrane depolarization. Most of the Ca2+ is actually released from the SR of the cell invaginations of the myocyte membrane known as T-tubules, which place L-type Ca2+ channels in close approximation to calcium-release channels (ryanodine receptors {RyR}) on the sarcoplasmic reticulum. The local increase in Ca2+ concentration that follows the opening of a single L-type calcium channel triggers the opening of the associated RyR channels, resulting in a large release of Ca2+ from the SR.15 Myocytes contain tens of thousands of couplons, clusters of L-type calcium channels and RyR channels. The Ca2+ released from one couplon is not sufficient to trigger firing of neighboring couplons. Therefore, myocyte contraction requires synchronized release of Ca2+ from numerous couplons throughout the myocyte. The cell membrane depolarization synchronizes opening of L-type channels and subsequent Ca2+ release from the sarcoplasmic reticulum.19,58 This phenomenon of Ca2+-induced Ca2+ release results in a rapid increase in the intracellular [Ca2+] and initiates a rapid myosin and actin interaction.18



At the conclusion of cellular contraction, SR-associated Ca2+-adenosine triphosphatase (ATPase) pumps return the cytosolic Ca2+-ATPase into the SR. This SR-associated Ca2+-ATPase pump is regulated by phospholamban, a cellular protein. When phospholamban is bound to the Ca2+-ATPase pump, the activity of the pump is decreased and less Ca2+-ATPase is stored in the SR. Phosphorylation of phospholamban decreases its affinity for binding to the Ca2+-ATPase pump. Dissociation of the phosphorylated phospholamban increases the activity of the Ca2+-ATPase pump. β-Adrenergic stimulation increases protein kinase activity and leads to phosphorylation of phospholamban, dissociation of the phosphorylated phospholamban from the pump, and an increase in the total SR Ca2+ stores.24,25 The increased activity of the SR associated Ca2+-ATPase pump enhances the contractility and increases the rate of relaxation of the myocytes.



Cellular contraction occurs when myosin filaments interact with the actin-tropomyosin helix. A complex of troponins T, I, and C binds to the actin helix near the myosin-binding site and act as regulators of the interaction. Troponin T binds the regulatory complex to the actin helix, troponin I prevents myosin from accessing its binding site on the actin helix, and troponin C acts as a Ca2+ trigger to initiate contraction. When the intracellular [Ca2+] increases, 4 molecules of Ca2+ bind to troponin C and a conformational shift occurs in the troponin complex. Troponin I shifts away and the myosin-binding site is exposed. Myosin then binds to the exposed site and myofibril contraction occurs (Fig. 16–3).36,37,64,65




FIGURE 16–3.


Troponin regulation of actin and myosin interaction. On the left, TnI blocks the binding site for myosin on the tropomyosin–actin helix. On the right, Ca2+ binding to TnC causes a conformational shift in the troponin molecules, and myosin binds to the actin helix and initiates myofibril contraction. TnC = troponin C; TnI = troponin I; TnT = troponin T.





Calcium transport through the cellular membrane ion channels is critical for normal cardiac muscle function and contractility and for maintenance of vascular smooth muscle tone. The physiologic response to Ca2+ channel blockers and to xenobiotics that interact with the α- or β-adrenergic receptors is mediated through changes in the intracellular Ca2+ concentration. Calcium channel blockers in current clinical use primarily block the L-type Ca2+ channel, although their specificity differs for the Ca2+ channels on the vascular smooth muscle cells versus on the myocardial cells. Dihydropyridine Ca2+ channel blockers preferentially act on peripheral vascular smooth muscle cells, whereas non-dihydropyridine Ca2+ channel blockers exert stronger central effects. This results in variable effects of the different Ca2+ channel blockers on the vascular tone and peripheral vascular resistance, and on the contractility and electrical activity of the myocardial cells.

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Nov 19, 2019 | Posted by in ANESTHESIA | Comments Off on Cardiologic Principles II: Hemodynamics
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