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.

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

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, G_s, G_i, and G_q, have different functions in the regulation of cellular activity. The G_s protein complexes contain α_s subunits that stimulate adenylate cyclase when “activated” by adrenergic receptor interaction. These G_s complexes are primarily responsible for the stimulatory activity of β-adrenergic agonist agents. β₁– and β₂-adrenergic receptors interact primarily with β_s subunits in stimulatory G_s protein complexes. The α_i subunits of G_s proteins inhibit the activity of adenylate cyclase. Some β₂-adrenergic receptors and the α₂-adrenergic receptors interact with inhibitory G_i proteins to decrease the activity of adenylate cyclase. A third form, G_q, interacts with the α₁-adrenergic receptors but does not interact directly with adenylate cyclase. Instead, the G_q 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 α_s 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

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

The β₁– and β₂-receptors interact with G_s 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 G_s proteins, their clinical effects would appear to be paradoxical. However, there are 2 primary reasons for their different effects when G_s 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 G_s-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 G_i-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 G_i 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 G_s proteins and adenylate cyclase, the α₁-adrenergic receptors are associated with G_q 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

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 G_s 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 G_s 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

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

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.