Adequate tissue perfusion depends on maintenance of volume status, vascular resistance, cardiac contractility, and cardiac rhythm. The components of the hemodynamic system are vulnerable to the effects of xenobiotics. Cardiovascular toxicity may therefore be 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") may suggest a particular class or type of xenobiotic. Conduction and rhythm disturbances are discussed in detail in Chapter 22.
An alteration in hemodynamic functioning may be a result of indirect metabolic effects. Poisoning with a xenobiotic may lead to hemodynamic changes secondary to the development of acid base disturbances, hypoxia, or electrolyte abnormalities. In these patients, supportive care with ventilation, oxygenation, and fluid and electrolyte repletion will usually improve the cardiovascular status
Maintaining cardiac contractility, heart rate and rhythm, and vascular resistance requires complex modulation of the cardiac and vascular systems. Xenobiotics can cause hemodynamic abnormalities as a result of direct effects on the myocardial cells, on 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. Ion channels are discussed in detail in Chapter 22.
The Autonomic Nervous System and Hemodynamics
In addition to the voltage dependent ion channels, the cell membrane contains channels that open in response to receptor binding of neurotransmitters or neurohormones.42,43,44 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 two systems, which share certain common features, function semi-independently of each other. Through complex feedback, the two systems provide the balance needed for existence under changing external conditions.
The sympathetic nervous system is primarily responsible for the maintenance of arteriolar tone and cardiac function. Although the ganglionic neurotransmitter of the sympathetic nervous system is acetylcholine, norepinephrine is its primary postganglionic neurotransmitter. On release into the synapse, norepinephrine binds to the postsynaptic adrenergic receptors to elicit an effect by the postsynaptic cell.
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 three components: the adrenergic receptor, a "G-protein" complex, and adenyl cyclase, the enzyme that synthesizes cAMP in the cell.7,19,59,60 These receptors are described in detail in Chap. 13.
The G protein serves as a "signal transducer" between the receptor molecule in the cell membrane and the effector enzyme, adenyl cyclase, in the cytosol. The G proteins consist of 3 subunits:α, β, and γ.11,37,38 The α subunit ...