EFFECTS OF INHALED ANESTHETICS ON BRONCHOMOTOR TONE
Transient increases in airway resistance may be caused, at least
in part, by an increase in bronchiolar smooth muscle tone. Retrospective reviews
found that patients without recent symptoms of asthma had a very low frequency of
perioperative respiratory complications,[1]
yet
perioperative bronchospasm developed in approximately 6% of patients with asthma.
[2]
[3]
Prospective
studies have demonstrated that 1.7% of patients with asthma experienced a severe
respiratory outcome[4]
and that 25% wheezed after
the induction of anesthesia.[5]
Of the 40 cases
of bronchospasm resulting in settled malpractice claims (from the American Society
of Anesthesiologists Closed Claims Project),[5A]
88% involved brain damage or death, and only half of these patients had a history
of asthma or chronic obstructive pulmonary disease. Significant bronchospasm may
occur in normal subjects without underlying lung disease as a result of exposure
to a noxious stimulus. Understanding the physiologic effects of inhaled agents on
bronchial smooth muscle is clinically important.
Pharmacology of Bronchial Smooth Muscle
Mougdil[6]
and Pinto-Pereira
and coworkers[7]
summarized the mechanisms by which
increases in airway resistance
might occur. Airway smooth muscle extends as far distally as the terminal bronchioles
and is affected by autonomic nervous system activity and nonadrenergic noncholinergic
mechanisms. Parasympathetic nerves located in the vagi mediate baseline airway tone
and reflex bronchoconstriction. Changes in intracellular calcium (ICa2+
)
levels and Ca2+
influx may be caused by alterations in cyclic nucleotides
within bronchial smooth muscle. Agonist-induced contraction is mediated by an increase
in myosin light chain kinase activity, phosphorylation of the 20-kd regulatory myosin
light chain, and an increase in Ca2+
sensitivity.[8]
Exogenous administration of acetylcholine or stimulation of the vagus nerve increases
the relative amount of cyclic guanosine monophosphate (cGMP) compared with cyclic
adenosine monophosphate (cAMP) and results in bronchial smooth muscle contraction.
Agonist activation of bronchial smooth muscle cells also involves the second messenger
cyclic adenosine diphosphate ribose (cADPR), which indirectly releases Ca2+
from the sarcoplasmic reticulum by activating ryanodine channels.[9]
Agonist-induced stimulation of particulate guanylyl cyclase relaxes bronchial smooth
muscle by decreasing Ca2+
current. In contrast, stimulation of soluble
guanylyl cyclase by substances such as nitric oxide (NO) reduces intracellular Ca2+
concentration and Ca2+
sensitivity.[10]
Release of histamine in the airway or various forms of mechanical
or chemical stimulation may increase afferent vagal activity to produce reflex bronchoconstriction.
This increase in bronchomotor tone is attenuated by the cholinergic antagonist atropine.
M2
and M3
muscarinic receptors on airway smooth muscle receptors
mediate bronchoconstriction by increasing Ca2+
sensitivity.[11]
Presynaptic M2
muscarinic receptors have also been identified that inhibit
acetylcholine release and cause bronchodilation. Low doses of drugs that preferentially
inhibit M2
receptors (e.g., ipratropium bromide) may paradoxically produce
bronchoconstriction.[12]
Adrenergic receptors in bronchial smooth muscle are classified
into α and β2
types. The α-receptors have been characterized
in the bronchial tree in humans, but the activity of these receptors appears to be
clinically insignificant. In contrast, the β2
-receptor subtypes
play an important role in bronchiolar smooth muscle responsiveness. Stimulation
of β2
-receptors causes relaxation that is mediated by a relative
increase in intracellular cAMP concentration. It appears that asthma, allergic,
and methacholine-induced bronchospasm are not genetically linked to a dominant β2
-adrenoceptor
gene.[13]
Respiratory epithelium releases substances that modulate bronchial
smooth muscle tone. Removal of epithelium enhances contractile responses to acetylcholine,
histamine, or serotonin in large airways and decreases relaxation responses to isoproterenol
in small airways.[14]
[15]
These actions are analogous to the effect of endothelial damage on vascular smooth
muscle tone. However, porcine bronchiolar epithelium-mediated bronchomotor activity
is not significantly affected by cardiopulmonary bypass, in contrast to vascular
endothelium-mediated smooth muscle dysfunction.[16]
Endogenous epithelial factors have been identified, but endothelium-derived relaxing
factor (i.e., NO) may play a role in respiratory epithelium similar to that of vascular
endothelium. Endothelin-1 is one such potent endogenous bronchoconstrictor that
functions by activation of the inositol triphosphate (IP3
) pathway.[17]
