Alpha 1-adrenergic system and arrhythmias in ischaemic heart disease.
Several lines of experimental evidence obtained over the last decade indicate that alterations in the alpha 1-adrenergic receptor system may contribute significantly to arrhythmogenesis in the ischaemic heart. Under normal physiological conditions, alpha 1-adrenergic stimulation of myocytes elicits a modest increase in inotropy, a lengthening of repolarization secondary to a decrease in IK through activation of protein kinase C, and a decrease in automaticity in Purkinje cells due to an increase in Na+/K+ ATPase activity. These findings suggest that alpha 1-adrenergic stimulation of the myocardium would elicit an antiarrhythmic effect. However, during both early ischaemia and reperfusion there is an enhanced responsivity to alpha-adrenergic stimulation and a potent antiarrhythmic effect of alpha 1-adrenergic blockade in several species including the conscious dog. This enhanced alpha-adrenergic responsivity may be due to an increase in alpha 1-adrenergic receptors in ischaemic myocardium originating from a site distinct from the intracellular site for trafficking of beta-adrenergic receptors, possibly within or near the sarcolemma. Recently, we developed an isolated adult canine ventricular myocyte preparation which also exhibits a 2- to 3-fold reversible increase in alpha 1-adrenergic receptors in response to severe hypoxia (PO2 = less than 15 mmHg) associated with marked sarcolemmal accumulation of long-chain acylcarnitines (LCA) secondary to hypoxia-induced inhibition of beta-oxidation of fatty acids. The increase in alpha 1-adrenergic receptors is prevented by inhibition of carnitine acyltransferase I which precludes accumulation of LCA. The sarcolemmal accumulation of LCA increases membrane fluidity, suggesting that the alpha 1-adrenergic receptor may be latent within or near the sarcolemma and becomes accessible to a surface ligand only as membrane fluidity is altered. This conclusion is also supported by our findings that hypoxia elicits a marked increase in the coupling of the alpha 1-adrenergic receptor to inositol 1,4,5-trisphosphate (IP3) production in canine myocytes exposed to norepinephrine. IP3 has been shown to mobilize Ca2+ from the sarcoplasmic reticulum, thereby modulating the levels of intracellular Ca2+. Stimulation of hypoxic myocytes with norepinephrine also results in the appearance of delayed after-depolarizations and triggered rhythms, probably in response to an increase in intracellular Ca2+. In conclusion, these findings indicate that the alpha 1-adrenergic system can contribute to arrhythmogenesis in the ischaemic heart and that approaches to reduce the incidence of sudden cardiac death should include blockade of alpha 1-adrenergic receptors.
Kurz
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T
Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63110.
Yamada
K A
KA
DaTorre
S D
SD
Corr
P B
PB
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology*; D004594:Electrophysiology; D006321:Heart / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology*; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*
D011942:Receptors, Adrenergic, alpha