Histamine Contributes to Ischemia-Related Activation of Cardiac Spinal Afferents: Role of H1 Receptors and PKC

Abstract

Myocardial ischemia activates cardiac spinal afferents that transmit the nociceptive information leading to chest pain and elicit excitatory cardiovascular reflexes. Previous studies have shown that histamine is increased in coronary sinus blood during myocardial ischemia and that this autacoid stimulates abdominal visceral afferents. The present investigation evaluated the role of endogenous histamine in stimulation of ischemically sensitive cardiac spinal afferents. Nerve activity of single-unit cardiac afferents was recorded from the left sympathetic chain or rami communicans (T2–T5) in anesthetized cats. Sixty-four cardiac afferents were identified. Injection (5–30 μg/kg) of histamine into the left atrium (LA) stimulated 7 ischemically sensitive cardiac afferents resulting in a significant increase in their activity in a dose-dependent manner. Also, LA injection of histamine (10 μg/kg) stimulated 7 of 8 ischemically insensitive cardiac spinal afferents. Administrations of 2-(3-chlorophenyl)histamine (250 μg/kg, LA), a specific H1 receptor agonist and histamine (10 μg/kg, LA), stimulated 9 other ischemically sensitive cardiac afferents (0.48 ± 0.10 to 1.40 ± 0.20 imp/s). In contrast, dimaprit (500 μg/kg, LA), an H2 receptor agonist, stimulated only one of the 9 afferents and thus did not alter their overall activity (0.40 ± 0.09 to 0.54 ± 0.09 imp/s). ( R)α-Methyl-histamine (500 μg/kg, LA), an H3 receptor agonist, did not stimulate any of the 9 afferents. Pyrilamine (300 μg/kg, iv), a selective H1 receptor antagonist, attenuated the activity of 8 afferents during 5 min of ischemia from 3.32 ± 0.38 to 1.87 ± 0.28 imp/s and abolished the response of 9 other cardiac afferents to histamine. Finally, administration of PKC-(19–36) (30 μg/kg, iv), a selective inhibitor of protein kinase C, attenuated the response of 8 cardiac afferents to histamine by 32%. These data indicate that endogenous histamine contributes to activation of cardiac sympathetic afferents during myocardial ischemia through H1 receptors and that the action of histamine on these cardiac afferents is partially dependent on the intracellular PKC pathway.