Possible Involvement of Calcium-Calmodulin Pathways in the Positive Chronotropic Response to Angiotensin II on the Canine Cardiac Sympathetic Ganglia

Abstract

ABSTRACT-We investigated the ganglionic effects of angiotensin II (Ang II) and the signal transduction involved in the cardiac sympathetic ganglia by the direct administration of agents to the ganglia through the right subclavian artery and monitoring the heart rate as an indicator of the ganglionic function in pithed dogs. Ang II given i.a. caused increases in the heart rate, which was inhibited by the treatment with the AT1-receptor antagonist forasartan, but not by the AT 2-receptor antagonist PD-123319. The stimulation by Ang II, but not by acetylcholine, was inhibited after treatment with an inhibitor of phospholipase C, U-73122; a cellpermeant modulator of the Ins(1,4,5)P3 receptors, 2-aminoethoxydiphenyl borate; an intracellular calcium and calcium-associated protein kinase inhibitor, HA-1077; calmodulin (CaM) inhibitor, W-7; Ca 2+ /CaMdependent protein kinase II inhibitor, KN-93; a selective protein kinase C inhibitor, calphostin C; and Na + -H + exchange inhibitor, dimethylamiloride. These results suggest that Ang II stimulates the ganglionic transmission at postsynaptic sites via the activation of AT1 receptor coupled to either activation of phospholipase C, phosphoinositide hydrolysis and subsequent increase in intracellular Ca 2+ and activation of protein kinase C and Ca 2+/ CaM kinase II, although this ganglionic stimulation seems to involve, at least in part, the protein kinases-dependent increase of amiloride-sensitive Na + inflow.

Dual mechanisms of angiotensin‐induced activation of mouse sympathetic neurones

“…Do ganglionic actions of Ang II significantly increase postganglionic sympathetic nerve activity in vivo ? Ang II administered after ganglionic blockade increases postganglionic sympathetic nerve activity, plasma noradrenaline concentration, heart rate and cardiac contractility (Aiken & Reit, 1968; Farr & Grupp, 1971; Knape & van Zwieten, 1988; Ma et al 2001 a ; Tokunaga et al 2001; Dendorfer et al 2002). Our earlier work defined the direct ganglionic actions of Ang II as evoking low‐amplitude, continuous discharge of renal sympathetic nerves (Ma et al 2001 a ).…”