Angiotensin II induces catecholamine release by direct ganglionic excitation.
Angiotensin II (ANG) is known to facilitate catecholamine release from peripheral sympathetic neurons by enhancing depolarization-dependent exocytosis. In addition, a direct excitation by ANG of peripheral sympathetic nerve activity has recently been described. This study determined the significance of the latter mechanism for angiotensin-induced catecholamine release in the pithed rat. Rats were anesthetized and instrumented for measuring either hemodynamics and renal sympathetic nerve activity or plasma catecholamine concentrations in response to successively increasing doses of angiotensin infusions. Even during ganglionic blockade by hexamethonium (20 mg/kg), angiotensin dose-dependently elevated sympathetic nerve activity, whereas blood pressure-equivalent doses of phenylephrine were ineffective. Independently of central nervous sympathetic activity and ganglionic transmission, angiotensin (0.1 to 1 microg/kg) also induced an up-to 27-fold increase in plasma norepinephrine levels, reaching 2.65 ng/mL. Preganglionic electrical stimulation (0.5 Hz) raised basal norepinephrine levels 11-fold and further enhanced the angiotensin-induced increase in norepinephrine (4.04 ng/mL at 1 microg/kg ANG). Stimulation of sympathetic nerve activity and norepinephrine release were suppressed by candesartan (1 mg/kg) or tetrodotoxin (100 microg/kg), respectively. Angiotensin enhanced plasma norepinephrine, heart rate, and sympathetic nerve activity at similar threshold doses (0.3 to 1 microg/kg), but raised blood pressure at a significantly lower dose (0.01 microg/kg). It is concluded that direct stimulation of ganglionic angiotensin type 1 (AT(1)) receptors arouses electrical activity in sympathetic neurons, leading to exocytotic junctional catecholamine release. In both the absence and presence of preganglionic sympathetic activity, this mechanism contributes significantly to ANG-induced enhancement of catecholamine release.
Dendorfer
Andreas
A
Institute of Experimental and Clinical Pharmacology and Toxicology, Medical University of Luebeck, Luebeck, Germany. dendorfe@medinf.mu-luebeck.de
Thornagel
Alexandra
A
Raasch
Walter
W
Grisk
Olaf
O
Tempel
Klaus
K
Dominiak
Peter
P
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000378:metabolism*; D005730:Ganglionic Blockers / Q000494:pharmacology; D005731:Ganglionic Stimulants / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D018738:Hexamethonium / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000294:innervation; D008297:Male; D009638:Norepinephrine / Q000097:blood*; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology
D005730:Ganglionic Blockers; D005731:Ganglionic Stimulants; D000804:Angiotensin II; D018738:Hexamethonium; D009638:Norepinephrine