Interactions between the renin-angiotensin system (RAS) and the sympathetic system.
Angiotensin II is able to modulate both the presynaptic sympathetic system and the adrenal medulla resulting in an enhanced release of noradrenaline and adrenaline. Consequently, the inhibition of the converting enzyme by ACE inhibitors resulting in a lower concentration of angiotensin II or blockade of the specific AT1 receptors by AT1 receptor blocking agents should lead to a decrease in both noradrenaline and adrenaline release. It has been demonstrated that ACE inhibition did not influence the net catecholamine overflow during stimulation of the sympathetic nerves in contrast to AT1 antagonists which can specifically and dose dependently diminish noradrenaline and adrenaline release, an effect that could be explained by a compensating mechanism of bradykinin. Bradykinin may accumulate during ACE inhibition and is able to stimulate catecholamine release via B2 receptors. To verify the class effect of AT1 antagonists on presynaptic AT1 receptors, the AT1 antagonist candesartan was investigated regarding its presynaptic effect in pithed spontaneously hypertensive rats. As could be demonstrated with losartan and HR 720, candesartan lowered AT1 receptor mediated angiotensin II-induced noradrenaline release in a dose-dependent manner. It is concluded that AT1 antagonists inhibit angiotensin II mediated catecholamine release on presynaptic sympathetic nerves and the adrenal medulla at the specific AT1 receptor site. The effect can be described as a class effect of these imidazole derivatives.
Dendorfer
A
A
Department of Pharmacology, Medical University of Lübeck, Germany.
Raasch
W
W
Tempel
K
K
Dominiak
P
P
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011945:Receptors, Angiotensin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; C094626:fonsartan; D000804:Angiotensin II; D019808:Losartan; C081643:candesartan; D009638:Norepinephrine