Effect of the AT1-receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II-induced facilitation of sympathetic neurotransmission in the rat mesenteric artery.
The effect of the AT1-receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II (Ang II)-induced facilitation of noradrenergic neurotransmission was investigated in the isolated rat mesenteric artery under isometric conditions. Electrical field stimulation (2, 4, and 8 Hz) caused a frequency-dependent increase of contractile force. At stimulation frequencies of 2, 4, and 8 Hz, Ang 11 (10 nM) increased the stimulation-induced vasoconstrictor responses by a factor 4.8 +/- 0.9, 2.9 +/- 0.7, and 1.3 +/- 0.1, respectively (p < 0.05 compared with control for all frequencies). The enhancement could be concentration-dependently antagonized by losartan (1 nM-1 microM), irbesartan (0.1 nM-0.1 microM), and telmisartan (0.01 nM-0.01 microM). At a stimulation frequency of 2 Hz, the relation between stimulation-induced vasoconstrictor responses (in presence of Ang II 10 nM) and the concentration of the AT1-antagonists used could be described by linear regression. The order of potency concerning sympathoinhibition was telmisartan > irbesartan > losartan (p < 0.05 between linear regression lines). Contractile responses to exogenous noradrenaline were unaltered in the presence of Ang II 10 nM. We conclude that the facilitating effect of Ang II on noradrenergic neurotransmission is mediated by presynaptically located AT1-receptors. Conversely, this facilitating effect can be dose-dependently counteracted by blockade of these receptors. Sympathoinhibitory properties are likely to contribute to the therapeutic effect of AT1-blockers, in particular in conditions in which the sympathetic nervous system is activated, such as congestive heart failure and hypertension.
Balt
J C
JC
Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.
Mathy
M J
MJ
Nap
A
A
Pfaffendorf
M
M
van Zwieten
P A
PA
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000077405:Irbesartan; D019808:Losartan; D000077333:Telmisartan