No involvement of the AT2-receptor in angiotensin II-enhanced sympathetic transmission in vitro.
Angiotensin II (Ang II) enhances sympathetic neurotransmission via AT(1)-receptors located on sympathetic nerve terminals. We recently demonstrated that inhibition of Ang II-mediated facilitation in the pithed rat by irbesartan resulted in a U-shaped dose response curve, which was not observed when PD 123319, at a concentration that selectively blocks the AT(2)-receptor, was co-administered. Hence, the irbesartan-mediated  upstroke  might be explained by the involvement of the AT(2)-receptor after AT(1) blockade with high-dose irbesartan. In the present study, we further investigated the possible role of the AT(2)-receptor in Ang II-mediated facilitation in vitro. We studied the effect of the AT(2)-receptor antagonist PD 123319 (10 nM) on Ang II-enhanced sympathetic outflow evoked by electrical field stimulation (EFS) in the rat isolated inferior vena cava. Additionally, we investigated the effect of the AT(1)-receptor blocker irbesartan (0.1 nM 1  M) on the sequelae of Ang II-enhanced, EFS-evoked sympathetic nerve traffic in the presence or absence of PD 123319 (10 nM). PD 123319 did not influence Ang II-enhanced sympathetic outflow. Irbesartan dose-dependently attenuate Ang II-augmented transmitter release (pIC50 7.99+0.03), whereas no U-shaped concentration-response relationship for irbesartan was observed. Co-administration of PD 123319 with irbesartan proved unable to influence Ang II-mediated facilitation differently compared with irbesartan alone. The experimental observations indicate that the AT(2)-receptor is not involved in Ang II-mediated enhancement of sympathetic nerve traffic in the present in vitro study.
Nap
Alexander
A
Department of Pharmacotherapy, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands. a.nap@amc.uva.nl
Balt
Jippe C
JC
Pfaffendorf
Martin
M
Zwieten
Pieter A van
PA
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D004357:Drug Synergism; D004558:Electric Stimulation; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D000077405:Irbesartan; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D014316:Tritium; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014682:Vena Cava, Inferior / Q000294:innervation
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D014316:Tritium; D000804:Angiotensin II; C073402:PD 123319; D000077405:Irbesartan