title: Involvement of the AT(2)-receptor in angiotensin II-induced facilitation of sympathetic neurotransmission.
abstract: Angiotensin II (Ang II) causes facilitation of sympathetic neurotransmission via prejunctionally-located AT(1)-receptors. The pithed rat is a suitable model to study the interactions between endogenously produced Ang II and the sympathetic nervous system at the peripheral level. Previously, we demonstrated that inhibition of the facilitatory actions of Ang II is a class effect of all AT(1)-receptor blockers (ARB). However, all ARBs caused less than maximal inhibition after the highest dose, thus causing a U-shaped dose-response curve with respect to sympatho-inhibition. In the present study, we investigated whether the AT(2)-receptor is involved in this upturn of the dose-response relationship. Accordingly, we studied the effect of the ARB, irbesartan (1 60 mg/kg), on the sequelae of electric stimulation of the thoraco-lumbar sympathetic outflow in the presence and absence of the AT(2)-blocker, PD 123319 (0.5 mg/kg +50 g/kg/min). Additionally, the effect of the combined (non- selective) AT(1)/AT(2)-receptor antagonist saralasin (0.001, 0.003, 0.01 or 0.03 mg/kg/min), on stimulation-induced responses was studied. In addition, we measured PRA-levels after administration of irbesartan, in this model. The stimulation-induced increase in diastolic blood pressure (DBP) could be dose-dependently reduced by irbesartan. Co-infusion with PD 123319 increased the sympatho-inhibitory potency of irbesartan, possibly through displacement of irbesartan from plasma protein binding sites. The U-shaped dose-response relationship observed with irbesartan, which is illustrative for other ARBs in this model, was not observed when PD 123319 was co-administered with irbesartan, nor with the non-selective AT(1)/AT(2)-blocker, saralasin. PRA-levels increased from 111.0+17.8 to 198.7+22.2 ng/ml/hour after administration of irbesartan. PRA-levels did not differ when measured after the three highest doses of irbesartan.
  
  
  CONCLUSIONS
  The present findings indicate a facilitatory role for the AT(2)-receptor, which is unmasked by the highest dose of irbesartan. Different plasma Ang II-levels are unlikely to have caused the less than maximal inhibition after the highest dose of irbesartan.
authors.affiliation: Department of Pharmacotherapy, University of Amsterdam, The Netherlands. J.C.Balt@amc.uva.nl
authors.forename: Jippe C
authors.initials: JC
authors.lastname: Balt
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Mathy
authors.forename: Alex
authors.initials: A
authors.lastname: Nap
authors.forename: Martin
authors.initials: M
authors.lastname: Pfaffendorf
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van Zwieten
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003655:Decerebrate State; D003971:Diastole; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006339:Heart Rate; D007093:Imidazoles / Q000494:pharmacology; D000077405:Irbesartan; D008297:Male; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology*; D012083:Renin / Q000097:blood; D012504:Saralasin / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D012083:Renin; D012504:Saralasin; D000077405:Irbesartan; D009638:Norepinephrine