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Involvement of the AT2-receptor in angiotensin II-induced facilitation of sympathetic neurotransmission

Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands, J.C.Balt{at}amc.uva.nl

Marie-Jeanne Mathy

Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands

Alex Nap

Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands

Martin Pfaffendorf

Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands

Pieter A van Zwieten

Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands

Angiotensin II (Ang II) causes facilitation of sympathetic neurotransmission via prejunctionallylocated AT₁-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 AT₁-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 AT₂-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 AT₂blocker, PD 123319 (0.5 mg/kg +50 µg/kg/min). Additionally, the effect of the combined (non-selective) AT₁/AT₂-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 AT₁/AT₂blocker, 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 AT₂-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.

Key Words: PD 123319 • irbesartan • AT2- and AT1-receptor blockade • pithed rat • sympathetic neurotransmission

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Journal of Renin-Angiotensin-Aldosterone System, Vol. 3, No. 3, 181-187 (2002)
DOI: 10.3317/jraas.2002.039


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