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Involvement of the AT(2)-receptor in angiotensin II-induced facilitation of sympathetic neurotransmission
- Source :
- Journal of the renin-angiotensin-aldosterone system, 3(3), 181-187. SAGE Publications Ltd, Journal of the Renin-Angiotensin-Aldosterone System, Vol 3 (2002)
- Publication Year :
- 2002
-
Abstract
- 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.
- Subjects :
- Male
0301 basic medicine
Medicine (General)
Sympathetic nervous system
Sympathetic Nervous System
Pyridines
Tetrazoles
Blood Pressure
urologic and male genital diseases
Synaptic Transmission
Norepinephrine
chemistry.chemical_compound
0302 clinical medicine
Endocrinology
Diastole
Heart Rate
Renin
Receptor
Decerebrate State
Receptors, Angiotensin
Chemistry
Angiotensin II
Imidazoles
female genital diseases and pregnancy complications
medicine.anatomical_structure
medicine.drug
medicine.medical_specialty
Receptor, Angiotensin, Type 2
Receptor, Angiotensin, Type 1
Angiotensin Receptor Antagonists
03 medical and health sciences
R5-920
Irbesartan
Internal medicine
Internal Medicine
medicine
Animals
Rats, Wistar
Antihypertensive Agents
Angiotensin II receptor type 1
Dose-Response Relationship, Drug
Biphenyl Compounds
Antagonist
Electric Stimulation
Rats
030104 developmental biology
Blood pressure
Saralasin
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 14703203
- Volume :
- 3
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of the renin-angiotensin-aldosterone system
- Accession number :
- edsair.doi.dedup.....ea35b8ce88f3c7c3f594e91f8f1dcc40