Angiotensin II AT2 receptor stimulation increases cerebrovascular resistance during hemorrhagic hypotension in rats.
The effects of the angiotensin II (ANG II) AT2 ligand PD 123319 and the AT1 antagonist losartan on cerebral blood flow (CBF) were studied during hemorrhagic hypotension in anesthetized rats using laser-Doppler flowmetry. In the control group CBF remained stable when mean arterial blood pressure (MABP) was lowered from 84 mmHg (baseline) to 45 mmHg, whereafter there was a pressure dependent decrease in CBF indicating inadequacy of autoregulation. Cerebrovascular resistance (CVR) was reduced until MABP 40 mmHg, where a maximum dilation was reached. PD 123319 dose-dependently (3-30 mg/kg i.v.) increased CVR through all blood pressures. Losartan 3 mg/kg i.v. had an effect similar to PD 123319. Selective stimulation of AT2 receptors with intravenous ANG II infusion, in the presence of AT1 receptor blockade by losartan, also increased CVR. As a result, reduced CBF was seen in the treatment groups. The effects of ANG II and PD 123319 30 mg/kg were antagonized by the nonselective ANG II antagonist Sar1,Ile8-ANG II (4 micrograms/kg/min i.v.). None of the treatments affected baseline CBF. The results confirm that ANG II contributes to cerebrovascular resistance and participates in the regulation of CBF apparently through AT2 receptors.
Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892.
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Näveri
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Strömberg
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Saavedra
D000704:Analysis of Variance; D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002540:Cerebral Cortex / Q000098:blood supply* / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D007022:Hypotension / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D017078:Laser-Doppler Flowmetry; D019808:Losartan; D008297:Male; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; C009210:sarleucin; D019808:Losartan