Nonpeptide Angiotensin AT₁ and AT₂ Receptor Ligands Modulate the Upper Limit of Cerebral Blood Flow Autoregulation in Rats

Abstract

Summary:We investigated the effect of angiotensin AT! and AT2 receptor blockade on the upper limit of CBF autoregulation in pentobarbital-anesthetized rats. CBF was measured by laser-Doppler flowmetry from the pari etal cortex and MABP was increased by intravenous phenylephrine infusion. Neither the AT! antagonist 10-sartan nor the AT2 ligand PD 123319 nor angiotensin II (ANG II) in the presence of losartan affected baseline CBF. When the blood pressure was increased in the con trol group, CBF remained fairly constant up to 145 mm Hg and increased steeply after 150 mm Hg. Both PD 123319 (7-10 mglkg) and losartan (1-10 mglkg) shifted the upper limit of CBF autoregulation toward higher presAngiotensin II (ANG II) is a key regulator of car diovascular function. On the basis of displacement with selective ligands, ANG II receptors have been classified in AT) and AT2 subtypes (Chiu et aI., 1989; Whitebread et aI., 1989 298sures. Intravenous infusion of PD 123319 was more ef fective than bolus injection. The losartan effect was dose dependent. Selective stimulation of AT 2 receptors with an intravenous ANG II infusion (0.54 J.Lg/min) in the pres ence of losartan did not reverse the effect of losartan on CBF autoregulation, but, on the contrary, appeared to further shift the upper limit of autoregulation toward higher pressures. The results implicate a role for both AT I and AT 2 angiotensin receptors in the regulation of CBF.

Effect of nephrectomy and captopril on autoregulation of cerebral blood flow in rats

“…By contrast, the angiotensin II AT2 antagonist PD-123319 in our laboratory did not influence the lower limit of autoregulation in SHR (5). Other studies of the effect of the AT1 antagonist losartan and PD-123319 have given somewhat contradictory results, and it is possible that these antagonists may display angiotensin receptor agonist activity (15,25,26).…”

“…Blockade of the reninangiotensin system by angiotensin-converting enzyme (ACE) inhibitors, e.g., captopril (2, 3, 30), shifts both the lower and upper limits of CBF autoregulation toward lower blood pressure, possibly by releasing angiotensin II-mediated tone in the larger cerebral resistance vessels (21), with a contribution of bradykinin accumulation (27). Angiotensin II subtype 1 (AT1) receptor antagonists and agonists also shift the limits of CBF autoregulation (15,26,33). Modulation of the angiotensin II AT2 receptors appears to have limited influence on CBF autoregulation (5, 15, 26).…”

“…ceptor antagonists and agonists also shift the limits of CBF autoregulation (15,26,33). Modulation of the angiotensin II AT2 receptors appears to have limited influence on CBF autoregulation (5,15,26).…”

“…Modulation of the angiotensin II AT2 receptors appears to have limited influence on CBF autoregulation (5,15,26).…”

No effect of angiotensin II AT2-receptor antagonist PD 123319 on cerebral blood flow autoregulation

“…Thus, Strömberg and co-workers showed that PD 123319 and losartan, an ARB, both shifted the upper limit of CBF autoregulation towards higher BP. 6,7 They suggested that stimulation of the AT 2 -receptor causes vasoconstriction, and that vasodilation is mediated through the AT 1 -receptor. According to these studies, PD 123319 functions as an agonist at the AT 2 -receptor, causing vasoconstriction, and losartan acts as an antagonist at the AT 1 -receptor, also causing vasoconstriction, resulting in a shift of the upper limit of autoregulation towards higher BP.…”