AT ₂ Receptor Stimulation Increases Aortic Cyclic GMP in SHRSP by a Kinin-Dependent Mechanism

Abstract

Abstract-In the present study we tested the hypothesis whether an anglotensm AT, receptor-mediated stlmulatlon of the bradykmm (BK)/mtnc oxide (NO) system can account for the effects of AT1 receptor antagonism on aortlc cGMP described previously m SHRSP Adult SHRSP were treated for 4 hours with anglotensm II (ANG II) (30 rig/kg per mm IV) or vehicle (0 9% NaCl IV) Animals were pretreated with vehicle, losartan (100 mg/kg PO), PD 123319 (30 mg/kg IV), losartan plus PD 123319, lcatlbant (500 @g/kg IV), NG-mtro-L-argmme methyl ester (L-NAME, 1 mg/kg IV), or mmoxldll (3 mg/kg IV) Mean arterial blood pressure (MAP) was contmuouqly monitored over the 4-hour experlmental period, and plasma ANG II and aortlc cGMP were measured by RIA at the end of the study ANG II infusion over 4 hours raised MAP by about 20 mm Hg. Losartan alone or losartan plus ANG II '1s well as mmoxldll plus ANG II markedly reduced blood pressure when compared to vehicle-treated or ANG II-treated ammals, respectively Plasma levels of ANG II were increased 2-fold by ANG II mfuslon alone or by ANG II m combmallon with lcatlbant, L-NAME, or mmoxldll The increase m plasma ANG II levels was even more pronounced after losartan treatment Aortlc cGMP content was slgmficantly increased by ANG II, losartan, losartan plus ANG II, and mmoxldll plus ANG II by 60%, 45%, 68%, and 52%, respectively (P< 05) The effects of ANG II and of losartan plus ANG II on aortlc cGMP content were both blocked by cotreatment with the AT2 receptor antagonist PD 123319 Icatlbant and L-NAME abohshed the effects of ANG II on aortlc cGMP Our results demonstrate the followmg (1) ANG II increases aortlc cGMP by an AT, receptor-medlated action because the effect could be prevented by an AT1 receptor antagonist, (2) the effect of ANG II was not secondary to blood pressure increase because it remained under reduction of MAP with mmoxldll, (3) losartan increased aortlc cGMP most likely by increasing plasma ANG II levels with a subsequent stlmulatlon of AT, receptors, and (4) the effects of AT1 receptor stlmulatlon are mediated by BK and, subsequently, NO because they were abolished by B, receptor blockade as well as by NO synthase mhlbltlon of ANG II generation, but, m addition, also potentlate the effects of bradykmm (BK) by mhlbltlon of BK degradation ' Two major tools have been introduced m recent years to study the contnbutlon of BK to the cardiovascular actlons of ACE inhibitors first, the combined treatment with an ACE mhlbltor and with a specific BK B2 receptor antagonist such as lcatlbant, and second, the comparison of the effects of an ACE inhibitor with those of an AT, receptor antagonist which block the RAS without an interaction with kmm metabolism. With these approaches, several mvestlgators have demonstrated that a number of actions of ACE mhlbltors IS related to cardiovascular control can be blocked by B2 receptor antagonism and thus be related to kuuns ' For example, m a series of expenrnents our laboratory demonstrated that longterm treatment with ACE inhibitors improved ca...

The role of bradykinin, AT2 and angiotensin 1–7 receptors in the EDRF‐dependent vasodilator effect of angiotensin II on the isolated mesenteric vascular bed of the rat

“…BK seems to play an important role in the vascular effects of Ang II (Seyedi et al, 1995;Gohlke et al, 1998;Tsutsumi et al, 1999;Sosa-Canache et al, 2000;Katada & Majima, 2002). Probably, the vasodilator effect of Ang II in the rat MVB is modulated by BK mechanisms, since we showed that captopril enhanced the vasodilator effects of BK and Ang II.…”

Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan

“…Recent studies have shown that stimulation of the AT 2 receptor increases the production of bradykinin, PGE 2 and NO, leading to arteriolar vasodilation and suppression of cell growth and proliferation. [40][41][42][43] Therefore, the inability of ARBs to prevent kinin degradation in contradistinction to ACE inhibitors is compensated by their ability to increase kinin production through the AT 2 receptor. Although these actions are shared by all ARBs, telmisartan has the additional advantage of being longer acting and more efficacious with respect to its antihypertensive effects and to effectively suppress the rise of blood pressure during the early hours of the morning when it is needed the most.…”

Blocking the tissue renin-angiotensin system: the future cornerstone of therapy

“…Part of this effect may be due to an AT 2 -mediated stimulation of tissue nitric oxide (NO) and cGMP levels. 69 Despite the success of ACE inhibitors in the clinical management of cardiovascular disease, mortality remains high in patients with chronic heart failure. This may be due, in part, to the ACE-independent pathways for angiotensin II formation.…”