Angiotensin II stimulation alters vasomotor response to adenosine in mouse mesenteric artery: role for A₁ and A_2B adenosine receptors

Abstract

BACKGROUND AND PURPOSEStimulation of the A 1 adenosine receptor and angiotensin II receptor type-1 (AT 1 receptor) causes vasoconstriction through activation of cytochrome P450 4A (CYP4A) and ERK1/2. Thus, we hypothesized that acute angiotensin II activation alters the vasomotor response induced by the non-selective adenosine receptor agonist, NECA, in mouse mesenteric arteries (MAs). EXPERIMENTAL APPROACHWe used a Danish Myo Technology wire myograph to measure muscle tension in isolated MAs from wild type (WT), A 1 receptor and A 2B receptor knockout (KO) mice. Western blots were performed to determine the expression of AT 1 receptors and CYP4A. KEY RESULTSAcute exposure (15 min) to angiotensin II attenuated the NECA-dependent vasodilatation and enhanced vasoconstriction. This vasoconstrictor effect of angiotensin II in NECA-treated MAs was abolished in A 1 receptor KO mice and in WT mice treated with the A 1 receptor antagonist DPCPX, CYP4A inhibitor HET0016 and ERK1/2 inhibitor PD98059. In MAs from A 2B receptor KO mice, the vasoconstrictor effect of angiotensin II on the NECA-induced response was shown to be dependent on A 1 receptors. Furthermore, in A 2B receptor KO mice, the expression of AT 1 receptors and CYP4A was increased and the angiotensin II-induced vasoconstriction enhanced. In addition, inhibition of K ATP channels with glibenclamide significantly reduced NECA-induced vasodilatation in WT mice. CONCLUSIONS AND IMPLICATIONSAcute angiotensin II stimulation enhanced A 1 receptor-dependent vasoconstriction and inhibited A 2B receptor-dependent vasodilatation, leading to a net vasoconstriction and altered vasomotor response to NECA in MAs. This interaction may be important in the regulation of BP. Abbreviations

Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1 receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K+ channels

“…A DMT (Danish Myo Technology A/S, Aarhus, Denmark) myograph system was used to perform muscle tension measurements as described previously [26]. After anesthetizing the mice with pentobarbital sodium (100 mg/kg, intraperitoneally), the mouse mesentery with intestines was carefully excised and placed in cold oxygenated and (5% CO2 and 95% O2) modified Krebs–Henseleit physiological salt solution (PSS, in mM: NaCl 120, NaHCO 3 25, KCl 4.7, KH 2 PO 4 1.2, CaCl 2 1.8, MgSO 4 1.2, glucose 15, and EDTA 0.05, pH 7.4).…”

“…Pharmacological inhibitors were used to study the role of CYP4A (HET0016 10 μM) and ERK1/2 (PD98059 1μM) [26]. The role of PKCα was studied by using GO6976 (1 μM) [25].…”

“…Moreover, in A 2A AR −/− mouse aorta, contraction occurred through CYP4A and ERK1/2 via upregulation of A 1 AR and PKCα [20]. We recently showed, in mouse mesenteric arteries (MAs), that, after acute angiotensin II stimulation, A 1 AR-dependent vascular contraction involved CYP4A and ERK1/2 [26]. Thus, it is likely that sEH modulates A 1 AR-dependent vascular contraction, which involves CYP4A, PKCα, and ERK1/2.…”

“…In A 2A AR −/− mouse aorta, higher A 1 AR expression [20] and reduced K ATP channel-dependent vascular relaxation were observed [29]. In mouse MAs, K ATP channels were involved in A 2B AR-dependent vascular relaxation [26]. Notably, in wild type (WT) mice, sEH inhibition resulted in enhanced A 2A AR-dependent aortic relaxation [21].…”

“…In mouse MAs, vascular contraction is A 1 AR-dependent, while A 2B AR is responsible for relaxation [26, 30]. Interestingly, A 2A AR has no functional role [26, 30], while A 2B AR-dependent vascular relaxation involves K ATP channels [26]. Similar to findings from A 2A R −/− mouse aorta [20], MAs from A 2B AR −/− mice showed higher A 1 AR expression [30].…”