Decreased anandamide transporter activity and calcitonin gene-related peptide production in spontaneously hypertensive rats: role of angiotensin II

Abstract

In the present study, we investigated the role of angiotensin II in regulating the anandamide transporter activity and resultant calcitonin gene-related peptide (CGRP) production in spontaneously hypertensive rats (SHRs). Systolic blood pressure, plasma levels of anandamide, angiotensin II and CGRP, CGRP mRNA expression in dorsal root ganglion and anandamide transporter activity in peripheral blood lymphocytes were measured in SHRs treated with selective angiotensin II type 1 receptor antagonist losartan. Rat peripheral blood lymphocytes were isolated to examine the effect of exogenous angiotensin II on anandamide-induced CGRP mRNA expression, anandamide transporter activity and intracellular reactive oxygen species production in presence or absence of losartan and antioxidant n-acetyl-cysteine. In SHRs, the plasma level of angiotensin II and anandamide was elevated, but the anandamide transporter activity was attenuated concomitantly with decreased CGRP production. Treatment with losartan for 2weeks produced depressor effect, restored the reduced anandamide transporter activity, decreased the plasma anandamide level and increased the plasma level and mRNA expression of CGRP in SHRs. In cultured lymphocytes, up-regulation of CGRP mRNA expression by exogenous administration of anandamide was inhibited by anandamide transporter blocker and angiotensin II. Angiotensin II also inhibited the anandamide transporter activity concentration-dependently while increased intracellular reactive oxygen species production, which was reversed by pretreatment with losartan or n-acetyl-cysteine. The present findings suggest that angiotensin II plays a critical role in mediating the decrease in anandamide transporter activity and CGRP production in SHRs, which is likely due to activation angiotensin II type 1 receptor and resultant reactive oxygen species production.