Differences in Cardiovascular Responses to Alamandine in Two-Kidney, One Clip Hypertensive and Normotensive Rats

BACKGROUND: Alamandine is a newly discovered component of the renin-angiotensin system, which regulates blood pressure. In this study, the effect of alamandine on cardiovascular parameters in two-kidney, one clip (2K1C) hypertensive rats and normotensive rats, and the possible roles of the angiotensin II type 1 receptor (AT1R) and the PD123319-sensitive receptors in mediating this effect was investigated. METHODS AND RESULTS: The cardiovascular parameters were monitored for 10 min before the infusion of the drugs or saline, and for 30 min afterward. In the 2K1C hypertensive rats, alamandine caused brief increases in mean arterial pressure (MAP), left-ventricular systolic pressure (LVSP) and maximum rate of pressure change in the left ventricle (dP/dt(max)). This was followed by decreases in these parameters, which extended throughout the remainder of the infusion period. Losartan, an AT1R blocker, abolished alamandine's initial pressor effect and PD123319, which can block AT2R and Mas-related G protein-coupled receptor D (MrgD) receptors, partially decreased the late depressor effect. Left ventricular end-diastolic pressure (LVEDP) decreased during alamandine infusion; this effect was reduced by PD123319. In the normotensive rats, alamandine increased MAP, LVSP, dP/dt (max), and it decreased LVEDP during the infusion period. These effects of alamandine were reduced by losartan. CONCLUSIONS: The results of this investigation suggest that, under normal conditions, alamandine acts via AT1R, but in pathological conditions such as hypertension, its effect on PD123319-sensitive receptors masks its effect on AT1R.