Effects of ANG II on bradykinin receptor gene expression in cardiomyocytesand vascular smooth muscle cells

Bradykinin has vasodilatory and tissue-protective effects exerted via its B -2 type receptor, whereas the B-1 receptor is constitutively absent but ind ucible by inflammation and toxins. In previous studies, we found that B-2 r eceptor gene knockout mice exhibit overexpression of the B-1 receptor, whic h assumes a vasodilatory function and is further upgraded in renovascular h ypertension. The present study was designed to explore the effects of exces s angiotensin II (ANG II) on B-1 receptor and B-2 receptor gene expression in mouse cardiomyocytes and rat vascular smooth muscle cells (VSMC) in vivo (after a 3-day infusion of 30 ng/min ANG II in 11 wild-type and in 13 gene tically engineered mice with deleted B-2 receptor gene) and in vitro (ANG I I added in rat VSMC culture in the presence or absence of AT(1) or AT(2) re ceptor antagonist), Expression of B-1 and B-2 receptor mRNA was assessed by reverse transcriptase-polymerase chain reaction. ANG II infusion caused up regulation by 30% of the already significantly overexpressed B-1 receptors in cardiomyocytes of the B-2 receptor gene knockout mice, but in the wild-t ype mice it upregulated only the B-2 receptor mRNA by 47%. The addition of ANG II in VSMC culture produced a time-dependent induction of B-1 and upreg ulation of B-2 receptor gene expression, maximal at 3 h (by fivefold), decl ining almost to baseline by 24 h. The addition of losartan completely, bloc ked this effect, whereas the AT(2) blocker PD-123319 made no difference, in dicating that this is an AT(1)-mediated effect of ANG II. The data indicate that excess ANG II in subpressor doses in vivo upregulates expression of t he B-2 receptor, but in its absence, the already overexpressed B-1 receptor is further upregulated, evidently assuming a counterregulatory response; i n vitro, it transiently upregulates both bradykinin receptors.