Effect of AT1 Receptor Blockade on Expression of Genes for Type-1 Angiotensin II(AT1) Receptor Subtypes in Spontaneously Hypertensive Rats.

Abstract

To elucidate the genetic alterations of gene expression and regulation of the type 1 angiotensin II receptor (ATl), we measured the relative levels of mRNAs of AT1A receptor and AT1B receptor subtypes in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The effect of treatment with a selective AT1 receptor antagonist, TCV-116 (1 mg/kg/day for a week), on the levels of mRNAs of AT1 receptor subtypes was also studied. The relative levels of AT1A and ATiB receptor mRNAs in the adrenal gland, heart, aorta, and kidney were measured by a sensitive reverse transcriptase-polymerase chain reaction method. AT1A receptor mRNA was predominantly expressed in the heart and kidney, but ATiB receptor mRNA was dominant in the adrenal gland in both strains. AT1A and ATiB receptor mRNAs were equally expressed in the aorta. There were no significant differences between WKY and SHR in the levels of AT1A and ATiB receptor mRNAs except for aortic ATiB receptor mRNA, which was expressed less in SHR. There were no differences between WKY and SHR in the effect of an AT1 receptor antagonist, TCV-116, on the levels of AT1A and AT1B receptor mRNAs in those four organs. TCV-116 administration reduced the expression of AT1A receptor mRNA in the heart and aorta, and reduced the expression of ATiB receptor mRNA in the adrenal gland and heart. These results indicate that the expression of genes for AT1A and ATiB receptor subtypes is regulated in a tissue-specific manner in both strains. (Hypertens Res 1994; 17: 187-192) Key Words: spontaneously hypertensive rat, Wistar-Kyoto rat, type-1 angiotensin II receptor subtypes, polymerase chain reaction, type-1 angiotensin II receptor antagonist Angiotensin II (Ang II) is an important effector peptide of the renin-angiotensin system (RAS), and it exerts a wide variety of effects on target organs (1). Ang II interacts with distinct subtypes of cellsurface receptors, type-1 (AT1) and type-2 (AT2) receptors (2, 3). The AT1 receptor is a G-proteincoupled receptor that mediates the functions generally assigned to Ang II, whereas the function of the AT2 receptor remains uncertain (4). The AT1 receptor (AT1A receptor) cDNA has been cloned from bovine (5), rat (6, 7), and human tissues (8). In the rat, the second form of the AT1 receptor, the AT1B receptor, has been cloned from the adrenal gland (9). These two subtypes of AT1 receptors have very similar sequences (95% identity). Although AT1A and AT1B receptor genes are widely expressed in various rat tissues, the possible alteration of the AT1 receptor subtype gene expression in the genetic hypertensive rat remains to be determined (10-12).In the present study, we investigated the difference between Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in the expression levels of AT1A and AT1B receptor mRNAs in the adrenal gland, heart, aorta, and kidney using the reverse transcriptase polymerase chain reaction (RT-PCR) (13). Furthermore, we studied the effect of a specific non-peptide AT1 receptor antagonist, TCV-116, on the l...

Recognition of Tissue- and Subtype-Specific Modulation of Angiotensin II Receptors Using Antibodies agains AT1 and AT2 Receptors.

“…It is important to recognize tissue-specific expression of angiotensin receptors in order to understand their physiological role. The tissue-specific expression of AT1 and AT2 receptors recognized by immunological methods basically agrees with previous reports on mRNA expression (17,18) and the dominance of subtype-specific binding sites of angiotensins (19).…”

“…The suppression of AT1 receptor expression in the adrenal cortex by AT1 receptor antagonist or angiotensin-converting enzyme inhibitor is consistent with previous reports using binding assay of angiotensins (20). Wakamiya et al (18) reported suppression of AT1 receptor mRNA in the adrenal and heart of Wistar-Kyoto rats and spontaneously hypertensive rats after 7-d treatment with an AT1 receptor antagonist. It was demonstrated that 6-wk treatment with lisinopril, an ACE inhibitor, suppressed ATl receptor binding in the adrenal medul-l a, but losartan, an AT1 receptor antagonist, did not affect it (20).…”