CROSS-TALK BETWEEN ANGIOTENSIN AT(1) AND ALPHA(1)-ADRENERGIC RECEPTORS - ANGIOTENSIN-II DOWN-REGULATES ALPHA(1A)-ADRENERGIC RECEPTOR SUBTYPE MESSENGER-RNA AND DENSITY IN NEONATAL RAT CARDIAC MYOCYTES

Signaling mediated by the angiotensin (Ang) II and alpha(1)-adrenergic receptor (alpha(1)-AR) pathways is important for cardiovascular homeo stasis. However, it is unknown whether Ang II has any direct effect on alpha(1)-AR expression and signaling in cardiac myocytes. In the pres ent study, we determined alpha(1)-AR subtype mRNA levels by RNase prot ection; receptor density by competition binding with 5-methylurapidil; and alpha(1)-AR-mediated c-fos expression by Northern blot analysis. We found that Ang II had no effect on alpha(1b)- and alpha(1d)-AR mRNA levels but decreased the alpha(1)-AR mRNA level in a time- and dose-d ependent manner. The maximal effect occurred at 6 hours with 100 nmol/ L Ang II (40.0 +/- 8.2% reduction, n=4, P<.01). The decrease in alpha( 1a)-AR mRNA level induced by Ang II is mediated by the Ang II AT(1) re ceptor subtype and is associated with decreased stability of alpha(1a) -AR mRNA. Corresonding to the changes in the alpha(1a)-AR mRNA level, Ang II (100 nmol/L, 24 hours) reduced the density of high-affinity sit es for 5-methylurapidil (alpha(1A)-AR) by 29% (56.5 +/- 6.4 versus 79. 0 +/- 11.6 fmol/mg protein, n=4, P<.05). alpha(1)-AR-stimulated c-fos induction, which could be blocked by 5-methylurapidil but not by chlor oethylclonidine, was attenuated by Ang II preincubation (100 nmol/L, 2 4 hours). We conclude that there is previously undescribed cross talk between AT(1) receptors and alpha(1)-ARs. Ang II selectively downregul ates alpha(1a)-AR subtype mRNA and its corresponding receptor as well as alpha(1a)-AR-mediated expression of the immediate-early gene c-fos in cardiac myocytes.