α 1 - and α 2 -Adrenoceptor Control of Sodium Transport Reverses in Developing Hypertension

Abstract

Abstract —α-Adrenergic receptor (AR) activation enhances sodium retention in certain forms of hypertension. The objective of the present study was to understand the role of α-ARs in regulating sodium transport by distal tubules (DT). DT cells were isolated from kidneys of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 6 weeks, when hypertension is developing, or at 12 weeks, when hypertension is established. The α 1 -AR agonist phenylephrine increased 22 Na uptake by 50% into DT cells of 6-week SHR; no effect was observed with WKY cells. The α 2 -AR agonist B-HT 933 increased uptake by only 10%. At 12 weeks, the pattern of α-AR regulation was reversed: α 1 -AR–induced sodium uptake was only 15%, whereas α 2 -AR activation increased sodium uptake by 35% in SHR and WKY cells. α 1 -AR–induced sodium uptake in 6-week SHR cells was abolished by prazosin; α 2 -AR–stimulated sodium uptake was blocked by yohimbine in 12-week SHR and WKY. Competitive binding studies were performed with [ 3 H]prazosin and α 1A -, α 1B -, and α 1D -selective antagonists with DT cell membranes from 6- and 12-week SHR and WKY. α 2 -AR subtypes were determined with [ 3 H]rauwolscine and α 2A - and α 2B -selective antagonists. Expression of α 1B -ARs was increased 4-fold in DT cells during the developing phase of hypertension in SHR. No change was detected in α 2 -AR expression. DT cells transiently increase [Ca 2+ ] i in response to α 1 -AR agonists from 6-week but not 12-week SHR. Conversely, α 2 -AR agonists increase [Ca 2+ ] i at 12 weeks. In summary, during developing hypertension, α 1 -ARs increase sodium uptake and [Ca 2+ ] i in SHR cells. Expression of α 1B -ARs is selectively upregulated during developing hypertension. In established hypertension (and normotension), α 2 -ARs regulate sodium transport and [Ca 2+ ] i in DT cells. We conclude that a molecular switch of α 1 -AR and α 2 -AR signaling occurs in DT cells during the development of hypertension.