ACTH-induced hypertension is dependent on the ouabain-binding site of the α₂-Na⁺-K⁺-ATPase subunit

Abstract

-ACTH-inducedhypertension is commonly employed as a model of stress-related hypertension, and despite extensive investigation, the mechanisms underlying elevated blood pressure (BP) are not well understood. We have reported that ACTH treatment increases tail-cuff systolic pressure in wild-type mice but not in mutant mice expressing ouabainresistant ␣ 2-Na ϩ -K ϩ -ATPase subunits (␣2 R/R mice). Since tail-cuff measurements involve restraint stress, the present study used telemetry to distinguish between an effect of ACTH on resting BP vs. an ACTH-enhanced stress response. We also sought to explore the mechanisms underlying ACTH-induced BP changes in mutant ␣2 R/R mice vs. wild-type mice (ouabain-sensitive ␣ 2 -NaS/S mice). Baseline BP was not different between the two genotypes, but after 5 days of ACTH treatment, BP increased in ␣2 S/S (104.0 Ϯ 2.6 to 117.7 Ϯ 3.0 mmHg) but not in ␣2 R/R mice (108.2 Ϯ 3.2 to 111.5 Ϯ 4.0 mmHg). To test the hypothesis that ACTH hypertension is related to inhibition of ␣2-Na ϩ -K ϩ -ATPase on vascular smooth muscle by endogenous cardiotonic steroids, we measured BP and regional blood flow. Results suggest a differential sensitivity of renal, mesenteric, and cerebral circulations to ACTH and that the response depends on the ouabain sensitivity of the ␣ 2-Na ϩ -K ϩ -ATPase. Baseline cardiac performance was elevated in ␣2 S/S but not ␣2 R/R mice. Overall, the data establish that the ␣2-Na ϩ -K ϩ -ATPase ouabain-binding site is of central importance in the development of ACTH-induced hypertension. The mechanism appears to be related to alterations in cardiac performance, and perhaps vascular tone in specific circulations, presumably caused by elevated levels of circulating cardiotonic steroids.

Arterial α2-Na+pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific α2mice

“…Furthermore, ␣ 2 CV-KO mice are resistant to adrenocorticotropic hormone-induced hypertension, an EO-dependent form of hypertension (10), as expected for mice with no arterial ouabain-sensitive ␣ 2 -Na ϩ pumps (10,30). In contrast, the BP in mice with a reduced, but finite, number of these pumps (vs. WT control mice) should be elevated under conditions that raise plasma EO, such as ANG II and HS (5,6,15), as observed in ␣ 2 SM-DN mice (Fig.…”

“…Indeed, prolonged ouabain administration induces hypertension in rodents (11,12,34). Furthermore, genetically engineered mice with ouabain-resistant ␣ 2 -Na ϩ pumps (␣ 2 R/R ) are resistant to adrenocorticotropic hormone-induced hypertension (10,30) and ouabain-induced hypertension (11). In addition, ␣ 2 R/R dams have unusually low BP during late pregnancy (38).…”

Activation of c-SRC underlies the differential effects of ouabain and digoxin on Ca2+ signaling in arterial smooth muscle cells

“…Moreover, digoxin is an effective antihypertensive in the OH rat (24,29,39), and Digitalis preparations have antihypertensive actions in some patients with essential hypertension (1). As the opposing effects of these CTS on long-term BP are not explained by differences in their ability to inhibit ␣2 Na ϩ pumps, the hypertensinogenic action of ouabain involves binding to ␣2 Na ϩ pumps (14,15,37) followed by the specific triggering of a co-related signaling event.…”

Nanomolar ouabain increases NCX1 expression and enhances Ca2+signaling in human arterial myocytes: a mechanism that links salt to increased vascular resistance?

“…human artery; ␣ 2-Na ϩ pumps; ouabain; Na/Ca exchanger-1; sarco-(endo)plasmic reticulum Ca 2ϩ -ATPase; receptor-operated channels THE ROLE OF SALT IN THE PATHOGENESIS of human essential hypertension is widely accepted, but the specific mechanisms by which salt elevates blood pressure (BP) are still poorly understood (28). Numerous studies link hypertension in rodents to elevated plasma endogenous ouabain (EO), an adrenocortical hormone (6,24,30), and to Na ϩ pumps with high affinity for ouabain (12,38,61). Increased expression and function of arterial myocyte Na/Ca exchanger-1 (NCX1) and cation channels with C-type transient receptor potential (TRPC) subunits are also involved (7,17,25,34,49,66).…”

“…Mice with mutant, ouabain-resistant, but otherwise normally functional, ␣ 2 -Na ϩ pumps (13) are resistant to ouabain-induced (14) and ACTH-induced forms of hypertension (12,38). These effects are likely mediated by ASMC ␣ 2 -Na ϩ pumps because smooth muscle-specific reduction of ␣ 2 -Na ϩ pump expression causes BP elevation (9,62).…”