Angiotensin II Hypertension Provokes Potassium Depletion (p 904)
Renal tubule Na-Cl cotransporter (NCC) plays key roles in potassium homeostasis and blood pressure control. Potassium depletion raises NCC transport activity to reduce Na+ delivery downstream to the epithelial sodium channel where Na+ reabsorption drives K+ secretion, associated with higher blood pressure; conversely, potassium-rich diets reduce NCC activity and increase epithelial sodium channel–driven K+ secretion associated with lower blood pressure. Experimental angiotensin II (AngII) hypertension is considered an excellent model of essential hypertension because most patients respond to ACE inhibitors that block AngII production or angiotensin receptor blockers. AngII infusion activates NCC by phosphorylation (NCCpT53, NCCpS71) and epithelial sodium channel by cleavage. Veiras et al, in this issue of Hypertension, discovered that AngII infusion also increases K+ excretion and lowers plasma [K+] in rats revealed during an overnight fast. Doubling K+ intake to normalize K+ homeostasis during AngII (AngII+2K versus AngII+1K) prevented NCC activation establishing this phenotype as secondary to K+ depletion rather than to AngII stimulation. The findings reinforce NCC as a key regulator of K+ homeostasis and the benefits of a K+-rich diet. Because most hypertensive patients have intrarenal or systemic renin–angiotensin system activation, K+-rich diets should be considered to prevent K+ depletion and reverse NCC activation (unless hyperkalemia is evident); on the contrary, an NCC-inhibiting thiazide diuretic may exacerbate K+ loss and have little effect on blood pressure in the setting of renin–angiotensin system activation. Ideally, treatments targeting renin–angiotensin system inhibition (ACE inhibitor, angiotensin receptor blockers) combined with K+-rich diets should be considered if plasma [K+] can be maintained within normal limits.
Vascular ADAM17 Mediates Organ Damage by Angiotensin II (p 949)
Optimally treated hypertensive patients still have a significantly greater risk than normotensive subjects, suggesting the urgent need of add-on therapy to specifically target end-organ damage (but not hypertension). Cardiovascular remodeling has been strongly implicated in end-organ damage and associated with poor cardiovascular outcomes. Therefore, the critical factors required for hypertensive vascular remodeling if identified will significantly contribute to the development of new therapies to reduce mortality of hypertensive patients. A metalloproteinase, ADAM17, cleaves proforms of epidermal growth factor receptor ligands and is involved in transactivation of the epidermal growth factor receptor and subsequent hypertrophic responses by angiotensin II in vitro. In mice, angiotensin II induces ADAM17 expression and epidermal growth factor receptor activation mainly in the vasculature. In genetically modified mice lacking ADAM17 in vascular smooth muscle cells, we showed that angiotensin II–induced cardiovascular remodeling is attenuated without affecting hypertension. To further support the role of ADAM17 as a potential therapeutic target for hypertensive end-organ damage, we showed that a human cross-reactive ADAM17 inhibitory monoclonal antibody, A9B8 (Figure), prevents vascular remodeling (vascular hypertrophy and perivascular fibrosis) but not hypertension in wild-type mice. Taken together with the reported ADAM17 polymorphism linking to cardiovascular mortality and our past pharmacological study showing epidermal growth factor receptor inhibition prevents angiotensin II–induced cardiovascular remodeling in mice; these preclinical findings strongly suggest that an ADAM17 inhibitor could be a new add-on therapy for hypertensive patients to prevent hypertensive end-organ damage and reduce cardiovascular mortality.
Orthostatic Hypotension in ACCORD (p 888)
Orthostatic hypotension (OH) occurs when sympathetic activity fails to maintain arterial blood pressure (BP) during the act of standing from a seated or supine position. The most widely accepted definition of OH is a decline of systolic BP ≥20 mm Hg or a decline of diastolic BP ≥10 mm Hg within 3 minutes of standing. Although diabetes mellitus, hypertension, and antihypertensive medications are all associated with OH, the relationship between OH and BP control in people with type II diabetes mellitus is unclear. We investigated OH in the ACCORD-BP trial, a randomized, controlled trial designed to test the effect of aggressive (<120 mm Hg) versus standard (<140 mm Hg) systolic BP targets on major cardiovascular events in 4622 participants with diabetes mellitus, hypertension, or prehypertension, and at least 1 additional cardiovascular risk factor. Approximately 20% of this ACCORD cohort had OH at one or more visit, although most instances resolved by the next visit. There was no difference in the incidence or prevalence of OH between treatment groups, and prevalence was lower during follow-up than at the baseline examination. Demographics, current smoking, seated systolic BP, hemoglobin A1c, and use of α-blockers, β-blockers, and insulin were associated with OH. Occurrence of OH was a marker for total mortality and heart failure death or hospitalization but not myocardial infarction, stroke, cardiovascular death, or their composite.
- © 2016 American Heart Association, Inc.