A gastrointestinal-renal kaliuretic signaling axis has been proposed to regulate potassium excretion in response to acute potassium ingestion independent of the extracellular potassium concentration and aldosterone. Here we studied this presumed axis in 32 individuals in our clinical pharmacology unit while on a 20 mmol sodium and 60 mmol potassium diet. The serum potassium concentration, potassium excretion, aldosterone, and insulin were measured following either a 35 mmol oral potassium load, a potassium- and sodium-deficient complex meal, or a potassium-deficient complex meal plus 35 mmol potassium. This design allowed determination of the component effects on potassium handling of the meal and potassium load separately. The meal plus potassium test was repeated following aldosterone blockade with eplerenone to specifically evaluate the role of aldosterone. In response to the potassium-deficient meal plus 35 mmol potassium, the serum potassium did not increase but the hourly mean potassium excretion increased sharply. This kaliuresis persisted following aldosterone blockade with eplerenone, further suggesting independence from aldosterone. Thus, a gastrointestinal-renal kaliuretic signaling axis exists in humans mediating potassium excretion independent of changes in the serum potassium concentration and aldosterone. The implication of this mechanism is yet to be determined but may account for a significant component of potassium excretion following a complex potassium-rich meal.

Even mild elevation of blood pressure may be sufficient to activate the expression of adhesion molecules. Mechanisms other than the endothelial expression of adhesion molecules may be important in mediating the accelerated target organ injury produced by SHT in humans. Concentrations of soluble adhesion molecules and vWF may depend more strongly upon factors in the hypertensive microenvironment other than the absolute level of blood pressure.

The combination of an aldosterone receptor antagonist added to an angiotensin-converting enzyme inhibitor has been demonstrated to reduce cardiovascular and renal end points in hypertensive humans but can produce hyperkalemia in the common clinical setting of impaired renal function. We investigated the effects of dual therapy on acute and chronic potassium handling in hypertensive humans with renal impairment by conducting a randomized crossover clinical trial of 4 weeks of 40 mg lisinopril/25 mg spironolactone versus placebo in 18 participants with a glomerular filtration rate of 25 to 65 mL/min. Study end points, following an established protocol, were hourly determinations of dynamic renal potassium excretion (mmol/h) and serum potassium (mmol/L) after 35 mmol oral potassium challenge in addition to ambulatory potassium concentration. After 4 weeks, ambulatory potassium concentration was 4.87 mmol/L with lisinopril/spironolactone versus 4.37 with placebo (P<0.001). Lisinopril/spironolactone produced only a modest 0.44 mmol/h reduction in stimulated potassium excretion (P=0.03) but a substantial 0.67 mmol/L increase in serum potassium (P<0.001) in response to 35 mmol potassium; these findings are consistent with impaired extrarenal/transcellular potassium disposition. We found the increase in serum potassium after an oral potassium challenge to be a strong predictor of the increase in ambulatory potassium with lisinopril/spironolactone. Our study suggests that dual renin-angiotensin-aldosterone blockade may impair extrarenal/transcellular potassium disposition in addition to reducing potassium excretion in humans with renal impairment, and that acute changes in dynamic potassium handling are predictive of chronic changes in ambulatory potassium concentration with dual renin-angiotensin-aldosterone blockade.

Our results suggest a significant additive BP-lowering effect of DRSP/E2 on both systolic and diastolic BP in hypertensive postmenopausal women receiving ENA, consistent with an antimineralocorticoid effect. DRSP/E2, a HRT with antimineralocorticoid effects, could offer a novel potential mechanism for reducing cardiovascular end points in postmenopausal women.

The thiazide-sensitive sodium-chloride cotransporter (NCC;SLC12A3) is central to sodium and blood pressure regulation. Metabolic syndrome induces NCC upregulation generating sodium-sensitive hypertension in experimental animal models. We tested the role of NCC in sodium sensitivity in hypertensive humans with metabolic syndrome. Conversely, oral potassium induces NCC downregulation producing potassium-induced natriuresis. We determined the time course and magnitude of potassium-induced natriuresis compared with the natriuresis following hydrochlorothiazide (HCTZ) as a reference standard. We studied 19 obese hypertensive humans with metabolic syndrome during 13-day inpatient confinement. We determined sodium sensitivity by change in 24-hour mean systolic pressure by automated monitor from days 5 (low sodium) to 10 (high sodium). We determined NCC activity by standard 50 mg HCTZ sensitivity test (day 11). We determined potassium-induced natriuresis following 35 mmol KCl (day 13). We determined (1) whether NCC activity was greater in sodium-sensitive versus sodium-resistant participants and correlated with sodium sensitivity and (2) time course and magnitude of potassium-induced natriuresis following 35 mmol KCl directly compared with 50 mg HCTZ. NCC activity was not greater in sodium-sensitive versus sodium-resistant humans and did not correlate with sodium sensitivity. Thirty-five-millimoles KCl produced a rapid natriuresis approximately half that of 50 mg HCTZ with a greater kaliuresis. Our investigation tested a key hypothesis regarding NCC activity in human hypertension and characterized potassium-induced natriuresis following 35 mmol KCl compared with 50 mg HCTZ. In obese hypertensive adults with metabolic syndrome ingesting a high-sodium diet, 35 mmol KCl had a net natriuretic effect approximately half that of 50 mg HCTZ.