Characterization of Potassium-Induced Natriuresis in Hypertensive Postmenopausal Women During Both Low and High Sodium Intake.

BACKGROUND: Potassium-induced natriuresis may contribute to the beneficial effects of potassium on blood pressure but has not been well-characterized in human postmenopausal hypertension. We determined the time course and magnitude of potassium-induced natriuresis and kaliuresis compared with hydrochlorothiazide in 19 hypertensive Hispanic postmenopausal women. We also determined the modulating effects of sodium intake, sodium-sensitivity, and activity of the thiazide-sensitive NCC (sodium-chloride cotransporter). METHODS: Sixteen-day inpatient confinement: 8 days low sodium followed by 8 days high sodium intake. During both periods, we determined sodium and potassium excretion following 35 mmol oral KCl versus 50 mg hydrochlorothiazide. We determined sodium-sensitivity as change in 24-hour systolic pressure from low to high sodium. We determined NCC activity by standard thiazide-sensitivity test. RESULTS: Steady-state sodium intake was the key determinant of potassium-induced natriuresis. During low sodium intake, sodium excretion was low and did not increase following 35 mmol KCl indicating continued sodium conservation. Conversely, during high sodium intake, sodium excretion increased sharply following 35 mmol KCl to ≈37% of that produced by hydrochlorothiazide. Under both low and high sodium intake, 35 mmol potassium was mostly excreted within 5 hours, accompanied by a sodium load reflecting the steady-state sodium intake, consistent with independent regulation of sodium/potassium excretion in the human distal nephron. CONCLUSIONS: Potassium-induced natriuresis was not greater in sodium-sensitive versus sodium-resistant hypertensives or hypertensives with higher versus lower basal NCC activity. We studied an acute KCl challenge. It remains to further characterize potassium-induced natriuresis during chronic potassium increase and when potassium is administered a complex potassium-containing meal.

Thiazide-Sensitive NCC (Sodium-Chloride Cotransporter) in Human Metabolic Syndrome: Sodium Sensitivity and Potassium-Induced Natriuresis.

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.

Outcomes of minority patients with very severe hypertension (>220/>120 mmHg).

OBJECTIVES: Acute severe hypertension is a common problem among inner-city ethnic minority populations. Nevertheless, the effects of currently employed treatment regimens on blood pressure have not been determined in a clinical practice setting. We determined the SBP responses to acute antihypertensive drug protocols and the 2-year natural history of patients presenting with severe hypertension. METHODS: Retrospective cohort investigation in consecutive patients with SBP at least 220 mmHg and/or DBP at least 120 mmHg during 3-month enrollment in 2014 with 2-year follow-up. Primary outcomes were SBP versus time for the first 5 h of emergency treatment and 2-year follow-up including repeat visits, target organ events, and hospitalizations. RESULTS: One hundred and fifty-six unique patients met criteria with 69% Black; 34% Hispanic; 56% had previous visits for severe hypertension; 31% had preexisting target injury. Acute management: Acute antihypertensive regimens resulted in grossly unpredictable and often exaggerated effects on SBP. Treatment acutely reduced SBP to less than 140 mmHg in 30 of 159 patients. Clonidine reduced SBP to less than 140 mmHg in 19/61. Two-year follow-up: We observed 389 repeat visits for severe hypertension, 99 new target events, and 76 hospitalizations accounting for 620 hospital days. CONCLUSION: Acute treatment of severe hypertension produced unpredictable and potentially dangerous responses in SBP. Two-year follow-up demonstrated extraordinary rates of recurrent visits, target organ events, and hospitalizations. Our findings indicate a need to develop effective management strategies to lower blood pressure safely and to prevent long-term consequences. Our findings may apply to other hospitals caring for ethnic minority populations.

Prevalence of Potentially Distracting Noncare Activities and Their Effects on Vigilance, Workload, and Nonroutine Events during Anesthesia Care.

BACKGROUND: When workload is low, anesthesia providers may perform non-patient care activities of a clinical, educational, or personal nature. Data are limited on the incidence or impact of distractions on actual care. We examined the prevalence of self-initiated nonclinical distractions and their effects on anesthesia workload, vigilance, and the occurrence of nonroutine events. METHODS: In 319 qualifying cases in an academic medical center using a Web-based electronic medical chart, a trained observer recorded video and performed behavioral task analysis. Participant workload and response to a vigilance (alarm) light were randomly measured. Postoperatively, participants were interviewed to elicit possible nonroutine events. Two anesthesiologists reviewed each event to evaluate their association with distractions. RESULTS: At least one self-initiated distraction was observed in 171 cases (54%), largely during maintenance. Distractions accounted for 2% of case time and lasted 2.3 s (median). The most common distraction was personal internet use. Distractions were more common in longer cases but were not affected by case type or American Society of Anesthesiologists physical status. Workload ratings were significantly lower during distraction-containing case periods and vigilance latencies were significantly longer in cases without any distractions. Three distractions were temporally associated with, but did not cause, events. CONCLUSIONS: Both nurse anesthetists and residents performed potentially distracting tasks of a personal and/or educational nature in a majority of cases. Self-initiated distractions were rarely associated with events. This study suggests that anesthesia professionals using sound judgment can self-manage nonclinical activities. Future efforts should focus on eliminating more cognitively absorbing and less escapable distractions, as well as training in distraction management.

Evidence for a gastrointestinal-renal kaliuretic signaling axis in humans.

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.

Effects of nebivolol versus metoprolol on sodium sensitivity and renal sodium handling in hypertensive Hispanic postmenopausal women.

Several consistent lines of evidence indicate an association between sodium sensitivity and impaired nitric oxide bioactivity. Nevertheless, whether restoring nitric oxide in humans by pharmacological means can ameliorate sodium sensitivity has not been investigated. Because nebivolol has been demonstrated to increase nitric oxide bioactivity in both laboratory and clinical investigations, we hypothesized that nebivolol might ameliorate sodium sensitivity and improve renal sodium handling in comparison to metoprolol. We therefore conducted a randomized, 2-treatment-period crossover trial in 19 Hispanic postmenopausal women with hypertension to determine the comparative effects of nebivolol versus metoprolol on (1) 24-hour ambulatory blood pressure response to an increase in dietary sodium from 5 days of low sodium to 5 days of high sodium, (2) renal natriuretic response to a 1-L saline challenge, and (3) asymmetrical dimethylarginine. Clinic blood pressure and heart rate were significantly reduced after 4 weeks of treatment with both nebivolol and metoprolol. Twenty-four­hour mean systolic blood pressure increased sharply from low sodium to high sodium for both nebivolol and metoprolol. Nevertheless, the increases in blood pressure did not differ between the 2 drugs: 7.7 (3.1, 12.3) mm Hg with metoprolol and 9.3 (4.6, 13.9) mm Hg with nebivolol (P=0.63). Furthermore, we observed no differences between the drugs in natriuretic response to saline challenge or asymmetrical dimethylarginine. In a sodium-sensitive population, at doses sufficient to produce reductions in blood pressure and heart rate, nebivolol did not demonstrate a significant effect on sodium sensitivity or sodium handling compared with metoprolol.

Racial differences in veterans' satisfaction with examination of disability from posttraumatic stress disorder.

OBJECTIVE: The examination that determines if a veteran has service-connected posttraumatic stress disorder (PTSD) affects veterans' lives for years. This study examined factors potentially associated with veterans' perception of their examination's quality. METHODS: Veterans (N=384) being evaluated for an initial PTSD service-connection claim were randomly assigned to receive either a semistructured interview or the examiner's usual interview. Immediately after the interview, veterans completed confidential ratings of the examinations' quality and of their examiners' interpersonal qualities and competence. Extensive data characterizing the veterans, the 33 participating examiners, and the examinations themselves were collected. RESULTS: Forty-seven percent of Caucasian veterans and 34% of African-American veterans rated their examination quality as excellent. African Americans were less likely than Caucasians to assign a higher quality rating (odds ratio=.61, 95% confidence interval=.38-.99, p=.047). Compared with Caucasians, African Americans rated their examiners as having significantly worse interpersonal qualities but not lower competence. Ratings were not significantly related to the veterans' age, gender, marital status, eventual diagnosis of PTSD, Global Assessment of Functioning score, the examiner's perception of the prevalence of malingering, or the presence of a third party during the examination. CONCLUSIONS: Ratings of disability examinations were generally high, although ratings were less favorable among African-American veterans than among Caucasian veterans.

Identification and characterization of a compound that protects cardiac tissue from human Ether-à-go-go-related gene (hERG)-related drug-induced arrhythmias.

The human Ether-à-go-go-related gene (hERG)-encoded K(+) current, I(Kr) is essential for cardiac repolarization but is also a source of cardiotoxicity because unintended hERG inhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that diminishes I(Kr) block by a known hERG antagonist would constitute a first step toward preventing hERG-related arrhythmias and facilitating drug discovery. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC(70) of dofetilide, a well characterized hERG blocker. One compound, VU0405601, with the desired activity was further characterized. In isolated, Langendorff-perfused rabbit hearts, optical mapping revealed that dofetilide-induced arrhythmias were reduced after pretreatment with VU0405601. Patch clamp analysis in stable hERG-HEK cells showed effects on current amplitude, inactivation, and deactivation. VU0405601 increased the IC(50) of dofetilide from 38.7 to 76.3 nM. VU0405601 mitigates the effects of hERG blockers from the extracellular aspect primarily by reducing inactivation, whereas most clinically relevant hERG inhibitors act at an inner pore site. Structure-activity relationships surrounding VU0405601 identified a 3-pyridiyl and a naphthyridine ring system as key structural components important for preventing hERG inhibition by multiple inhibitors. These findings indicate that small molecules can be designed to reduce the sensitivity of hERG to inhibitors.

Sodium challenge does not support an acute gastrointestinal-renal natriuretic signaling axis in humans.

A gastrointestinal-renal natriuretic signaling axis has been proposed to regulate sodium excretion in response to acute sodium ingestion. Such an axis is thought to be regulated by a gastrointestinal sodium sensor coupled to the activation/release of a natriuretic signal and could have important clinical and scientific implications. Here we systematically tested for this putative axis and the potential involvement of the gastrointestinal-derived natriuretic prohormones prouroguanylin and proguanylin in 15 healthy volunteers. There was no difference in sodium excretion following equivalent oral or intravenous sodium loads during either high- or low-sodium diets. Furthermore, serum concentrations of prouroguanylin and proguanylin did not increase, did not differ following oral or intravenous sodium, and did not correlate with sodium excretion. Thus, our results do not support an acute gastrointestinal-renal natriuretic axis or a central role for prouroguanylin or proguanylin in humans. If such an axis does exist, it is not characterized by a significant difference in the pattern of sodium excretion following either an oral or intravenous sodium load.

Mechanisms of impaired potassium handling with dual renin-angiotensin-aldosterone blockade in chronic kidney disease.

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.

Recursive estimation method for predicting residual bladder urine volumes to improve accuracy of timed urine collections.

Clinical research studies often collect data via repeated measurements of collected urine. Unfortunately, the accuracy of timed urine collections is limited by the presence of a residual volume of urine remaining in the bladder following each timed void due to incomplete emptying of the bladder. This residual urine volume adds significant imprecision to the urine collection method, rendering an important and fundamental clinical research tool inaccurate. We present an unbiased method to estimate the residual bladder volumes via a mathematical model of the bladder process. Regardless of the substance of primary interest, the model leverages conservation of mass and conservation of concentration principles towards a substance of secondary interest in order to solve a system of recursive equations, resulting in our Recursive Residual Estimation method to predict the residual volumes at each time point. We verify the model on simulated patients and also investigate the sensitivity of the model to initial value specification.