RÉSUMÉ
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.
Sujet(s)
Hypertension artérielle , Sodium alimentaire , Femelle , Humains , Hydrochlorothiazide/pharmacologie , Hypertension artérielle/traitement médicamenteux , Natriurèse , Post-ménopause , Potassium , Sodium , Sodium alimentaire/pharmacologieRÉSUMÉ
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.
Sujet(s)
Pression sanguine/physiologie , Hypertension artérielle/métabolisme , Syndrome métabolique X/métabolisme , Natriurèse/physiologie , Symporteurs des ions sodium-chlorure/métabolisme , Sodium/métabolisme , Adulte , Sujet âgé , Pression sanguine/effets des médicaments et des substances chimiques , Femelle , Humains , Hypertension artérielle/physiopathologie , Mâle , Syndrome métabolique X/physiopathologie , Adulte d'âge moyen , Natriurèse/effets des médicaments et des substances chimiques , Chlorure de potassium/pharmacologie , Sodium alimentaireRÉSUMÉ
Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M-II, and minor metabolites. The objective of this study was to determine the effect of mild to moderate hepatic impairment on the pharmacokinetics of AZL and its major metabolite. This was a single-center, open-label, phase 1 parallel-group study that examined the single-dose (day 1) and multiple-dose (days 4-8) - 40 mg - pharmacokinetics of AZL and M-II in 16 subjects with mild and moderate hepatic impairment by Child-Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or moderate hepatic impairment did not cause clinically meaningful increases in exposure to AZL and M-II. Mild or moderate hepatic impairment had no clinically meaningful effect on the plasma protein binding of AZL and M-II. Single and multiple doses of AZL-M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with mild and moderate hepatic impairment.
Sujet(s)
Antagonistes du récepteur de type 1 de l'angiotensine-II/effets indésirables , Antagonistes du récepteur de type 1 de l'angiotensine-II/pharmacocinétique , Benzimidazoles/effets indésirables , Benzimidazoles/pharmacocinétique , Lésions hépatiques dues aux substances/étiologie , Oxadiazoles/effets indésirables , Oxadiazoles/pharmacocinétique , Antagonistes du récepteur de type 1 de l'angiotensine-II/usage thérapeutique , Antagonistes des récepteurs aux angiotensines/effets indésirables , Antagonistes des récepteurs aux angiotensines/pharmacocinétique , Antagonistes des récepteurs aux angiotensines/usage thérapeutique , Antihypertenseurs/effets indésirables , Antihypertenseurs/pharmacocinétique , Antihypertenseurs/usage thérapeutique , Benzimidazoles/usage thérapeutique , Pression sanguine/effets des médicaments et des substances chimiques , Femelle , Humains , Hypertension artérielle/traitement médicamenteux , Mâle , Adulte d'âge moyen , Oxadiazoles/usage thérapeutiqueRÉSUMÉ
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.
RÉSUMÉ
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.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Benzopyranes/usage thérapeutique , Éthanolamines/usage thérapeutique , Hypertension artérielle/traitement médicamenteux , Rein/effets des médicaments et des substances chimiques , Métoprolol/usage thérapeutique , Post-ménopause/métabolisme , Sodium/métabolisme , Sujet âgé , Antihypertenseurs/pharmacologie , Benzopyranes/pharmacologie , Pression sanguine/effets des médicaments et des substances chimiques , Pression sanguine/physiologie , Études croisées , Éthanolamines/pharmacologie , Femelle , Hispanique ou Latino , Humains , Hypertension artérielle/métabolisme , Hypertension artérielle/physiopathologie , Rein/métabolisme , Rein/physiopathologie , Métoprolol/pharmacologie , Adulte d'âge moyen , NébivololRÉSUMÉ
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.
Sujet(s)
Tube digestif/métabolisme , Rein/métabolisme , Natriurèse , Transduction du signal , Chlorure de sodium/sang , Administration par voie orale , Adulte , Aldostérone/sang , Pression sanguine , Créatinine/sang , Régime pauvre en sel , Femelle , Floride , Hormones gastrointestinales/sang , Humains , Perfusions veineuses , Mâle , Précurseurs de protéines/sang , Chlorure de sodium/administration et posologie , Chlorure de sodium alimentaire/sang , Comprimés , Facteurs temps , Jeune adulteRÉSUMÉ
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.
Sujet(s)
Antagonistes du récepteur de type 1 de l'angiotensine-II/effets indésirables , Inhibiteurs de l'enzyme de conversion de l'angiotensine/effets indésirables , Hyperkaliémie/étiologie , Maladies du rein/traitement médicamenteux , Spironolactone/effets indésirables , Adulte , Sujet âgé , Pression sanguine/effets des médicaments et des substances chimiques , Maladie chronique , Études croisées , Femelle , Humains , Rein/métabolisme , Maladies du rein/métabolisme , Mâle , Adulte d'âge moyen , Antagonistes des récepteurs des minéralocorticoïdes/effets indésirables , Potassium/métabolismeRÉSUMÉ
OBJECTIVE: Drospirenone (DRSP), a spironolactone analog with aldosterone antagonist activity, is a novel progestogen developed for use as hormone therapy in postmenopausal women in combination with 17beta-estradiol (E2). DRSP/E2 lowers blood pressure when used alone in hypertensive postmenopausal women or when administered concomitantly with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. DRSP/E2 has not been studied in combination with the widely prescribed hydrochlorothiazide (HCTZ). We investigated the effects of 3 mg DRSP/1 mg E2 versus placebo on blood pressure and potassium balance when added to existing therapy with 25 mg HCTZ in postmenopausal women with established stage I hypertension. DESIGN: This was a single-center, double-blind, randomized, placebo-controlled, two-treatment, two 4-week treatment period crossover study in 36 postmenopausal women with stage I hypertension maintained on 25 mg HCTZ. The endpoint was a change from baseline in systolic and diastolic blood pressures by 24-hour ambulatory blood pressure monitoring. Safety monitoring included serum potassium (mEq/L) and adverse events. RESULTS: Mean systolic and diastolic blood pressures by 24-hour ambulatory blood pressure monitoring were reduced significantly, by -7.2 and -4.5 mm Hg, respectively, with DRSP/E2 as compared with placebo. The decrease in potassium with HCTZ was 0.2 mEq/L less with DRSP/E2 than placebo, suggesting a potassium-sparing effect. The most frequently observed adverse events with DRSP/E2 were vaginal bleeding and breast tenderness, which were attributable to the hormone therapy. CONCLUSIONS: DRSP/E2 substantially lowers systolic and diastolic blood pressure when added to existing antihypertensive therapy with HCTZ in hypertensive postmenopausal women. In addition, DRSP/E2 has a potassium-sparing effect that counteracts HCTZ-induced potassium loss.
Sujet(s)
Androstènes/usage thérapeutique , Antihypertenseurs/usage thérapeutique , Hydrochlorothiazide/usage thérapeutique , Hypertension artérielle/traitement médicamenteux , Antagonistes des récepteurs des minéralocorticoïdes/usage thérapeutique , Sujet âgé , Pression sanguine/effets des médicaments et des substances chimiques , Mesure de la pression artérielle/méthodes , Relation dose-effet des médicaments , Méthode en double aveugle , Association médicamenteuse , Oestrogénothérapie substitutive , Femelle , Humains , Hypertension artérielle/prévention et contrôle , Adulte d'âge moyen , Post-ménopause/effets des médicaments et des substances chimiques , Potassium/sang , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: Uncontrolled severe hypertension is associated with alarming rates of cardiovascular events but the mechanisms of vascular injury are not well understood. Recent investigative interest has focused on platelet activation and platelet P-selectin (CD62P) as direct mediators of vascular inflammation and injury. We investigated the association of extreme blood pressure (BP) elevation with platelet P-selectin and fibrinolytic markers in high risk patients with severe hypertension. METHODS: Cross-sectional comparison of platelet CD62, tissue plasminogen activator antigen (tPA), and plasminogen activator inhibitor-1 activity (PAI-1) among 3 BP groups: untreated severely hypertensive patients (SHT; n=18), untreated mildly hypertensive patients (MHT; n=19), and normotensive controls (NT; n=16). RESULTS: Platelet CD62 was greatest in SHT (p=0.00008) and showed a strong correlation with both systolic (p=0.0002, r=0.52) and diastolic (p=0.0003, r=0.52) BP. tPA was greater in SHT than MHT or NT (ANOVA; p=0.02) and correlated with diastolic BP but not SBP. PAI-1 did not correlate with either SBP or DBP but was related to body mass index, diabetes, and dyslipidemia. CONCLUSIONS: Platelet CD62 demonstrated a strong and graded association with both systolic and diastolic BP that persisted in the presence of multiple concomitant risk factors. The association of BP with CD62P was stronger than with either PAI-1 or tPA-Ag. Platelet activation and platelet CD62 increase in a BP-dependent manner and this relationship persists at extreme levels of BP. Platelet activation and platelet CD62 may participate in the accelerated target organ injury observed in high risk patients with severe hypertension.
Sujet(s)
Hypertension artérielle/sang , Sélectine P/métabolisme , Activation plaquettaire/physiologie , Activateur tissulaire du plasminogène/sang , Pression sanguine/physiologie , Indice de masse corporelle , Études cas-témoins , Études transversales , Femelle , Humains , Hypertension artérielle/complications , Hypertension artérielle/métabolisme , Mâle , Adulte d'âge moyen , Sélectine P/sang , Inhibiteur-1 d'activateur du plasminogène/sang , Facteurs de risque , Indice de gravité de la maladieRÉSUMÉ
Both ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) are renoprotective beyond their effects on blood pressure (BP), but their widespread use is limited by their tendency to provoke hyperkalemia. The comparative effects of ACEI and ARB on potassium handling have not been investigated. The objective of this study was to determine whether there are differences in dynamic renal potassium handling between ACEI and ARB in response to an oral potassium challenge. This was a randomized crossover study of candesartan versus lisinopril titrated to control BP followed by an inpatient study of renal potassium handling in 24 hypertensive patients with type II diabetes mellitus (DMII) and preserved renal function. Following an oral potassium challenge (0.75 mmol/kg), differences in hourly serum K (mmol/L), rate of urinary potassium excretion (UkV, micromol/min), and fractional excretion of potassium (FEK) were assessed by repeated-measures ANOVA. Hourly UkV(p = .45) and FEK (p = .19) were similar for candesartan and lisinopril, although FEK at 2 hours for candesartan tended to exceed that for lisinopril (.34 [.04] vs. .26 [.03]) and approached significance (p = .096). UkVfor candesartan at hour 2 was 177 (26) and 121 (21) for lisinopril and also approached significance (p = .10). Serial serum potassium did not differ (p = .70). No statistical differences were discovered in renal potassium handling between candesartan and lisinopril in patients with DMII and preserved renal function. Whether there are differences between the drug classes in renal impairment remains to be determined.