The effect of losartan and losartan/hydrochlorothiazide fixed-combination on magnesium, zinc, and nitric oxide metabolism in hypertensive patients: a prospective open-label study

BACKGROUND: Thiazide diuretics and angiotensin-converting enzyme inhibitors can cause excessive urinary zinc (Zn) loss and Zn depletion. Thiazides may also induce magnesium (Mg) deficiency, which may exacerbate hypertension. Data on the effects of angiotensin receptor blockers on Zn and Mg homeostasis are scarce. METHODS: Seventeen hypertensive patients were studied (ten men and seven women, age 50 +/- 3 years, blood pressure 158 +/- 5 / 95 +/- 3 mm Hg). Patients were treated with losartan 50 mg/day for 4 weeks followed by a fixed combination of 50 mg losartan and 12.5 mg hydrochlorothiazide for 4 weeks more. Blood and 24-h urine were collected at baseline and after each study period. Zinc and Mg levels were measured in serum, urine, and peripheral blood mononuclear cells. Nitric oxide metabolites were measured in urine. RESULTS: Treatment with losartan resulted in a significant increase in the urinary Zn/creatinine ratio (from 0.020 +/- 0.004 microg/mg to 0.034 +/- 0.005 microg/mg, P = .02), which was further increased by the losartan/hydrochlorothiazide combination (from 0.034 +/- 0.005 microg/mg to 0.053 +/- 0.008 microg/mg, P = .03). Serum Zn levels were significantly decreased after losartan/hydrochlorothiazide (from 80.0 +/- 4.0 microg/dL at baseline to 74.0 +/- 3.0 microg/dL, P = .007). Peripheral blood mononuclear Zn concentrations were decreased also, but this was not statistically significant. Serum, urinary, and peripheral blood mononuclear Mg levels were not significantly affected by treatment. Nitric oxide urinary metabolites were unchanged throughout the study. CONCLUSIONS: Treatment with losartan causes an increase in urinary Zn excretion and induces Zn deficiency in patients with hypertension. The addition of hydrochlorothiazide has an additive effect. Magnesium and nitric oxide metabolism are not affected by either treatment.     

Maternal psychological growth following childbirth

Although maternal postpartum mental health has been extensively studied, rather little is known regarding the factors that may facilitate psychological growth following childbirth. The present study set forth to examine various pre-birth, birth, and post-birth correlates of overall psychological growth and growth domains in postpartum women, assessed within the first months following childbirth. A sample of 428 women completed self-report measures pertaining to psychological growth, mental health, maternal attachment, and childbirth characteristics. We found that the majority of women reported psychological growth following childbirth, with those experiencing stressors in childbirth reporting the highest levels of appreciation for life. In regression analyses, postpartum factors were significantly associated with overall growth and growth domains, taking into account other factors. The more the childbirth was perceived as central to the mothers’ identity and the better the maternal attachment was to the child, the higher levels of growth. Growth was also negatively related to endorsement of childbirth PTSD. Background factors, such as maternal age, education, and prior mental health, were associated with specific growth domains, although the association was small and there was no association with overall growth. Post-birth factors are important in ensuing psychological growth in the first months following birth. Attention to opportunities of growth following childbirth is warranted in clinical care, in particular following traumatic childbirth.

     

N-Acetylcysteine ameliorates lithium-induced renal failure in rats.

BACKGROUND: Prolonged lithium treatment may induce progressive deterioration of renal function in humans and experimental animals. N-Acetylcysteine (NAC) has been shown to be effective in the prevention of hypoperfusion and toxin-induced renal failure, but its effect on lithium nephrotoxicity has not been evaluated yet. The purpose of this study was to examine a possible renoprotective effect of NAC against lithium-induced renal failure in a rat model. METHODS: Moderate renal failure was induced in 40 Sprague-Dawley rats using a 5 week protocol including 3 weeks of lithium chloride administration in the drinking water. The animals were divided randomly into two equal groups receiving either 10 mg/kg NAC or saline by two daily intraperitoneal injections. In week 6, the glomerular filtration rate (GFR) was assessed by 99mTechnetium diethylene triaminepentaacetic acid, and serum creatinine, blood urea nitrogen (BUN) and 24 h urinary protein and osmolarity were measured. Kidneys were excised for pathological evaluation. RESULTS: At the end of the lithium protocol, the GFR was significantly higher in the NAC-treated group compared with the control group, 0.92+/-0.35 vs 0.56+/-0.25 ml/min/100 g, respectively, P = 0.002. Serum creatinine and BUN were also significantly lower in the NAC-treated group 1.009+/-0.107 vs 1.143+/-0.118 mg/dl, P = 0.001, and 83.9+/-6.8 vs 88.95+/-7.1 mg/dl, P = 0.28, respectively. The percentages of tubular necrosis and tubular lumen obstruction, evaluated by light microscopy, were significantly lower in the NAC-treated group, P = 0.002 and P = 0.007, respectively. CONCLUSIONS: NAC treatment has a renoprotective effect against lithium-induced renal failure in a rat model.     

Alpha 1A-adrenergic receptor polymorphism and vascular response

OBJECTIVE: The alpha(1A)-adrenergic receptor is highly expressed in human vasculature including resistance arteries and veins, and its stimulation is primarily responsible for adrenergically mediated smooth muscle contraction. Variability in sensitivity to phenylephrine, an alpha(1A) adrenergic agonist, has a large genetic component. We examined the hypothesis that a common polymorphism of alpha(1A)-adrenergic receptor (Arg347Cys) affects in vivo response. METHODS: We measured vascular sensitivity to phenylephrine using the dorsal hand vein linear variable differential transformer technique and determined alpha(1A)-adrenergic receptor genotype in 74 healthy, nonsmoking adults (28 Arg/Arg, 30 Arg/Cys, and 16 Cys/Cys). RESULTS: Sensitivity to phenylephrine, expressed as the dose of phenylephrine resulting in 50% venoconstriction (Phe(50)), was not significantly different in subjects with the 3 alpha(1A) adrenergic receptor genotypes: Phe(50) geometric mean (95% confidence interval) was 513 ng/min (287-918 ng/min) for Arg/Arg, 431 ng/min (274-680 ng/min) for Arg/Cys, and 471 ng/min (197-1124 ng/min) for Cys/Cys (P =.90). CONCLUSION: We conclude that the Arg347Cys receptor polymorphism does not alter agonist-mediated venoconstriction in vivo.     

beta2-Adrenergic receptor genotype and preterm delivery

OBJECTIVE: Our purpose was to determine whether the functional genetic polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) that result in changes in amino acid residues 16 and 27 are associated with preterm delivery. STUDY DESIGN: A case-control study comparing the distribution of beta(2)AR genotype between 251 Hispanic women delivered at term and 28 Hispanic women delivered preterm. Preterm delivery was defined as spontaneous onset of labor resulting in delivery before 37 weeks of gestation, in a singleton pregnancy, with no apparent etiology for preterm labor and delivery. Genomic DNA was isolated from peripheral blood, and beta( 2)AR alleles were identified by established techniques. RESULTS: Only one woman (4%) with preterm labor was homozygous for Arg16 versus 79 (31%) in the control group (P =.01, odds ratio 0.08). There was no association of preterm labor with genotype at position 27. CONCLUSION: Our data demonstrate that homozygosity for Arg16, which in vitro is associated with decreased down-regulation of the beta(2)AR, protects from preterm delivery.     

The effect of simvastatin,ezetimibe and their combination on the lipid profile,arterial stiffness and inflammatory markers

OBJECTIVE: Arterial stiffness and highly sensitive C-reactive protein (hsCRP) serum level predict the risk for cardiovascular events. The most commonly used drugs for lowering cholesterol levels, the statins, also have anti-inflammatory effects and can decrease arterial stiffness. Ezetimibe is the first drug of a new class of cholesterol absorption inhibitors in common use and, to date, its effect on arterial stiffness has not yet been studied. The aim of this study was to compare the effect of simvastatin and ezetimibe, both singly and in combination, on arterial stiffness and hsCRP serum concentration in hypercholesterolemic patients. METHODS: Forty hypercholesterolemic patients were studied. Group1 comprised previously untreated patients, who received simvastatin at doses of 40 mg/day during the study; group 2 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 80 mg/day during the study; group 3 consisted of patients previously untreated, who received ezetimibe at doses of 10 mg/day during the study; group 4 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 40 mg/day and ezetimibe at 10 mg/day during the study. Arterial stiffness expressed as the Augmentation Index (AIx) (assessed by pulse wave analysis), the lipid profile and the hsCRP level were measured at baseline and after 3 months of treatment. RESULTS: The reduction in low-density lipoprotein (LDL) after treatment was significantly greater in groups 1 and 4 (39.9 and 35.7%) than in groups 2 and 3 (17.7 and 16.9%; p = 0.005). The AIx decreased significantly only in group 1 patients, from 30.2 +/- 8.3% before treatment to 21.6 +/- 6.5% after treatment (p < 0.001). Changes in hsCRP paralleled the changes in AIx, with a significant decrease in patients in group 1 only, from 2.8 +/- 2.5 mg/L before treatment to 1.6 +/- 1.5 mg/L after treatment (p = 0.016). CONCLUSION: Ezetimibe as a monotherapy had no effect on arterial stiffness or hsCRP, while the administration of simvastatin at 40 mg per day improved arterial stiffness and CRP. However, increasing the dose of simvastatin or administering ezetimibe in combination with simvastatin had no beneficial effects on arterial stiffness.     

The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men

BACKGROUND: Sildenafil, a treatment for erectile dysfunction, is a specific phosphodiesterase type 5 (PDE 5) inhibitor that enhances nitric oxide (NO)-mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanosine monophosphate breakdown. Since PDE 5 is widely expressed in the vasculature, we examined the hypothesis that sildenafil could enhance NO-mediated vasodilation in other vascular beds and improve endothelial function. METHODS: NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in healthy men in the dorsal hand vein (n = 13), after the administration of either sildenafil 50 mg or placebo. Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia were measured before and after sildenafil 50 mg, isosorbide dinitrate 5 mg, and placebo in a double-blind, randomized, crossover study (n = 11). RESULTS: In the hand vein, sildenafil administration increased sensitivity to local nitroglycerin. The 50% effective dose decreased approximately 4-fold from 13.5 ng/min (range, 6.9-26.6 ng/min) to 2.7 ng/min (range, 1.1-6.4 ng/min) (P =.025). Sildenafil decreased the maximum venoconstriction induced by phenylephrine from 81% +/- 3% to 74% +/- 3% (P =.025). Sildenafil did not significantly affect the maximal venodilatory response to acetylcholine (35% +/- 7% after placebo versus 32% +/- 8% after sildenafil) (P =.7). In the arterial vasculature, flow-mediated dilation before (2.4% +/- 1%) and after (2.8% +/- 1.4%) sildenafil (P =.8) and postischemic reactive hyperemia area under the curve before (1807 +/- 393 mL. min. s/100 mL) and after (1467 +/- 257 mL. min. s/100 mL) sildenafil were not different (P =.8). Resting heart rate, blood pressure, and resting brachial artery diameter were unchanged after sildenafil administration. Isosorbide dinitrate, an endothelium-independent vasodilator, caused a significant increase in resting brachial artery diameter from 0.53 +/- 0.01 cm to 0.56 +/- 0.02 cm (P =.005), without altering flow-mediated dilation. CONCLUSIONS: In healthy men sildenafil increased sensitivity to nitroglycerin, an exogenous NO donor, approximately 4-fold but did not affect endothelium-dependent, NO-mediated responses in either the hand vein or forearm vasculature. Differential vascular responses to sildenafil may localize its enhancement of endogenous NO-mediated vasodilation to vascular beds such as the corpus cavernosum.     

Nitric oxide production decreases after salt loading but is not related to blood pressure changes or nitric oxide-mediated vascular responses

BACKGROUND: Nitric oxide production is a homeostatic mechanism that may regulate blood pressure during salt loading. Salt-sensitive hypertension in animal models and in humans is characterized by increased blood pressure and decreased nitric oxide production after salt loading. It is not known if this impaired nitric oxide production is the result of hypertension or is a mechanism contributing to the blood pressure response to salt. METHODS AND RESULTS: The effects of salt loading on blood pressure, nitric oxide-mediated vasodilation and nitric oxide production were measured in 25 normotensive subjects after 6 days on either a high (400 mmol/day) or low (10 mmol/day) sodium, low nitrate diet. Mean arterial pressure increased during the high-salt diet [4 +/- 1 mmHg (mean +/- SEM)] in 12 subjects and remained unchanged or decreased (-4 +/- 1 mmHg) in 13 subjects. Plasma nitrite and nitrate, a measure of nitric oxide production, decreased significantly from 39 +/- 3.3 micromol/l during the low-salt diet to 22.4 +/- 2.4 micromol/l during the high-salt diet (P = 0.0001). However, changes in mean arterial pressure from low- to high-salt diet did not correlate with changes in plasma nitrite and nitrate (r = 0.14, P = 0.51). Forearm blood flow increased significantly (P <0.0001) in response to mental stress, a nitric oxide-mediated response, but was not affected by sodium intake (from 7.8 +/- 0.9 to 11.2 +/- 1.4 ml/min per 100 ml during low salt versus 8.5 +/- 1.2 to 10.4 +/- 1.3 ml/min per 100 ml during high salt,P = 0.3). CONCLUSIONS: Salt loading results in a decrease in nitric oxide production in both salt-sensitive and salt-resistant normotensive subjects, which is independent of changes in blood pressure and does not affect the nitric oxide-mediated vascular response to mental stress. In contrast to salt-resistant animal models, salt loading in healthy subjects does not increase nitric oxide production. Therefore, the increased blood pressure response to salt loading may occur through mechanisms other than nitric oxide, or salt-sensitive individuals are more sensitive to the reduced nitric oxide production that occurs after salt loading in both salt-sensitive and salt-resistant subjects.