Comparative effects of potassium chloride and bicarbonate on thiazide-induced reduction in urinary calcium excretion.
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BACKGROUND: The chronic low-grade metabolic acidosis that occurs in various renal disorders and in normal people, and that is related both to dietary net acid load and age-related renal functional decline, may contribute to osteoporosis by increasing urine calcium excretion. Administration of potassium (K) alkali salts neutralizes acid and lowers urine calcium excretion. Urine calcium excretion also can be reduced by the administration of thiazide diuretics, which are often given with supplemental K to avoid hypokalemia. We determined whether the K alkali salt potassium bicarbonate (KHCO3) and the thiazide diuretic hydrochlorothiazide (HCTZ) combined is more effective in reducing urinary calcium than KHCO3 alone or HCTZ combined with the conventionally coadministered nonalkalinizing K salt potassium chloride (KCl). METHODS: Thirty-one healthy men and women aged 50 or greater were recruited for a four-week, double-blind, randomized study. After a baseline period of 10 days with three 24-hour urine and arterialized blood collections, subjects were randomized to receive either HCTZ (50 mg) plus potassium (60 mmol daily) as either the chloride or bicarbonate salt. Another 19 women received potassium bicarbonate (60 mmol) alone. After two weeks, triplicate collections of 24-hour urines and arterialized bloods were repeated. RESULTS: Urinary calcium excretion decreased significantly in all groups. KHCO3 alone and HCTZ + KCl induced similar decreases (-0.70 +/- 0.60 vs. -0.80 +/- 1. 0 mmol/day, respectively). Compared with those treatments, the combination of HCTZ + KHCO3 induced more than a twofold greater decrease in urinary calcium excretion (-1.8 +/- 1.2 mmol/day, P < 0. 05). Both HCTZ + KHCO3 and KHCO3 alone reduced net acid excretion significantly (P < 0.05) to values of less than zero. CONCLUSIONS: KHCO3 was superior to KCl as an adjunct to HCTZ, inducing a twofold greater reduction in urine calcium excretion, and completely neutralizing endogenous acid production so as to correct the pre-existing mild metabolic acidosis that an acid-producing diet usually induces in older people. Accordingly, for reducing urine calcium excretion in stone disease and osteoporosis, the combination of HCTZ + KHCO3 may be preferable to that of HCTZ + KCl. (+info)
Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy.
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BACKGROUND: The objectives of this study were to compare the effects of the angiotensin II receptor blocker, losartan, to those of the angiotensin-converting enzyme inhibitor, enalapril, on albuminuria and renal function in relationship to clinic and ambulatory blood pressure (ABP) in hypertensive type 2 diabetic subjects with early nephropathy. The tolerability of these agents and their effect on the metabolic profile were also evaluated. METHODS: The study was a one-year prospective, double-blind trial with losartan and enalapril administered alone or in combination with hydrochlorothiazide and other antihypertensive agents. ABP and renal and biochemical parameters were measured at baseline and after 12, 28, and 52 weeks of active treatment. Ninety-two hypertensive type 2 diabetics with early nephropathy completed the study. RESULTS: Both losartan and enalapril administered alone or in combination with other agents induced significant reductions in sitting clinic (P < 0.05) and ABP (P < 0.002) without a statistical difference between groups. Geometric means for urinary albumin excretion (UAE) decreased significantly (P < 0.001) in patients treated with losartan from 64. 1 to 41.5 microg/min and in those treated with enalapril from 73.9 to 33.5 microg/min after 52 weeks of therapy. A significant relationship (P < 0.05) between changes in systolic and diastolic ABP and the decrease in UAE at 52 weeks was seen in both groups. The decline in glomerular filtration rate (GFR) was stabilized at the end of therapy and was identical in both treatment groups. Treatment with enalapril was associated with a significantly higher incidence of cough (P = 0.006) and a rise in serum uric acid (P = 0.002) compared with losartan. CONCLUSIONS: Our results indicate that a one-year course of antihypertensive therapy with either losartan or enalapril significantly reduces UAE in hypertensive type 2 diabetic patients with early nephropathy. The reduction in UAE with each treatment is similarly related to decrements in ABP. In addition, the rate of decline in GFR is similar in both treatment groups. (+info)
Efficacy of candesartan cilexetil alone or in combination with amlodipine and hydrochlorothiazide in moderate-to-severe hypertension. UK and Israel Candesartan Investigators.
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This multicenter study evaluated the efficacy of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, used alone or in combination with amlodipine or in combination with amlodipine and hydrochlorothiazide in the treatment of patients with moderate-to-severe essential hypertension. After a 2-week, single-blind, placebo run-in period, patients entered a 12-week, open-label, dose-titration period. The candesartan cilexetil dose was increased from 8 to 16 mg once daily; amlodipine (5 mg once daily), hydrochlorothiazide (25 mg once daily), and additional medication were also added sequentially if necessary. Patients then entered a final 4-week, parallel-group, double-blind, randomized, placebo-controlled withdrawal period of candesartan alone. A total of 216 patients were recruited. After a 2-week run-in period on placebo tablets, mean sitting blood pressure (BP) was 175/108 mm Hg. At the end of the 12-week dose-titration/maintenance period, mean sitting BP fell to 141/88 mm Hg. In 67 patients who were randomized to placebo and had their candesartan withdrawn, there was a highly significant increase in mean systolic/diastolic BP (13/6 mm Hg) compared with those patients who continued with candesartan (ANCOVA, P:<0.0001). In conclusion, candesartan cilexetil is an effective BP-lowering drug when used alone or in combination with amlodipine or amlodipine plus hydrochlorothiazide in the treatment of moderate-to-severe essential hypertension. The drug was well tolerated throughout the investigation period. (+info)
Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1.
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The renal tubular secretion of thiazides and loop diuretics via the organic anion transport system in renal tubules is required for them to reach their principal sites of action. Similarly, acetazolamide, a diuretic clinically administered for glaucoma, is excreted from the kidney by glomerular filtration and tubular secretion. In this study, we investigated the interaction and transport of these diuretics via the rat renal organic anion transporter rOAT1 by using Xenopus laevis oocyte expression system. p-[(14)C]Aminohippurate (PAH) uptake by rOAT1-expressing oocytes was inhibited in the presence of a thiazide (chlorothiazide, cyclothiazide, hydrochlorothiazide), a loop diuretic (bumetanide, ethacrynic acid, furosemide), or a carbonic anhydrase inhibitor (acetazolamide, ethoxzolamide, methazolamide). Dixon plot analysis demonstrated that the inhibition constant (K(i)) value was 1.1 mM for acetazolamide, 150 microM for hydrochlorothiazide, 9.5 microM for furosemide, and 5. 5 microM for bumetanide. Kinetic analysis revealed that acetazolamide inhibited rOAT1 competitively and that inhibition style of furosemide was a mixture of competitive and noncompetitive. [(14)C]PAH efflux was significantly enhanced when the rOAT1-expressing oocytes were incubated in the presence of unlabeled PAH, alpha-ketoglutarate, acetazolamide, chlorothiazide, or hydrochlorothiazide. rOAT1 stimulated acetazolamide uptake, which was inhibited by probenecid. Although the loop diuretics had little trans-stimulation effect on [(14)C]PAH efflux via rOAT1, the rOAT1-mediated furosemide uptake was observed. These findings suggest that rOAT1 contributes, at least in part, to the renal tubular secretion of acetazolamide, thiazides, and loop diuretics. (+info)
Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease.
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BACKGROUND: In arterial hypertension, left ventricular hypertrophy (LVH) includes myocyte hypertrophy and fibrosis, which leads to LV diastolic dysfunction and, finally, heart failure. In spontaneously hypertensive rats, myocardial fibrosis was regressed and LV diastolic function was improved by treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether this holds true for patients with hypertensive heart disease was addressed in this prospective, randomized, double-blind trial. METHODS AND RESULTS: A total of 35 patients with primary hypertension, LVH, and LV diastolic dysfunction were treated with either lisinopril (n=18) or hydrochlorothiazide (HCTZ; n=17). At baseline and after 6 months, LV catheterization with endomyocardial biopsy, Doppler echocardiography with measurements of LV peak flow velocities during early filling and atrial contraction and isovolumic relaxation time, and 24-hour blood pressure monitoring were performed. Myocardial fibrosis was measured by LV collagen volume fraction and myocardial hydroxyproline concentration. With lisinopril, collagen volume fraction decreased from 6.9+/-0.6% to 6. 3+/-0.6% (P:<0.05 versus HCTZ) and myocardial hydroxyproline concentration from 9.9+/-0.3 to 8.3+/-0.4 microg/mg of LV dry weight (P:<0.00001 versus HCTZ); this was associated with an increase in the early filling and atrial contraction LV peak flow velocity ratio from 0.72+/-0.04 to 0.91+/-0.06 (P:<0.05 versus HCTZ) and a decrease in isovolumic relaxation time from 123+/-9 to 81+/-5 ms (P:<0.00002 versus HCTZ). Normalized blood pressure did not significantly change in either group. No LVH regression occurred in lisinopril-treated patients, whereas with HCTZ, myocyte diameter was reduced from 22. 1+/-0.6 to 20.7+/-0.7 microm (P:<0.01 versus lisinopril). CONCLUSIONS: In patients with hypertensive heart disease, angiotensin-converting enzyme inhibition with lisinopril can regress myocardial fibrosis, irrespective of LVH regression, and it is accompanied by improved LV diastolic function. (+info)
Vascular relaxation via endothelium-derived hyperpolarizing factor (EDHF) declines in association with aging and also with hypertension, and antihypertensive treatment improves the endothelial dysfunction connected with hypertension. We tested whether the angiotensin-converting enzyme inhibitor improves EDHF-mediated responses in normotensive rats, with special reference to the age-related process. Wistar-Kyoto rats (WKY) were treated with either 20 mg. kg(-1). d(-1) enalapril (WKY-E group) or a combination of 50 mg. kg(-1). d(-1) hydralazine and 7.5 mg. kg(-1). d(-1) hydrochlorothiazide (WKY-H group) from 9 to 12 months of age. Twelve-month-old WKY (WKY-O) and 3-month-old WKY (WKY-Y) served as controls (n=6 to 10 in each group). The 2 treatments lowered systolic blood pressure comparably. EDHF-mediated hyperpolarization to acetylcholine (ACh) in mesenteric arteries was significantly improved in WKY-E, but not in WKY-H, compared with WKY-O, and the hyperpolarization in WKY-E was comparable to that in WKY-Y (hyperpolarization to 10(-)(5) mol/L ACh in the presence of norepinephrine: WKY-O, -14+/-2 mV; WKY-E, -22+/-3 mV; WKY-H, -15+/-2 mV; and WKY-Y, -28+/-0 mV). EDHF-mediated relaxation, as assessed by relaxation to ACh in norepinephrine-precontracted rings in the presence of indomethacin and NO synthase inhibitor, was also significantly improved in WKY-E, but not in WKY-H, to a level comparable to that in WKY-Y (maximum relaxation: WKY-O, 45+/-6%; WKY-E, 63+/-8%; WKY-H, 43+/-4%; and WKY-Y, 72+/-4%). Hyperpolarization and relaxation to levcromakalim, an ATP-sensitive K(+) channel opener, were similar in all groups. These findings suggest that the angiotensin-converting enzyme inhibitor prevents the age-related decline in EDHF-mediated hyperpolarization and relaxation in normotensive rats, presumably through an inhibition of the renin-angiotensin system. (+info)
Prolonged exercise after diuretic-induced hypohydration: effects on substrate turnover and oxidation.
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To determine the influence of a diuretic-induced reduction in plasma volume (PV) on substrate turnover and oxidation, 10 healthy young males were studied during 60 min of cycling exercise at 61% peak oxygen uptake on two separate occasions > or =1 wk apart. Exercise was performed under control conditions (CON; placebo), and after 4 days of diuretic administration (DIU; Novotriamazide; 100 mg triamterene and 50 mg hydrochlorothiazide). DIU resulted in a calculated reduction of PV by 14.6 +/- 3.3% (P < 0.05). Rates of glucose appearance (R(a)) and disappearance (R(d)) and glycerol R(a) were determined by using primed constant infusions of [6,6-(2)H]glucose and [(2)H(5)]glycerol, respectively. No differences in oxygen uptake during exercise were observed between trials. Main effects for condition (P < 0.05) were observed for plasma glucose and glycerol, such that the values observed for DIU were higher than for CON. No differences were observed in plasma lactate and serum free fatty acid concentrations either at rest or during exercise. Hypohydration led to lower (P < 0.05) glucose R(a) and R(d) at rest and at 15 and 30 min of exercise, but by 60 min, the effects were reversed (P < 0. 05). Hypohydration had no effect on rates of whole body lipolysis or total carbohydrate or fat oxidation. A main effect for condition (P < 0.05) was observed for plasma glucagon concentrations such that larger values were observed for DIU than for CON. A similar decline in plasma insulin occurred with exercise in both conditions. These results indicate that diuretic-induced reductions in PV decreases glucose kinetics during moderate-intensity dynamic exercise in the absence of changes in total carbohydrate and fat oxidation. The specific effect on glucose kinetics depends on the duration of the exercise. (+info)
Furosemide stimulates macula densa cyclooxygenase-2 expression in rats.
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BACKGROUND: During a low salt intake, maintenance of renal blood flow and renin secretion depends on intact formation of prostaglandins. In the juxtaglomerular apparatus, the inducible isoform of cyclooxygenase, cyclooxygenase-2 (COX-2), is restricted to the macula densa and the cortical thick ascending limb of Henle (cTALH) cells, and is inversely regulated by dietary salt intake. This study aimed to elucidate whether the effect of NaCl on macula densa COX-2 expression is mediated by transepithelial transport of NaCl. METHODS: To this end, male Sprague-Dawley rats received subcutaneous infusions of the loop diuretic furosemide (12 mg/day) or were fed with the diuretic hydrochlorothiazide (30 mg/kg day) for seven days each. To compensate for their salt and water loss, the animals had free access to normal water and to salt water (0.9% NaCl, 0.1% KCl). COX-2 expression in kidney cortex was assessed by immunohistochemical staining and by semiquantitative ribonuclease protection assay for COX-2 mRNA. RESULTS: After six days of furosemide infusion to salt-substituted rats, there was no change of extracellular volume. Furosemide led to a fivefold and threefold increase of plasma renin activity and renocortical renin mRNA level, respectively. In parallel, there was a threefold increase of renocortical COX-2 abundance, while the COX-1 mRNA level remained unchanged. Moreover, the percentage of juxtaglomerular apparatuses immunopositive for COX-2 increased threefold in response to furosemide compared with vehicle-infused animals. Hydrochlorothiazide treatment increased plasma renin activity twofold but did not change kidney cortical renin mRNA, COX-2 mRNA, or COX-2 immunoreactivity. CONCLUSION: Our findings suggest that inhibition of salt transport in the loop of Henle, but not in the distal tubule, causes a selective stimulation of COX-2 expression in the macula densa region. This up-regulation may be of relevance for macula densa signaling, which links tubular salt transport rate with glomerular filtration rate and renin secretion. (+info)