Nitric oxide-inhibited chloride transport in cortical thick ascending limbs is reversed by 8-iso-prostaglandin-F2α

Background: Salt reabsorption in the cortical thick ascending limb (cTAL) is regulated by opposing effects. Thus, while nitric oxide (NO) inhibits sodium chloride (NaCl) reabsorption, 8-iso-prostaglandin-F2α (8-iso-PGF2α) stimulates it. Their interaction, however, has not been evaluated in the cTAL. Because 8-iso-PGF2α has considerable stability while NO is a free radical with a short half-life, we hypothesized that, in the cTAL, the inhibition of NaCl absorption will be reversed by 8-iso-PGF2α. Methods: Chloride absorption (JCl) was measured in isolated perfused cTALs. We also evaluated whether activation of protein kinase A (PKA) is required for this interaction. Since cyclic adenosine monophosphate (cAMP) is a major messenger for the 8-iso-PGF2α signaling cascade, and NO inhibits JCl by decreasing cAMP bioavailability, we measured 8-iso-PGF2α-stimulated cAMP in the presence of sodium nitroprusside (SNP). Results: Basal JCl was 274 ± 85 pmol/min/mm. The NO donor, SNP (10-6 M), decreased JCl by 41% (333.5 ± 35.2 pmol/min/mm vs. 195.9 ± 26.1 pmol/min/mm), while 8-iso-PGF2α (100 μM) increased JCl to 315 ± 46 pmol/min/mm (p \u3c 0.01), reversing the effects of the NO donor. While SNP inhibited JCl, 8-iso-PGF2α failed to increase JCl in the presence of H89. Basal cAMP was 56.3 ± 13.1 fmol/min/mm, that in the presence of the NO donor was 57.8 ± 6.1 fmol/min/mm, and that with 8-iso-PGF2α increased it to 92.1 ± 2.9 fmol/min/mm (n = 10, p \u3c 0.04). Conclusion: We concluded that 1) NO-induced inhibition of JCl in the cTAL can be reversed by 8-iso-PGF2α, 2) 8-iso-PGF2α and NO interaction requires PKA to control JCl in this nephron segment, and 3) in the presence of NO, 8-iso-PGF2α continues to stimulate JCl because NO cannot reverse 8-iso-PGF2α-stimulated cAMP level

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

The antihypertensive actions of statins: Modulation by salt intake

Hydroxy methyl glutaryl CoA inhibitors (statins) are the agents most frequently used to reduce elevated serum cholesterol. In addition to their cholesterol lowering effects, statins also have nonlipid lowering pleiotropic properties. These include reducing oxidative stress, reninangiotensin and endothelin synthesis and activity, and improving nitric oxide (NO) synthesis and availability. Thus, one would predict that statins might be able to exert an antihypertensive effect. Experimental models bear out the blood pressure lowering effects but the data from clinical trials have been inconsistent perhaps due to inappropriate experimental designs, sample size, blood pressure measurement techniques etc. Moreover, although experimental models strongly suggest a role for salt intake in the potential antihypertensive responses to statins, available clinical trials fail to report salt intake in the studied populations. The statins' antihypertensive effects remain an unsettled hypothesis and calls for a large clinical trial at a wide range of doses and a controlled salt intake. Statins meanwhile remain as a excellent option to control high cholesterol and in tissue injury prevention.Fil: Juncos, Luis I.. Fundacion J Robert Cade; ArgentinaFil: Juncos, Luis A.. University of Mississippi; Estados UnidosFil: Garcia, Nestor Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentin

The Association Between Inflammatory Markers and Hypertension. A Call for Anti-Inflammatory Strategies?

The most important goal of antihypertensive therapy is to prevent the complications associated with hypertension (stroke, myocardial infarction, end-stage renal disease, etc). For this, secondary targets such as left ventricular hypertrophy, proteinuria, dementia, and other signs of hypertension-induced organ damage help the physician to assess risks and monitor treatment efficacy. New treatment targets may be arising, however. One such target may be endothelial dysfunction. In effect, endothelial dysfunction not only may precede the elevation of blood pressure, but may also pave the way to conditions often associated with hypertension, such as diabetes, arteriosclerosis, microalbuminuria, congestive heart failure, and tissue hypertrophy. Because inflammation often accompanies endothelial dysfunction, approaches to counteract inflammation are now being evaluated. For this, antagonists of the renin-angiotensin-aldosterone system, statins, and beta blockers are all being tested. All of these agents seem to prevent or delay the induction of proinflammatory molecules aside from, and in addition to, their specific effects on blood pressure. The focus of this review is to update some of the animal and human research showing that hypertension sets off an inflammatory state and also to consider some of the anti-inflammatory approaches that may prevent the development of endothelial dysfunction, and the subsequent renal and cardiovascular damage

The efficiency of potassium removal during bicarbonate hemodialysis

Patients on chronic hemodialysis often portray high serum [K+]. Although dietary excesses are evident in many cases, in others, the cause of hyperkalemia cannot be identified. In such cases, hyperkalemia could result from decreased potassium removal during dialysis. This situation could occur if alkalinization of body fluids during dialysis would drive potassium into the cell, thus decreasing the potassium gradient across the dialysis membrane. In 35 chronic hemodialysis patients, we compared two dialysis sessions performed 7 days apart. Bicarbonate or acetate as dialysate buffers were randomly assigned for the first dialysis. The buffer was switched for the second dialysis. Serum [K+], [HCO3-], and pH were measured in samples drawn before dialysis; 60, 120, 180, and 240 min into dialysis; and 60 and 90 min after dialysis. The potassium removed was measured in the dialysate. During the first 2 hr, serum [K+] decreased equally with both types of dialysates but declined more during the last 2 hr with bicarbonate dialysis. After dialysis, the serum [K+] rebounded higher with bicarbonate bringing the serum [K+] up to par with acetate. The lower serum [K+] through the second half of bicarbonate dialysis did not impair potassium removal (295.9 ± 9.6 mmol with bicarbonate and 299.0 ± 14.4 mmol with acetate). The measured serum K+ concentrations correlated with serum [HCO3-] and blood pH during bicarbonate dialysis but not during acetate dialysis. Alkalinization induced by bicarbonate administration may cause redistribution of K during bicarbonate dialysis but this does not impair its removal. The more marked lowering of potassium during bicarbonate dialysis occurs late in dialysis, when exchange is negligible because of a low gradient.Fil: Capdevila, M.. Fundación Robert Cade, Instituto de Especialidades Médicas; ArgentinaFil: Martinez Ruiz, I.. Fundación Robert Cade, Instituto de Especialidades Médicas; ArgentinaFil: Ferrer, C.. Fundación Robert Cade, Instituto de Especialidades Médicas; ArgentinaFil: Monllor, F.. Fundación Robert Cade, Instituto de Especialidades Médicas; ArgentinaFil: Ludjvick, C.. Fundación Robert Cade, Instituto de Especialidades Médicas; ArgentinaFil: Garcia, Nestor Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Juncos, Luis Isaias. Fundación Robert Cade, Instituto de Especialidades Médicas; Argentin