Erik G Persson

Colloid osmotic pressure of the subcapsular interstitial fluid of rat kidneys during hydropenia and volume expansion

SummaryTo determine the colloid osmotic pressure of subcapsular interstitial fluid in rat kidneys two different methods were used. Collection of subcapsular fluid with glass pipettes or implanted microcatheters and subsequent protein analysis resulted in a protein concentration of 1.8g%±0.6 and 2.0g%±0.8, respectively. Lymph protein concentration was not significantly different from that of subcapsular fluid samples. During extracellular volume expansion both subcapsular and lymph protein concentration fell to 0.42g%±0.23 and 0.7g%±0.5. Application of anin vivo oncometric method resulted in an effective oncotic pressure about twice that estimated from protein determinations. Using average values for intratubular and intracapillary oncotic and hydrostatic pressures a tubulo-interstitial net driving force of 20 mm Hg and an interstitial-capillary net driving force of 13 mm Hg is estimated in hydropenic animals. During volume expansion net transtubular pressure gradient is reduced to about 60–70% of control while the transcapillary gradient is virtually unchanged.

Enhanced XOR activity in eNOS-deficient mice: Effects on the nitrate-nitrite-NO pathway and ROS homeostasis

Xanthine oxidoreductase (XOR) is generally known as the final enzyme in purine metabolism and as a source of reactive oxygen species (ROS). In addition, this enzyme has been suggested to mediate nitric oxide (NO) formation via reduction of inorganic nitrate and nitrite. This NO synthase (NOS)-independent pathway for NO generation is of particular importance during certain conditions when NO bioavailability is diminished due to reduced activity of endothelial NOS (eNOS) or increased oxidative stress, including aging and cardiovascular disease. The exact interplay between NOS- and XOR-derived NO generation is not fully elucidated yet. The aim of the present study was to investigate if eNOS deficiency is associated with changes in XOR expression and activity and the possible impact on nitrite, NO and ROS homeostasis. Plasma levels of nitrate and nitrite were similar between eNOS deficient (eNOS-/-) and wildtype (wt) mice. XOR activity was upregulated in eNOS-/- compared with wt, but not in nNOS-/-, iNOS-/- or wt mice treated with the non-selective NOS inhibitor L-NAME. Following an acute dose of nitrate, plasma nitrite increased more in eNOS-/- compared with wt, and this augmented response was abolished by the selective XOR inhibitor febuxostat. Livers from eNOS-/- displayed higher nitrite reducing capacity compared with wt, and this effect was attenuated by febuxostat. Dietary supplementation with nitrate increased XOR expression and activity, but concomitantly reduced superoxide generation. The latter effect was also seen in vitro after nitrite administration. Treatment with febuxostat elevated blood pressure in eNOS-/-, but not in wt mice. A high dose of dietary nitrate reduced blood pressure in naïve eNOS-/- mice, and again this effect was abolished by febuxostat. In conclusion, eNOS deficiency is associated with an upregulation of XOR facilitating the nitrate-nitrite-NO pathway and decreasing the generation of ROS. This interplay between XOR and eNOS is proposed to play a significant role in NO homeostasis and blood pressure regulation.

Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II-mediated hypertension.

NO deficiency and oxidative stress are crucially involved in the development or progression of cardiovascular disease, including hypertension and stroke. We have previously demonstrated that acute treatment with the newly discovered organic nitrate, 2‐nitrate‐1,3‐dibuthoxypropan (NDBP), is associated with NO‐like effects in the vasculature. This study aimed to further characterize the mechanism(s) and to elucidate the therapeutic potential in a model of hypertension and oxidative stress.

Renal function in the dog in acute disturbances of the acid-base balance.

The excretion of electrolytes in urine was studied in nine dogs in which acute acid‐base disturbances were induced. In respiratory alkalosis the urine flow and bicarbonate excretion increased very rapidly. Potassium and often also sodium excretion increased. The glomerular filtration rate (GFR) measured as creatinine clearance was not affected. Respiratory acidosis caused a decreased GFR and electrolyte excretion. The urine flow decreased very rapidly when Pco2 was increased. In metabolic alkalosis a high bicarbonate excretion caused an osmotic diuresis. The GFR was not affected. The excretion of electrolytes (sodium, potassium, chloride, calcium, magnesium) increased. In metabolic acidosis the GFR decreased leading to a low urine flow. The excretion of acid increased initially, but with increasing acidosis the urine flow decreased causing a reduced acid excretion. At a certain stage of the acidosis the ion gradient between blood and urine could not be maintained. This caused an increased acidosis, leading to a further reduction of the renal blood flow and GFR. The excretion of electrolytes was reduced when the urine flow decreased, in spite of increased concentrations in the urine. Preliminary studies of the effect of mannitol infusions showed that the urine flow increased despite the metabolic acidosis. The excretion of electrolytes was reduced following the mannitol injections. Possible mechanisms for the action of mannitol are discussed.

Endothelin regulates NOS1 and NOS3 isoforms in the renal medulla

Guanylins are small, heat-stable peptides produced in the intestinal epithelium and involved in intraluminal pH and fluid homeostasis. Ingestion of a salty meal induces apical and basolateral secretion of guanylins resulting in luminocrine stimulation of Cl, HCO 3 and water secretion in the intestine and natriuresis, kaliuresis and diuresis in the kidney. This action helps to prevent hypernatraemia and hypervolaemia and, by inducing HCO 3 secretion, to protect the duodenal mucosa from gastric acid injury. The study by Bengtsson et al. in this issue not only confirms the action of intra-luminal guanylins on bicarbonate secretion in rat duodenum in vivo, but additionally demonstrates that intraarterial guanylins, expected to be inactive on the basis of previous in vitro studies, are able to mimic this effect, albeit through a different signalling mechanism. Whereas luminal guanylins provoke HCO 3 secretion by binding to guanylyl cyclase in the apical membrane and cGMP signalling, peripheral guanylins apparently act through stimulation of enteric cholinergic neurons and release of the calcium-linked secretagogue melatonin from enterochromaffin cells. This study paves the way for further work to evaluate the physiological importance of guanylins in the secretory response to luminal acid, when compared with other known regulators such as VIP, 5-HT and PGE2. It also raises the intriguing question whether intra-arterial guanylin signals through the classical guanylyl cyclase pathway or through a recently discovered alternative pathway involving the G-protein-coupled urotensin II receptor, GPR14.