Purinergic P2X1 receptor, purinergic P2X7 receptor, and angiotensin II type 1 receptor interactions in the regulation of renal afferent arterioles in angiotensin II-dependent hypertension

In ANG II-dependent hypertension, ANG II activates ANG II type 1 receptors (AT1Rs), elevating blood pressure and increasing renal afferent arteriolar resistance (AAR). The increased arterial pressure augments interstitial ATP concentrations activating purinergic P2X receptors (P2XRs) also increasing AAR. Interestingly, P2X1R and P2X7R inhibition reduces AAR to the normal range, raising the conundrum regarding the apparent disappearance of AT1R influence. To evaluate the interactions between P2XRs and AT1Rs in mediating the increased AAR elicited by chronic ANG II infusions, experiments using the isolated blood perfused juxtamedullary nephron preparation allowed visualization of afferent arteriolar diameters (AAD). Normotensive and ANG II-infused hypertensive rats showed AAD responses to increases in renal perfusion pressure from 100 to 140 mmHg by decreasing AAD by 26 ± 10% and 19 ± 4%. Superfusion with the inhibitor P2X1Ri (NF4490; 1 μM) increased AAD. In normotensive kidneys, superfusion with ANG II (1 nM) decreased AAD by 16 ± 4% and decreased further by 19 ± 5% with an increase in renal perfusion pressure. Treatment with P2X1Ri increased AAD by 30 ± 6% to values higher than those at 100 mmHg plus ANG II. In hypertensive kidneys, the inhibitor AT1Ri (SML1394; 1 μM) increased AAD by 10 ± 7%. In contrast, treatment with P2X1Ri increased AAD by 21 ± 14%; combination with P2X1Ri plus P2X7Ri (A438079; 1 μM) increased AAD further by 25 ± 8%. The results indicate that P2X1R, P2X7R, and AT1R actions converge at receptor or postreceptor signaling pathways, but P2XR exerts a dominant influence abrogating the actions of AT1Rs on AAR in ANG II-dependent hypertension.

Necrotising enterocolitis in a newborn infant treated with octreotide for chylous effusion: is octreotide safe?

Octreotide is a somatostatin analogue used for treating congenital chylothorax and congenital hyperinsulinism in infants. By increasing splanchnic arteriolar resistance and decreasing gastrointestinal blood flow, octreotide indirectly reduces lymphatic flow in chylous effusions.Splanchnic ischaemia following octreotide predisposes infants to necrotising enterocolitis (NEC). Although NEC occurrence in infants treated with octreotide for hyperinsulinaemic hypoglycaemia has been reported widely, its incidence in infants with chylothroax is low. We describe a case of congenital chylothorax in a preterm infant who had poor response to thoracentesis. Although octreotide initiation lead to resolution of chylothorax, he developed NEC. Cessation of octreotide and medical management resulted in rapid resolution of NEC. Since octreotide is generally used as the first-line treatment for chylous effusion, the risk of NEC should be considered, especially when the dosage is increased. Infants on octreotide should be closely observed for early signs and symptoms of NEC to avert surgical emergency.

Increased Glomerular Hydrostatic Pressure is Associated with Tubular Creatinine Reabsorption in Healthy Subjects

<b><i>Background:</i></b> Cr is secreted by the proximal tubules and thus Cr clearance (<i>C</i>_cr) can overestimate inulin clearance (<i>C</i>_in). However, in some cases, <i>C</i>_cr can even underestimate <i>C</i>_in. This suggests that Cr could be reabsorbed in the tubuli. We examined the clinical parameters that are associated with tubular Cr reabsorption. <b><i>Methods:</i></b> In 80 kidney donor candidates (53.9 ± 13.2 years, 29 males), <i>C</i>_in and para-aminohippuric acid clearance were measured simultaneously. Intrarenal hemodynamic parameters were calculated by Gomez’s formulae. To quantify the secretory component of <i>C</i>_cr (SF_cr), it was calculated as follows: SF_cr = (<i>C</i>_cr − <i>C</i>_in)/<i>C</i>_cr. <b><i>Results:</i></b> Twenty-five subjects (31.3%) showed SF_cr values &#x3c;0. SF_cr that correlated significantly and negatively with efferent arteriolar resistance (<i>R</i>_e) and glomerular hydrostatic pressure (<i>P</i>_glo) (<i>R</i>_e: <i>r</i> = −0.30, <i>p</i> = 0.008; <i>P</i>_glo: <i>r</i> = −0.28, <i>p</i> = 0.025). In multiple regression analyses, <i>R</i>_e and <i>P</i>_glo were significantly and negatively associated with SF_cr after adjustment for other confounders. <b><i>Conclusions:</i></b> These findings suggest that tubular reabsorption of Cr can occur in some cases. Intrarenal glomerular hemodynamic burden may be related to tubular creatinine reabsorption, which possibly leads to lower <i>C</i>_cr values.

Function of the normal glomerulus

Glomerular filtration, the first step leading to the formation of primitive urine, is a passive phenomenon. The composition of this primitive urine is the consequence of the ultrafiltration of plasma depending on renal blood flow, on hydrostatic pressure of glomerular capillary, and on glomerular coefficient of ultrafiltration. Glomerular filtration rate (GFR) can be precisely measured by the calculation of the clearance of freely filtrated exogenous substances that are neither metabolized nor reabsorbed nor secreted by tubules: its mean value is 125 mL/min/1.73 m² in men and 110 mL/min/1.73 m² in women, which represents 20% of renal blood flow. In clinical practice, estimates of GFR are obtained by the measurement of creatininaemia followed by the application of various equations (MDRD or CKD-EPI) and more recently by the measurement of plasmatic C-cystatin. Under physiological conditions, GFR is a stable parameter that is regulated by the intrinsic vascular and tubular autoregulation, by the balance between paracrine and endocrine agents acting as vasoconstrictors and vasodilators, and by the effects of renal sympathetic nerves. The mechanisms controlling GFR regulation are complex. This is due to the variety of vasoactive agents and their targets, and multiple interactions between them. Nevertheless, the relative stability of GFR during important variations of systemic haemodynamics and volaemia is due to three major operating mechanisms: autoregulation of the afferent arteriolar resistance, local synthesis and action of angiotensin II, and the sensitivity of renal resistance vessels to respond to NO release.

Relaxin-mediated renal vasodilation in the rat is associated with falls in glomerular blood pressure

Relaxin (RLX) is a pleiotropic peptide hormone with marked renal vasodilatory actions that are physiologically important during pregnancy. RLX also has potent antifibrotic actions and is being tested therapeutically in various fibrotic diseases, including chronic kidney disease (CKD). Since renal vasodilation may expose the glomerulus to increased blood pressure [glomerular capillary pressure (PGC)], which exacerbates progression of CKD, we assessed the glomerular hemodynamic actions of acute (0.89 µg·100 g body wt−1·h−1 iv over 75 min) and chronic (1.5 µg·100 g body wt−1·h−1 sc) administration of RLX. Both acute and chronic RLX produced marked renal vasodilation and increased renal plasma flow (RPF) in euvolemic, anesthetized male rats. Glomerular filtration rate also increased with RLX, but the magnitude of the rise was much less than the increase in RPF due to concomitant decreases in filtration fraction. The fall in filtration fraction was the result of significant decreases in PGC, despite a slight increase in mean arterial blood pressure (MAP) with acute RLX and no net change in MAP with chronic RLX. This fall in PGC occurred because of the “in-series” arrangement of the afferent and efferent arteriolar resistance vessels, which can regulate PGC independently of MAP. With both acute and chronic RLX, efferent arteriolar resistance vessels relaxed to a greater extent than afferent arteriolar resistance vessels, thus producing falls in PGC. Based on this finding, RLX has a beneficial hemodynamic impact on the kidney, which, together with the antifibrotic actions of RLX, suggests a strong therapeutic potential for use in CKD.

U-shaped relationship between serum uric acid levels and intrarenal hemodynamic parameters in healthy subjects

Hyperuricemia has been reported to affect renal hemodynamics. In a recent study, both low and high levels of serum uric acid (SUA) were found to be associated with loss of kidney function. The goal of this study was to evaluate the relationship between SUA levels and intrarenal hemodynamic parameters in healthy subjects, using plasma clearance of para-aminohippurate (CPAH) and inulin (Cin). Renal and glomerular hemodynamics were evaluated by simultaneous measurements of CPAH and Cin in 48 healthy subjects (54.6 ± 13.4 yr). Intrarenal hemodynamic parameters, including efferent and afferent (Ra) arteriolar resistance, were calculated using Gómez’s formulas. Relationships of SUA levels with these intrarenal hemodynamic parameters were examined. In quadratic regression analysis, SUA levels had a significant inverse U-shaped relationship with Cin ( P < 0.0001, R2 = 0.350) and CPAH ( P = 0.0093, R2 = 0.188) and a U-shaped relationship with Ra ( P = 0.0011, R2 = 0.262). In multiple regression analysis with normal (3.5–6.0 mg/dl) and mildly low or high (<3.5 or >6.0 mg/dl) SUA levels entered as dummy variables of zero and one, respectively, mildly low or high SUA levels were significantly and independently associated with Ra (β = 0.230, P = 0.0403) after adjustment for several factors ( R2 = 0.597, P < 0.0001). Both mild hyperuricemia and mild hypouricemia are significantly associated with increased Ra, although weakly. The increase in Ra in subjects with mild hyperuricemia or hypouricemia may be related to renal hemodynamic abnormalities, possibly leading to a decline in renal function.

High-end arteriolar resistance limits uterine artery blood flow and restricts fetal growth in preeclampsia and gestational hypertension at high altitude

The reduction in infant birth weight and increased frequency of preeclampsia (PE) in high-altitude residents have been attributed to greater placental hypoxia, smaller uterine artery (UA) diameter, and lower UA blood flow (QUA). This cross-sectional case-control study determined UA, common iliac (CI), and external iliac (EI) arterial blood flow in Andeans residing at 3,600–4,100 m, who were either nonpregnant (NP, n = 23), or experiencing normotensive pregnancies (NORM; n = 155), preeclampsia (PE, n = 20), or gestational hypertension (GH, n = 12). Pregnancy enlarged UA diameter to ∼0.62 cm in all groups, but indices of end-arteriolar vascular resistance were higher in PE or GH than in NORM. QUAwas lower in early-onset (≤34 wk) PE or GH than in NORM, but was normal in late-onset (>34 wk) illness. Left QUAwas consistently greater than right in NORM, but the pattern reversed in PE. Although QCIand QEIwere higher in PE and GH than NORM, the fraction of QCIdistributed to the UA was reduced 2- to 3-fold. Women with early-onset PE delivered preterm, and 43% had stillborn small for gestational age (SGA) babies. Those with GH and late-onset PE delivered at term but had higher frequencies of SGA babies (GH=50%, PE=46% vs. NORM=15%, both P < 0.01). Birth weight was strongly associated with reduced QUA( R2= 0.80, P < 0.01), as were disease severity and adverse fetal outcomes. We concluded that high end-arteriolar resistance, not smaller UA diameter, limited QUAand restricted fetal growth in PE and GH. These are, to our knowledge, the first quantitative measurements of QUAand pelvic blood flow in early- vs. late-onset PE in high-altitude residents.

Maintained tubuloglomerular feedback responses during acute inhibition of P2 purinergic receptors in mice

Tubuloglomerular feedback (TGF), the change of afferent arteriolar resistance initiated by changes of luminal NaCl concentration, is thought to be related to NaCl-dependent release of ATP by macula densa cells. In the present study, we have explored the possibility that the released ATP may directly interact with vasoconstrictor P2 purinergic receptors in the vicinity of the glomerular vascular pole. In two different strains of wild-type mice (SWR/J and FVB), TGF responses were determined in vivo by measuring the stop flow pressure (PSF) change caused by a saturating increase in loop of Henle flow rate before and during the administration of the P2 receptor inhibitors PPADS (12 mg/kg + 35 mg·kg−1·h−1 iv) or suramin (50 mg/kg + 150 mg·kg−1·h−1). Both agents significantly reduced the blood pressure response to the P2X agonist α,β-methylene ATP. In SWR/J and FVB mice, elevating flow to 30 nl/min reduced PSF by 16.4 ± 2.2 and 17.1 ± 1.8%. During infusion of PPADS, PSF fell by 18.8 ± 2 ( P = 0.4) and 16.5 ± 1.5% ( P = 0.82) in the two strains of mice. During suramin infusion, PSF decreased by 14.7 ± 2.4 ( P = 0.62) and 15 ± 1.3% ( P = 0.4) in SWR/J and FVB mice, respectively. Including PPADS (10−4 M) in the loop perfusate did not significantly alter the PSF response (18.9 ± 1.8%; P = 0.54). Arterial blood pressure was not systematically affected by the P2 inhibitors. As measured by free-flow micropuncture, PPADS significantly reduced proximal tubular fluid reabsorption in both fractional and absolute terms. These results indicate that the direct activation of P2 purinergic receptors by ATP is not a major cause of TGF-induced vasoconstriction in vivo.