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PubMed1991

Stimulation of NaCl reabsorption by antidiuretic hormone in the cortical thick ascending limb of Henle's loop of the mouse.

The effect of antidiuretic hormone (ADH) on transepithelial Na+ Cl-, Ca2+ and Mg2+ net fluxes (JNa, JCl, JMg, JCa) was investigated in isolated perfused cortical thick ascending limb segments (cTAL) of the mouse nephron, using the microperfusion technique and the electron microprobe analysis to determine the ionic composition of the collected tubular fluid. Simultaneously, the transepithelial potential difference (PDte) and the transepithelial resistance (Rte) were recorded. Prior to the flux measurements cTAL segments were perfused for one hour. During this equilibration period PDte decreased significantly from +19.9 +/- 1.6 to +14.9 +/- 1.1 mV and Rte increased from 30.6 +/- 3.5 omega cm2 to 38.8 +/- 2.4 omega cm2 (n = 7), reflecting a decline in NaCl transport. After ADH was added to the bath solution at 10(-10) mol.l-1, PDte increased from +14.4 +/- 1.1 to +18.0 +/- 1.5 mV, accompanied by a rise in JNa and JCl from 205 +/- 11 to 273 +/- 19 and from 216 +/- 12 to 283 +/- 21 pmol.min-1.mm-1 (n = 7), respectively. JCa and JMg also increased from 0.81 +/- 0.07 to 1.50 +/- 0.12 and from 0.43 +/- 0.11 to 0.76 +/- 0.08 pmol.min-1.mm-1 (n = 7), respectively. All these effects were fully reversible after withdrawal of the hormone. In conclusion our data indicate that ADH stimulates divalent cation transport and NaCl transport in the cortical thick ascending limb of Henle's loop of the mouse.

Animals↗
PubMed1997

The effects of respiratory alkalosis and acidosis on net bicarbonate flux along the rat loop of Henle in vivo.

We have studied the effects of acute respiratory alkalosis (ARALK, hyperventilation) and acidosis (ARA, 8% CO2), chronic respiratory acidosis (CRA; 10% CO2 for 7-10 days), and subsequent recovery from CRA breathing air on loop of Henle (LOH) net bicarbonate flux (JHCO3) by in vivo tubule microperfusion in anesthetized rats. In ARALK blood, pH increased to 7.6, and blood bicarbonate concentration ([HCO3-]) decreased from 29 to 22 mM. Fractional urinary bicarbonate excretion (FEHCO3) increased threefold, but LOH JHCO3 was unchanged. In ARA, blood pH fell to 7.2, and blood [HCO3-] rose from 28 to 34 mM; FEHCO3 was reduced to < 0.1%, but LOH JHCO3 was unaltered. In CRA, blood pH fell to 7.2, and blood [HCO3-] increased to > 50 mM, whereas FEHCO3 decreased to < 0.1%. JHCO3 was reduced by approximately 30%. Bicarbonaturia occurred when CRA rats breathed air, yet LOH JHCO3 increased (by 30%) to normal. These results suggest that LOH JHCO3 is affected by the blood-to-tubule lumen [HCO3-] gradient and HCO3- backflux. When the usual perfusing solution at 20 nl/min was made HCO3- free, mean JHCO3 was -34.5 +/- 4.4 pmol/min compared with 210 +/- 28.1 pmol/min plus HCO3-. When a low-NaCl perfusate (to minimize net fluid absorption) containing mannitol and acetazolamide (2 x 10(-4) M, to abolish H(+)-dependent JHCO3) was used, JHCO3 was -112.8 +/- 5.6 pmol/min. Comparable values for JHCO3 at 10 nl/min were -35.9 +/- 5.8 and -72.5 +/- 8.8 pmol/min, respectively. These data indicate significant backflux of HCO3-along the LOH, which depends on the blood-to-lumen [HCO3-] gradient; in addition to any underlying changes in active acid-base transport mechanisms, HCO3- permeability and backflux are important determinants of LOH JHCO3 in vivo.

Acidosis, Respiratory↗
PubMed1986

Cl(-)-channel blockers in the thick ascending limb of the loop of Henle. Structure activity relationship.

On the basis of our findings with diphenylamine-2-carboxylate we have searched for compounds which possess an even higher affinity for the Cl(-)-channels in the basolateral membrane of the thick ascending limb of the loop of Henle. To quantity the inhibitory potency, we performed measurements of the equivalent short circuit current, corresponding to the secondary active transport of Cl- and measurements of the voltage across the basolateral membrane. A survey of 219 compounds reveals that relatively simple modifications in the structure of diphenylamine-2-carboxylate led to very potent blockers such as 5-nitro-2-(3-phenylpropylamino)-benzoate which inhibits the short circuit current half maximally (IC50) at 8 X 10(-8) mol/l. A comparison of the structural formula and the respective IC50 values leads to several empirical conclusions: The potent compounds are lipophilic due to the apolar residue (e.g. phenyl- or cycloalkyl group). Replacing this part of the molecule by an aliphatic chain (up to 4 C-atoms) leads to inactive compounds. Most of the inhibitors are secondary amines. Linking other than with -NH- between the phenyl ring and the benzoic acid results in inactive compounds. Tertiary amines, such as in case of 2-(N,N-diphenylamine)benzoic acid or N-methylphenylamine-benzoic acid are poorly active. The carboxylate group of the benzoate moiety must be in ortho position to the amino group. Introduction of substituents into the benzoate moiety e.g. -NO2 (in meta position to the carboxylate group), or by -Cl (in para position to the carboxylate group) results in an increase of inhibitory potency. A -CH2-, -C2H4-, -C3H6- spacer between the amino bridge and the phenyl ring increases the affinity for the Cl(-)-channel by several orders of magnitude. The above described structure activity relationship renders it likely that these chloride channel blockers possess several sites of interaction: The negatively charged carboxylate group, the secondary amine group which probably carries a positive partial charge, and for the very potent agents (nos. 130, 143, 144, and 145) an additional negative partial charge at the respective -Cl or -NO2 substituent. Finally, also an apolar interaction with an cycloalkyl or cycloaryl residue seems to be required, and this site of interaction has a defined spacing from the secondary amino nitrogen.

Animals↗
PubMed1979

Regional membrane specialization in the thin limbs of Henle's loops as seen by freeze-fracture electron microscopy.

Rat thin limbs of Henle were studied by freeze-fracture electron microscopy. Thin limb segments in both short- and long-looped nephrons were identified by previously developed ultrastructural criteria, continuity with known thick segments, and architectural relationships in the outer medulla. Intramembrane particle (IMP) density and the number of intramembrane fibrils comprising the zonula occludens were determined for each morphologically identifiable thin limb segment. The IMP density on the protoplasmic faces of both the luminal and abluminal membranes of the upper portion of the descending thin limb (DTL) of the long-looped nephron is quantitatively greater than in the short-looped thin limb, lower portion of the long-looped DTL, and in the ascending thin limb. The zonulae occludens in the long-looped upper DTL consists of a single fibril; the long-looped lower DTL contains 3.13 +/- 0.14 fibrils; the ascending thin limb contains 1.31 +/- 0.09 fibrils; and the short-looped DTL contains 3.75 +/- 0.19 fibrils. These studies further support the contention that there is anatomic heterogeneity among the thin limb segments. Because direct physiologic studies in the thin limbs are incomplete and conflicting, the need for correlative physiologic studies on anatomically characterized structures is indicated.

Animals↗
PubMed1973

Tubuloglomerular feedback. Nonlinear relation between glomerular hydrostatic pressure and loop of henle perfusion rate.

The present experiments were performed to quantify the effect of changes in distal tubular sodium delivery on glomerular flow dynamics both below and above the normal physiologic range. Glomerular capillary pressure as derived from the tubular stop flow pressure was assessed while the loop of Henle of the same nephron was perfused with varying flow rates. During Ringer perfusion no change of glomerular capillary pressure was observed when flow was increased from 0 to 13 nl/min. Further increasing flow to 27 nl/min was associated with a reduction of glomerular hydrostatic pressure by an average of 7.0+/-4.4 cm H(2)O (+/-SD). During perfusion at a rate of 43 nl/min glomerular pressure was decreased by a mean of 10.5+/-4.0 cm H(2)O. Changing the flow rate in small steps revealed that a significant reduction of capillary pressure was found when increasing the flow rate from 13 to 21 nl/min and that the maximum response was reached at 32 nl/min. No effect of perfusion rate changes on glomerular capillary pressure was observed when 300 mM mannitol was used as perfusion fluid. These results imply that a nonlinear relationship exists between end-proximal flow rate and glomerular capillary pressure. It is suggested that during deviations of distal sodium delivery into a positive direction filtration rate is intrarenally regulated probably by prevalence of afferent arteriolar constriction. During reductions of distal sodium load intrarenal regulation is either abolished or it involves proportionate resistance changes of both afferent and efferent arterioles.

Animals↗
PubMed1995

DARPP-32 promoter directs transgene expression to renal thick ascending limb of loop of Henle.

DARPP-32, a dopamine- and adenosine 3',5'-cyclic monophosphate (cAMP)-regulated inhibitor of protein phosphatase-1, is highly colocalized with neuronal and nonneuronal D1-type receptors. DARPP-32 concentration is enriched in the renal outer medulla and in the medium-size spiny neurons of the brain. In the ascending limb of the loop of Henle, DARPP-32 is phosphorylated following stimulation by dopamine and other first messengers, and in this form inhibits the activity of the Na(+)-K(+)-adenosinetriphosphatase pump. For functional analysis of the DARPP-32 promoter in the kidney, we characterized the murine gene. There are two groups of transcription start sites utilized in the brain, but the proximal set appears to be preferentially used in the kidney. In four of four lines of mice carrying a DARPP-32/lacZ transgene with 2.1 kb of 5'-flanking DNA, adult kidney lacZ transgene expression mimicked that of endogenous DARPP-32. There was no ectopic expression in peripheral organs. We conclude that the sequences necessary for direction of DARPP-32 expression to the medullary thick ascending limb are contained within this 2.1-kb fragment.

Animals↗
PubMed1988

Pharmacokinetic and pharmacodynamic studies of piretanide in rabbits. IV. Effect of piretanide on the proximal tubules and the loop of Henle under a hydrated condition.

In order to evaluate the effect of piretanide on the renal transport of water and osmotic substances, a clearance study was carried out in well hydrated rabbits. After intravenous bolus administration of piretanide, glomerular filtration rate, proximal tubular clearance and urine flow rate, as well as the pharmacokinetics of piretanide, were determined. A pharmacokinetic and pharmacodynamic link model which was developed in the previous paper was applied to the present experimental results. The results indicated that the effect of piretanide on the renal transport of water and osmotic substances in the hydrated rabbits was reasonably described by the model. The model analysis suggested that the diuretic response to piretanide was attributable to the inhibition of reabsorption of electrolytes in the proximal tubule, as well as in the loop of Henle.

Animals↗
PubMed2003

Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle.

Our purpose here is to test the hypothesis that Randall's plaques, calcium phosphate deposits in kidneys of patients with calcium renal stones, arise in unique anatomical regions of the kidney, their formation conditioned by specific stone-forming pathophysiologies. To test this hypothesis, we performed intraoperative biopsies of plaques in kidneys of idiopathic-calcium-stone formers and patients with stones due to obesity-related bypass procedures and obtained papillary specimens from non-stone formers after nephrectomy. Plaque originates in the basement membranes of the thin loops of Henle and spreads from there through the interstitium to beneath the urothelium. Patients who have undergone bypass surgery do not produce such plaque but instead form intratubular hydroxyapatite crystals in collecting ducts. Non-stone formers also do not form plaque. Plaque is specific to certain kinds of stone-forming patients and is initiated specifically in thin-limb basement membranes by mechanisms that remain to be elucidated.

Adult↗
PubMed1996

Calcium and magnesium: low passive permeability and tubular secretion in the mouse medullary thick ascending limb of Henle's loop (MTAL).

Recent studies from our laboratory have shown that in the mouse and rat nephron Ca2+ and Mg2+ are not reabsorbed in the medullary part of the thick ascending limb (mTAL) of Henle's loop. The aim of the present study was to investigate whether the absence of transepithelial Ca2+ and Mg2+ transport in the mouse mTAL is due to its relative low permeability to divalent cations. For this purpose, transepithelial ion net fluxes were measured by electron probe analysis in isolated perfused mouse mTAL segments, when the transepithelial potential difference (PDte.) was varied by chemical voltage clamp, during active NaCl transport inhibition by luminal furosemide. The results show that transepithelial Ca2+ and Mg2+ net fluxes in the mTAL are not driven by the transepithelial PDte. At zero voltage, a small but significant net secretion of Ca2+ into the tubular lumen was observed. With a high lumen-positive PDte generated by creating a transepithelial bath-to-lumen NaCl concentration gradient, no Ca2+ and Mg2+ reabsorption was noted; instead significant and sustained Ca2+ and Mg2+ net secretion occurred. When a lumen-positive PDte was generated in the absence of apical furosemide, but in the presence of a transepithelial bath-to-lumen NaCl concentration gradient, a huge Ca2+ net secretion and a lesser Mg2+ net secretion, not modified by ADH, were observed. Replacement of Na+ by K+ in the lumen perfusate induced, in the absence of PDte changes, important but reversible net secretions of Ca2+ and Mg2+. In conclusion, our results indicate that the passive permeability of the mouse mTAL to divalent cations is very low and not influenced by ADH. This nephron segment can secrete Ca2+ and Mg2+ into the luminal fluid under conditions which elicit large lumen-positive transepithelial potential differences. Given the impermeability of this epithelium to Ca2+ and Mg2+, the secretory processes would appear to be of cellular origin.

Animals↗
PubMed1988

Pharmacokinetic and pharmacodynamic studies of piretanide in rabbits. II: Effects on the proximal tubules and the loop of Henle.

In order to clarify the effect of piretanide in the nephrons, pharmacokinetics and pharmacodynamics of piretanide were studied under a hydropenic condition in the rabbit. The hydropenic condition was developed by a simultaneous infusion of an antidiuretic hormone and hyperosmotic saline. Lithium was used as the indicator of the proximal sodium reabsorption. Plasma concentrations and urinary excretion rates of piretanide were not influenced by the hydration state of the body. The glomerular filtration rate (GFR) showed a long lasting decrease after piretanide administration; however, the urinary excretion rates of salts and water were increased prominently just after administration. The lithium clearance ratio, which was obtained by dividing the lithium renal clearance by GFR, indicated that piretanide inhibited the proximal reabsorption of sodium. The urine osmolarity after piretanide administration showed a significant decrease, and this indicated that the osmolarity of the renal medulla was also influenced by piretanide. From these observations, a model describing the transport of water and osmotic substances in the nephrons was constructed to calculate the effect of piretanide. The results indicated that the diuretic effect of piretanide in the hydropenic rabbit was reasonably described by the model. The model parameters obtained suggested that the site of action of piretanide in the proximal tubules might be in the peritubular side rather than inside the lumen, whereas the site of action in the loop of Henle might be inside the lumen.

Animals↗
PubMed1988

Short-term stimulation of cellular autophagy by furosemide in the thick ascending limb of Henle's loop in the rat kidney.

In an effort to investigate the functional relationship between cell-specific work and intracellular degradative processes, the effect of furosemide on cellular autophagy was investigated in two different portions of the nephron, namely, the thick ascending limb of Henle's loop (TAL), which is a main target of this drug, and the proximal convoluted tubule (PCT) as a reference structure. Eight male adult rats were treated with furosemide (60 mg/kg body weight, s.c.). Eight control animals received physiological saline. 1 to 4 h after the injections the animals were killed by perfusion fixation. Small specimens of kidney tissue from the inner stripe of the outer medulla and from the outer cortex were processed for electron microscopy; they were investigated morphometrically for volume fraction and numerical density of autophagic vacuoles (AVs). A significant increase of both parameters (volume fraction: 0.42 x 10(-4) to 1.09 x 10(-4); numerical density: 4.2 x 10(5)/mm3 to 15.5 x 10(5)/mm3) was seen under the influence of furosemide in TAL cells, whereas PCT cells did not show a significant increase in volume fraction or any increase in numerical density of AVs. These data suggest that the functional unloading of TAL, via blocking of the Na+-2Cl- -K+ co-transport by furosemide, results in adaptative "structural unloading", i.e., an increased sequestration of cytoplasmic components into AVs, within a short-time interval.

Animals↗
PubMed2001

Does methylene blue protect the kidney tissues from damage induced by ciclosporin A treatment?

Ciclosporin A (CsA) is the first-choice immunosuppressant universally used in allotransplantation and autoimmune diseases. However, it has been demonstrated that this drug produces negative side effects in several organs and in particular in the lymphoid organs and in the kidney. It has been suggested that the CsA causes deleterious effects because it increases the oxygen free radical production. Here we wanted to test whether antioxidants protect the kidney parenchyma from the toxicity induced by CsA. We used methylene blue (MB), because it inhibits the formation of oxygen free radicals. The study was carried out in four groups of Wistar rats. Group I animals were intraperitoneally injected with MB (1 mg/kg/day) for 21 days; group II animals were subcutaneously injected with CsA (15 mg/kg/day) for 21 days; group III animals were treated with CsA combined with MB at the same doses and for the same periods as groups I and II, and group IV animals were injected subcutaneously with olive oil for 21 days as controls. The kidneys and the thymuses were subsequently removed and examined by conventional morphological staining (hematoxylin-eosin and Masson's trichrome) and enzymatic (NADPH-diaphorase, cytochrome, c oxidase, and superoxide anion production) and immunoenzymatic (inducible nitric oxide synthase--iNOS, endothelial nitric oxide synthase--eNOS) techniques. The thymuses were used to check the persistence of CsA-immunosuppressive effects during MB administration. Group I, III, and IV animals showed a normal kidney architecture and low levels of NADPH-diaphorase and of superoxide anion in all structures studied (proximal and distal tubules, glomeruli and the Henle loops). The cytochrome c oxidase showed a strong activity in proximal tubules, a moderate activity in distal tubules, and a weak activity in glomeruli and in the Henle loops. The expression of iNOS was weak in the proximal tubular epithelial cells and negative in the glomeruli, while eNOS was found to be moderately positive in the glomeruli and in the interstitial arteries, but not in the tubules and in the Henle loops. Degenerative changes with tubulointerstitial injury in the cortex of CsA-treated kidneys (group II) and increases of NADPH-diaphorase levels, iNOS activity, and superoxide staining were found in all structures. The expression of eNOS did not change in group I, III and IV animals. MB combined with CsA prevented the degenerative changes caused by CsA, preserving the structural, enzymatic, and immunoenzymatic integrity of the renal parenchyma. The mechanism by which MB exerts its protective action is not yet clear, but it seems to be due to its ability to inhibit xanthine oxidase and to quench nitric oxide production. Moreover, these data have been also supported by the following: (1) the superoxide anion levels were very high after CsA treatment and reduced after CsA-MB treatment, and (2) the iNOS levels increased in CsA-treated rats and showed normal levels after CsA-MB treatment. Moreover we demonstrated that MB administration did no compromise the CsA immunosuppressive effects, since the thymus showed a cytoarchitecture like that observed in CsA-treated rats.

Animals↗
PubMed1986

Permselectivity for cations over anions in the upper portion of descending limbs of Henle's loop of long-loop nephron isolated from hamsters.

The permselectivity of the upper portion of long descending limb of Henle (LDLu) was investigated with electrophysiological methods in the isolated perfused tubule preparation of hamster kidney. The diffusion potential (Vt) was determined in three different protocols. In protocol 1, the tubules were initially perfused with modified Krebs Ringer's solution on both sides of the epithelium. Then the bath solution was exchanged consecutively with another solution in which 50 mmol/l NaCl replaced by 50 mmol/l KCl, RbCl, NH4Cl, CsCl, LiCl, NaBr, NaNO3, NaI, Na acetate or 75 mmol/l NaCl replaced by mannitol. The permeabilities for these ions relative to chloride were calculated by Goldman's constant field equation. The segment was found to be cation selective, with all cations being 5-9 times more permeable than all anions. The sequence of permeability was K+ greater than Rb+ greater than Li+ greater than NH+4 = Cs+ greater than or equal to Na+ much greater than Cl- greater than or equal to Br- greater than or equal to NO3- greater than or equal to I- greater than Acetate-. In protocol 2, pure 150 mM NaCl was used for the basal solution to avoid interference by other ions. The bathing solution was exchanged by other solutions which contained 150 mmol/l KCl, NH4Cl, CsCl, RbCl, LiCl, NaI, NaBr, NaNO3, Na acetate or 75 mmol/l NaCl with mannitol. Thus simple biionic substitution was performed. Again, the segment was found to be cation selective, with all cations being 4-10 times more permeable than all anions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Flow-correlated influx of K, Ca, P, and Mg during continuous microperfusion of the loop of Henle in the rat.

Investigations on hydropenic rats were undertaken enabling us to determine the relative loop influx rates for potassium, calcium, magnesium, and phosphorus during end proximal continuous microperfusions at 15 or 35 nl . min-1 with saline free of these ions. Replicate quantitative collections were taken at collected flow rates of 9 or 26 nl . min-1. Element concentrations were determined by electron probe analysis. Results showed a significant influx of all four ions in the fluid collected at the early distal site, with magnesium showing the smallest entry rate. As expected, calcium and potassium concentrations at the early distal site increased with the perfusion flow rate. In contrast, phosphorus concentration decreased with flow. Phosphorus concentration at low flow was 0.43 +/- 0.06 mmole . liter-1 vs. 0.25 +/- 0.03 at high flow (P less than 0.01). However, increasing influx was seen with increasing flow for phosphorus (r = 0.58, P less than 0.001). Magnesium concentrations did not significantly change with flow although they were clearly different from zero: 0.12 +/- 0.02 vs. 0.10 +/- 0.02 mmole . liter-1. The rate of magnesium influx as a function of flow was also highly significant (r = 0.48, P less than 0.01). Thus, there is an increase in loop influx in all four ions with high flow rates despite disparate flow influences on early distal concentrations. In conclusion, these experiments demonstrate that (1) magnesium can enter the tubular lumen of the loop when this structure is perfused with a magnesium-free solution and (2) under our experimental conditions, phosphate can also enter the lumen suggesting that the concentration of phosphate at the early distal site is limited by the rate of entry.

Animals↗
PubMed1986

Lack of effect of non-steroid antiinflammatory drugs on lithium clearance and on delivery of tubular fluid to the loop of Henle in rats.

This paper examines a possible interaction between non-steroid antiinflammatory drugs (NSAI drugs) and renal lithium clearance in conscious, unoperated rats with diabetes insipidus (Brattleboro strain) and ordinary Wistar rats. The drugs were given with the food for 5 days before clearance determinations in the following daily doses per kg body weight: acetylsalicyclic acid 115 mg/kg, phenylbutazone 20 mg/kg, indomethacin 5 mg/kg, and penicillamine 65 mg/kg. None of the drugs affected the lithium clearance. Also urine flow, sodium clearance, potassium clearance, and prostaglandin E2 excretion remained unaffected by the treatments. The results suggest that a continued lowering of lithium clearance cannot be produced, at least not by administration of the drugs with the food. Since lithium clearance is a quantitative measure of the delivery of tubular fluid from the proximal tubules to the loop of Henle, the results also suggest that chronic administration of NSAI drugs does not influence delivery from the proximal tubules in rats. The lowering of lithium clearance observed by others after administration of the drugs by injection or by gastric tube may have been transient, lasting only for a short period after each administration.

Animals↗
PubMed1978

Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter's syncrome.

Maximal free-water clearance was measured in five patients with Bartter's syndrome and in five patients with the hypokalemic alkalosis of persistent psychogenic vomiting. Hypokalemic alkalosis, hyperreninemia, hyperaldosteronism and excessive renal production of prostaglandin E2 were present in the patients with both disorders. Maximal free water clearance was abnormally low, in association with a high clearance of chloride, in all the patients with Bartter's syndrome; it was normal in all the patients with psychogenic vomiting. In the patients with Bartter's syndrome, apparent distal delivery of proximal tubular fluid was inversely related to glomerular filtration rate and was excessive only in those patients with a low glomerular filtration rate. Patients with psychogenic vomiting showed mean distal fractional chloride reabsorption of 0.92 +/- 0.04 (standard error [SE]). In the patients with Bartter's syndrome, distal fractional reabsorption of chloride was 0.49 +/- 0.08 and was the same (0.46 +/- 0.06) during inhibition of prostaglandin synthesis with indomethacin therapy. Thus, a prostaglandin-independent defect in chloride reabsorption in the loop of Henle is the most proximal cause for the abnormalities in Bartter's syndrome thus far identified.

Bartter Syndrome↗