[Nitric oxide and the kidney during the development].
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Animals↗
Biomedical subjects
J J Helwig
Publications and source records attributed to J J Helwig.
Parathyroid hormone-related protein detection and interaction with NO and cyclic AMP in the renovascular system.
The presence of parathyroid hormone-related protein (PTHrP) in human kidney vasculature and the signal transduction pathways stimulated during PTHrP-induced vasodilation of the rabbit kidney were investigated. Immunostaining of human kidney revealed the abundant presence of PTHrP in media and intima of all microvessels as well as in macula densa. In isolated perfused rabbit kidney preconstricted with noradrenaline, 10(-5) M Rp-cAMPS, a direct inhibitor of protein kinase A, produced comparable inhibition of 2.5 x 10(-7) M forskolin- and 10(-7) M PTHrP-induced vasorelaxations. Renal vasorelaxation and renal microvessel adenylyl cyclase stimulation underwent comparable desensitization following exposure to PTHrP. Nitric oxide (NO)-synthase inhibition by L-NAME (10(-4) M), NO scavenging by an imidazolineoxyl N-oxide (10(-4) M) and guanylyl cyclase inhibition by methylene blue (10(-4) M) decreased PTHrP-induced vasorelaxation by 27 to 53%, abolished bradykinin-induced vasorelaxation and did not affect forskolin-induced vasorelaxation. The effects of Rp-cAMPS and L-NAME were not additive on PTHrP-induced vasorelaxation. Damaging endothelium by treating the kidney with either anti-factor VIII-related antibody and complement, gossypol or detergent, did not affect PTHrP- or forskolin-induced vasorelaxations but reduced bradykinin-induced vasorelaxation by 53 to 92%. Conversely, endothelial damage did not alter the inhibitory action of L-NAME on PTHrP-induced vasorelaxation. In conclusion, PTHrP is present throughout the human renovascular tree and juxtaglomerular apparatus. Activation of both adenylyl cyclase/protein kinase A and NO-synthase/guanylyl cyclase pathways are directly linked to the renodilatory action of PTHrP in a way that does not require an intact endothelium in the isolated rabbit kidney.
Adenylyl Cyclases↗
Effect of intrarenally infused parathyroid hormone-related protein on renal blood flow and glomerular filtration rate in the anaesthetized rat.
1. Parathyroid hormone-related protein (PTHrP) is expressed in the kidney and acts on vascular PTH/ PTHrP receptors to vasodilate the isolated kidney and to stimulate renin release. However, effects of PTHrP on renal blood flow (RBF) and glomerular filtration rate (GFR) in vivo have not been assessed in the absence of its cardiac, peripheral and central effects. We investigated the renal effects of PTH and PTHrP infused into the left renal artery of anaesthetized rats. 2. Intrarenal infusions, adjusted to generate increasing concentrations of human PTHrP(1-34) and rat PTH(1-34) in renal plasma (2 x 10(-11) to 6 x 10(-9) M) produced a comparable dose-dependent increase in RBF. The rise was 4% at the lowest and 34% at the highest concentrations of peptides. Up to a concentration of 2 x 10(-9) M, mean arterial pressure (MAP) and heart rate were not affected, but at 6 x 10(-9) M, intrarenally infused peptides reached the peripheral circulation, and caused a fall in MAP within a few minutes. While MAP returned to basal value after the last peptide infusion, RBF remained more than 10% above control for at least 30 min. 3. Two competitive PTH/PTHrP receptor antagonists, [Nle8,18, Tyr34]-bPTH(3-34)amide and [Leu11, D-Trp12]-hPTHrP(7-34)amide (2 x 10(-8) M) were devoid of agonist activity, but markedly antagonized the dose-dependent increase in RBF elicited by PTHrP. 4. GFR and urine flow were measured in left PTHrP-infused experimental kidney and right control kidney. Renal PTHrP concentration of 10(-10) M elevated left RBF by 10%, and GFR by 20% without significantly increasing filtration fraction, and increased urine flow by 57%. In the right control kidney GFR and diuresis did not change. 5. The results indicate that PTHrP has similar renal haemodynamic effects as PTH and increases RBF, GFR and diuresis in anaesthetized rats.
Animals↗
Parathyroid hormone-related protein as a cardiovascular regulatory peptide.
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Animals↗
Vascular effects of parathyroid hormone and parathyroid hormone-related protein in the split hydronephrotic rat kidney.
1. The effects of locally applied parathyroid hormone-related protein (PTHRP), a putative autocrine/paracrine hormone, on vascular diameters and glomerular blood flow (GBF) in the split hydronephrotic rat kidney were studied. As PTHRP interacts with parathyroid hormone (PTH) receptors in all tissues tested so far, the effects of PTHRP were compared with those of PTH. 2. Preglomerular vessels dilated in a concentration- and time-dependent manner that was almost identical for PTH and PTHRP. A significant preglomerular vasodilation (5-17%) occurred at a threshold concentration of 10(-10) mol l-1 PTH or PTHRP, which raised GBF by 20 +/- 2 and 31 +/- 4%, respectively (means +/- S.E.M., n = 6). PTH or PTHRP (10(-7) mol l-1) increased preglomerular diameters (11-36%) and GBF (60 +/- 10 and 70 +/- 8%, respectively) to near maximum. The most prominent dilatation was located at the interlobular artery and at the proximal afferent arteriole. 3. Efferent arterioles were not affected by either PTH or PTHRP. 4. Estimated concentrations of half-maximal response (EC50) for preglomerular vasodilatation and GBF increase were in the nanomolar to subnanomolar range. 5. After inhibition of angiotensin I-converting enzyme by 2 x 10(-6) mol kg-1 quinapril I.V. (n = 6), 10(-8) mol l-1 PTHRP dilated preglomerular vessels and efferent arterioles (9 +/- 1% proximal and 6 +/- 1% distal). 6. We conclude that the renal vasculature of the hydronephrotic kidney is highly sensitive to vasodilatation by PTH and PTHRP, which, in addition, may constrict efferent arterioles by stimulating renin release.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin-Converting Enzyme Inhibitors↗
Parathyroid-hormone-related protein: a previously unrecognized renal vasodilator.
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Animals↗
Involvement of nitric oxide in the vasodilatory response to parathyroid hormone-related peptide in the isolated rabbit kidney.
1. The present study was designed to explore the role of NO derived from L-arginine in the vasodilatory response to synthetic human parathyroid hormone-related peptide-(1-34) in the isolated rabbit kidney perfused in the presence of indomethacin (10 mumol/l) and preconstricted with noradrenaline (7.2 nmol/min). 2. Under control conditions, bolus administrations of acetylcholine (10 mumol/l), an NO-dependent renal vasodilator, verapamil (0.1 mmol/l), an NO-independent renal vasodilator, and parathyroid hormone-related peptide (87 nmol/l) decreased the preconstriction pressure, by 31%, 71% and 43%, respectively. 3. Bolus administration of 100 mumol/l NG-nitro-L-arginine-methyl ester caused a 20% increment in the perfusion pressure of the noradrenaline-preconstricted kidney. NG-nitro-L-arginine methyl ester inhibited the vasodilatory effect of acetylcholine and parathyroid hormone-related peptide, by 68% and 44%, respectively, but did not alter the verapamil-induced vasodilatation. 4. Unlike L-arginine, the bolus administration of 1 mumol/l of a mono-substituted L-arginine derivative, N-alpha-benzoyl-L-arginine ethyl ester, durable decreased the noradrenaline/NG-nitro-L-arginine methyl ester-induced preconstriction by 57%. 5. Both L-arginine and N-alpha-benzoyl-L-arginine ethyl ester effectively reversed the inhibition induced by NG-nitro-L-arginine methyl ester on the vasodilatation elicited by acetylcholine and parathyroid hormone-related peptide. 6. In conclusion, the formation of NO from L-arginine contributes a substantial part to the vasodilatory action of parathyroid hormone-related peptide. Therefore, parathyroid hormone-related peptide appears to have a place among the renal haemodynamically active substances, whose vasodilatory actions are tuned by NO.
Acetylcholine↗
Specific developmental profiles of lysosomal and brush border enzymuria in the human.
Various enzymatic urinary activities have been proposed to assess renal proximal tubule damage in children, including neonates. Nevertheless comprehensive knowledge on the developmental aspects of physiological enzymuria is limited, particularly with regard to lysosomal and brush border enzymuria. Urinary activities of two lysosomal enzymes, N-acetyl-beta-D-glucosaminidase (NAG) and beta-galactosidase (GAL), and of two brush border enzymes, alanine aminopeptidase (AAG) and gamma-glutamyltransferase (GGT) were comparatively investigated in normal prematures (n = 28), term neonates (n = 52), infants aged less than 2 years (n = 19) and children (n = 33), and compared to urinary excretion of beta 2-microglobulin (B2M). Enzymatic activities were assayed using either spectrophotometrical (NAG, AAP, GGT) fluorimetrical (GAL) or radioimmunological (B2M) methods, and were related to urinary creatinine excretion. Developmental profiles of both the studied lysosomal enzymes and of B2M were similarly characterized with significantly decreasing values from prematures (NAG 9.29 +/- 1.44, GAL 2.26 +/- 0.26 IU/mmol creatinine, indicated as mean +/- SEM) to term neonates (6,94 +/- 0.58 and 1.76 +/- 0.15 IU/mmol creatinine, respectively) and older infants and children. Lysosomal enzymatic urinary activities correlated linearly with a coefficient of r = 0.75, (p < 0.05), while correlations between each lysosomal enzymatic activity and B2M urinary excretion were weaker.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylglucosaminidase↗
Evidence for adenylyl cyclase-dependent receptors for parathyroid hormone (PTH)-related protein in rabbit kidney glomeruli.
Studies were conducted to test whether parathyroid hormone-related protein (PTHrP) is able to stimulate adenylate cyclase activity in isolated rabbit glomeruli. Maximal stimulations were reached at 10(-7) M of human PTHrP-(1-34) or rat PTH-(1-34) and showed a 3-3.3 fold increase over basal activity. The potency (EC50) values were close to 10(-9) M. The guanyl nucleotide GTP, at 10(-5) M, potentiated the effect of PTH and PTHrP but reduced their potency. The combined effect of maximal concentrations of PTHrP and PTH was not additive, and the PTH antagonist [Nle8.18, Tyr34]-bPTH-(3-34)amide inhibited both PTHrP- and PTH-stimulated adenylate cyclase activities. These findings suggest that PTHrP could affect glomerular function through changes in glomerular cAMP content by interaction with PTH receptors.
Adenylyl Cyclases↗
Renin stimulating properties of parathyroid hormone-related peptide in the isolated perfused rat kidney.
Previous studies showed that PTHrP exhibits renal vasodilating, arteriolar cAMP stimulating and receptor binding properties. The present experiments were designed to study whether PTHrP may influence renin secretion. Rat kidneys were isolated and single-pass perfused at constant flow and stabilized pressure. Exposures to PTHrP or PTH stimulated a dose-dependent renin release reaching similar Vmax. The affinity (0.1 nM) and threshold concentration (0.01 nM) for PTHrP were about 10 times lower than for PTH. Compared to 10 microM isoproterenol, the maximum renin responses to PTHrP were similar but of shorter duration. The PTHrP dose-response curve was not affected by 10 microM indomethacin. Administered simultaneously, PTHrP and PTH displayed no additive effects. PTHrP-induced renin release as well as the role of extracellular calcium were further studied in nonfiltering kidneys, which were perfused at a constant flow and stable pressure in a closed circuit. Basal renin release was inversely related with perfusate calcium and was depressed by the calcium ionophore BAY-K8644. PTHrP (100 nM) induced a 1.6-fold increase of basal renin release in normocalcic perfusate. Removing calcium abolished renin responses. PTHrP reversed the inhibiting effects of hypercalcic media or BAY-K8644 on basal renin release. The results support calcium-mediated renin stimulating properties for PTHrP, via PTH receptors, independently from baroreceptors, macula densa and prostaglandins.
Animals↗
Stimulatory action of parathyroid hormone on renin secretion in vitro: a study using isolated rat kidney, isolated rabbit glomeruli and superfused dispersed rat juxtaglomerular cells.
1. We have previously reported that pharmacological concentrations (125nmol/l) of parathyroid hormone may stimulate renin release in the stable recirculating and non-filtering isolated rat kidney. 2. In the present study we have attempted to extend these initial observations by examining the concentration-related response of renin release to parathyroid hormone, using the same model of isolated kidney, and determining whether the effect of parathyroid hormone on renin release can be demonstrated by more direct approaches. Thus, the effects of parathyroid hormone on renin secretion were investigated in two other renal preparations: isolated rabbit glomeruli and isolated rat juxtaglomerular cells. 3. In the isolated kidney, rat parathyroid hormone significantly stimulated renin accumulation in the perfusate in a concentration-related manner with a threshold of 1 nmol/l. 4. In both glomeruli and juxtaglomerular cells bovine [Nle8,18,Tyr34]parathyroid hormone-(1-34)amide effectively and repeatedly stimulated renin release. These results imply that there is a direct stimulatory effect of parathyroid hormone on renin release. 5. We also examined the effect of [Nle8,18,Tyr34]parathyroid hormone-(1-34)amide during extracellular calcium buffering in the glomeruli. [Nle8,18,Tyr34]parathyroid hormone-(1-34)amide was uneffective in calcium-free medium. Increasing the extracellular ionized calcium concentration to 2.5 mmol/l increased the extent of stimulation in accordance with the reported ability of parathyroid hormone to block calcium channels and relax vascular smooth muscle cells. 6. These results provide further support for the role of parathyroid hormone as a direct mediator of renin secretion; moreover, the renin-stimulating action of parathyroid hormone may be mediated through the inhibition of calcium influx.
Animals↗
[The scintigraphic effect of extracorporeal lithotripsy: prospective series of 25 cases].
25 patients with non complicated renal stones were treated by extracorporeal shockwave lithotripsy (ESWL) using Sonolith 3000 an electrohydraulic generator type. They were evaluated before, 15 days and 3 months after ESWL by renal scintigraphy, using for 15 of them technetium -99m dimer captosuccinic acid and technetium -99m-diethylene-triamine acetate for the last 10. This follow up scintigraphic study shows no reduction of glomerular filtration rate after ESWL but some focal parenchymal lesions. Very few of these lesions persist at 3 months. These parenchymal damages seem to be less frequent and less persistent than with piezo-electric lithotripter.
Adult↗
Parathyroid hormone and calcium: interactions in the control of renin secretion in the isolated, nonfiltering rat kidney.
The present study was designed to characterize the interaction of calcium and PTH in the control of renin release in isolated rat kidneys perfused in a closed circuit at constant flow. Kidneys were rendered nonfiltering using low perfusion pressures (70 mm Hg) and a hyperoncotic perfusate (100 g/liter BSA). Under these conditions, differences in perfusion pressure were less than 9 mm Hg between control and PTH-treated kidneys over the 50 min of perfusion. In the absence of PTH, renin release was inversely correlated with ionized calcium (Ca2+) concentration, with the highest release of renin noted with 1 mM EGTA and no added calcium. Also, verapamil treatment markedly elevated renin release, even in the presence of 2 mM Ca2+. In contrast, renin secretion was strongly depressed by 20 nM BAY-K8644 in the perfusate. In medium containing normal calcium concentrations (1 mM Ca2+), rat PTH(1-34) induced a 2-fold greater renin accumulation than in the control, non-PTH-treated kidneys. Isoproterenol induced a 5-fold stimulation under the same conditions. In the 0 Ca2+/1 mM EGTA perfusion, PTH did not elevate renin secretion. Renin release in response to PTH in 2 mM Ca2+ was similar to that observed in the 1 mM Ca2+ perfusion. PTH also reversed the effects of BAY-K8644 to suppress renin release. In verapamil-treated kidneys, PTH failed to stimulate renin release. These results indicate that PTH stimulates renin release by a process independent of the baroreceptors and macula densa. The Ca2+ modulation of PTH-induced renin release is consistent with the reported ability of PTH to block calcium channels and relax vascular smooth muscle.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Binding of parathyroid hormone and parathyroid hormone-related protein to vascular smooth muscle of rabbit renal microvessels.
The humoral hypercalcemia of malignancy factor (also called PTH-related protein or PTHrp) has been shown to produce effects similar to PTH in the kidney, bone, and cardiovascular system. Binding of PTHrp and PTH has been characterized in renal and osseous tissues, but not in vascular tissue. We have attempted to characterize the interaction of both human PTHrp and rat PTH to renal microvessels as a model of vascular smooth muscle and in a renal tubule preparation from the same rabbit kidneys. Previous studies have shown the microvessel and tubule preparations to be distinct based upon morphological examination, differential enzyme markers, calcitonin and vasopressin-sensitive adenylate cyclase distribution, and different characteristics of guanine nucleotide and of oxidized PTH activation of the adenylate cyclases associated with the preparations. Human PTHrp and rat PTH were iodinated by standard techniques and purified by HPLC. Both ligands bound to microvessels and tubules in a saturable, specific manner, Maximal specific binding of either ligand was 65-75% in microvessels and 80-90% in renal tubules. The time courses of binding of both ligands were identical with steady state achieved within 20 min in the smooth muscle of microvessels and 15 min in the tubules at 22 C. In equilibrium competition binding experiments, bound 125I-PTHrp was displaced by both PTHrp and PTH in microvessels and tubules. Rat PTH displayed slightly higher affinity in microvessels and tubules than PTHrp. Identical results were obtained with 125I-PTH as ligand. Specificity of binding of PTHrp and PTH to both microvessels and tubules was excellent, with competition observed between the radioactive ligand and bovine and rat PTH, PTHrp, and the antagonists, [Nle8,18, Tyr34]bovine PTH and [Nle8,18, Tyr34]bovine PTH but not with several other peptides of unrelated structure. The only major difference in binding between microvessels and tubules was a smaller number of binding sites in microvessels compared to tubules. These results indicate that vascular tissue contains receptor sites for PTH and PTHrp as identified by radioligand binding techniques. These receptors are similar in characteristics to the receptors of renal tubular tissue. Both PTH and PTHrp appear to interact with the receptors of rabbit kidney microvessels and tubules.
Animals↗
Renal vasodilatation and microvessel adenylate cyclase stimulation by synthetic parathyroid hormone-like protein fragments.
The hypercalcemia caused by malignancy factor, also called parathyroid hormone-related protein (PTHrP), exhibits most of the biological activities of parathyroid hormone (PTH) in kidney and bone. On the basis of the well-documented vascular action of PTH, we characterized the vasodilator action of human (h) PTHrP-(1-34) on a preparation of the isolated rat kidney, and its activity to stimulate adenylate cyclase in microvessels isolated from rabbit kidney cortex. Injection of sequential cumulative doses of hPTHrP-(1-34) into the isolated kidney preparation produced increasing vasodilatation up to 10(-8) M (EC50 of 3 x 10(-9) M) and decreasing responses thereafter. The maximal effect represented 26% of the reference relaxation induced by papaverine. Single injections of hPTHrP-(1-34) resulted in a greater (over 60%) vasodilatation. These results were reminiscent of the tachyphylaxis that occurs after repeated exposure to the peptide. The (3-34) PTH antagonist inhibited the hPTHrP-induced vasodilatation. Human PTHrP-(1-34) was equipotent with hPTH-(1-34) (EC50 values of 3 x 10(-9) M) but 5-fold less potent than rat (r) PTH-(1-34) in stimulating microvessel adenylate cyclase. GTP enhanced the enzyme responses to the peptides but reduced their potency. Both (3-34) and (7-34) PTH antagonists were inhibitors of hPTHrP- or PTH-stimulated microvascular adenylate cyclase. Synthetic hPTHrP-(1-16) had neither vasodilator nor adenylate cyclase-stimulating activity. This hPTHrP fragment exhibited some inhibitory effect on the hPTHrP-(1-34)-induced stimulation of microvessel adenylate cyclase. These results indicate that hPTHrP possesses PTH-like activity to cause vasorelaxation and to stimulate microvascular adenylate cyclase in the kidney.
Adenylyl Cyclases↗
Effects of bradykinin on prostaglandin synthesis and cytosolic calcium in rabbit subcultured renal cortical smooth muscle cells.
Smooth muscle cells were cultured from an arteriole-rich fraction of the rabbit renal cortex and characterized by their ultrastructural and immunohistochemical features, their high content in creatine kinase (60-times that of the initial preparation) and their ability to synthesize renin. Cells, studied between passages 2 and 5, produced mainly PGE2 and, to a lesser extent, PGF2 alpha. Bradykinin (BK) (0.1 nM-1 microM) induced a concentration-dependent increase in PGE2 (28-40-times basal value at 1 microM after a 5 min incubation period) and stimulated also the free cytosolic calcium concentration [( Ca2+]i) with a 2-fold maximal rise to its basal value. Both effects, inhibited by the anti-B2 receptor [Thi5.8D-Phe7] BK, were not reproduced by DesArg9 BK. A decrease in the extracellular calcium concentration and incubation in the presence of a calcium-channel blocker (lanthanum chloride) inhibited the BK-dependent rise of [Ca2+]i but not that of PGE2. Preincubation with phorbol myristate acetate increased basal and BK-induced PGE2 synthesis but prevented the effect of BK on [Ca2+]i. These results demonstrate the ability of BK to increase [Ca2+]i and PGE2 production in cultured vascular cells from the rabbit renal cortex and suggest that kinins might act on the cortical microcirculation via their direct effects on arteriolar smooth muscle cells.
Animals↗
The vasodilator action of parathyroid hormone fragments on isolated perfused rat kidney.
The renal vasodilator responses to various fragments of PTH were quantified on a model of isolated perfused rat kidney (IPK), under non-filtering conditions. The 1-34 fragment of bovine PTH, its Nle analogue and rat PTH, injected in sequential cumulative doses, caused concentration-dependent vasodilatation in the vasculature of the IPK which was preconstricted with prostaglandin F2 alpha. The EC50 of PTH for renal vasodilatation ranged from 1 to 2 nM for all PTH fragments and maximum vasodilatation ranged from 33 to 41% of the maximum vasodilatation induced by papaverine. Renal vasodilation was not related to prostaglandin release since similar vasodilatation occurred after the inhibition of prostaglandin synthesis with indomethacin. When PTH was administered in single bolus injections, using a separate kidney for each hormone concentration, rather than repeated injections into the same kidney, higher maximum vasodilatations were obtained (64%). These results most likely reflected tachyphylaxis of the renal vasculature to PTH occurring after repeated exposure of a single kidney to the hormone. The antagonist analogue [Nle8,18, Tyr34]-bPTH-(3-34)A shifted the concentration-related response curve to the right, indicating that the renal vasodilator response to rPTH-(1-34) involved specific vascular receptors.
Animals↗
Assay of tissue angiotensin converting enzyme.
The distinction between a circulating renin-angiotensin system and a tissue renin-angiotensin system led us to determine tissue angiotensin converting enzyme (ACE) activity. This study establishes the experimental conditions for a good reproducibility of the fluorimetric assay of ACE and describes the use of [3H]ramiprilat to characterize ACE. Angiotensin converting enzyme activity was determined in rat lung, heart, aorta, and kidney (cortex and medulla) and in rabbit kidney (cortex, medulla, tubules, and glomeruli). ACE activity and [3H]ramiprilat binding does not increase in a linear fashion with the protein content of tissue extracts. Linearity limits varied from 1.0 to 2.0 mg of protein/ml (fluorimetry) and from 0.4 to 1.0 mg of protein/ml [( 3H]ramiprilat binding). Comparing ACE activity, measured by fluorimetry, with the amount of [3H]ramiprilat bound shows that the two techniques yield similar results.
Animals↗