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T Maack

Publications and source records attributed to T Maack.

At least 19 recordsLinked to original sources
PubMed1997

Cloning of an unusual natriuretic peptide from the South American coral snake Micrurus corallinus.

In the course of cloning abundant cDNAs from the South American coral snake Micrurus corallinus venom gland, we characterized a cDNA coding for a putative natriuretic peptide. All the natural natriuretic peptides described so far, possess a ring structure composed of 17 amino acids formed through an S-S bridge which is extended at the N-terminus by few to several amino acids and may be extended at the C-terminus, usually 4-7 amino acids. In contrast, the M. corallinus natriuretic peptide presents several distinct features: (a) the proform of the deduced natriuretic peptide displays an unusual C-terminus extension. This implies that the mature peptide has a long C-terminal tail or it is further extensively processed to result in the mature natriuretic peptide with the expected 4-7 amino-acid extension. (b) the deduced natriuretic peptide presents an unusual internal Cys within the ring structure. This raises the possibility of natriuretic peptides with a smaller ring structure. (c) the putative natriuretic peptide is flanked by two homologous peptides of unknown function. In addition, an analogous peptide was synthesized and assayed on perfused rat kidney, showing a dose-dependent response in urinary volume and sodium excretion. Moreover, northern-blot studies showed that M. corallinus natriuretic peptide transcripts were highly expressed in venom glands, but they were not detectable in other tissues like heart and brain, suggesting a main role for this M. corallinus natriuretic peptide in the venom gland or in the envenomation by this coral snake's bite.

Amino Acid Sequence↗
PubMed1996

Molecular determinants of the clearance function of type C receptors of natriuretic peptides.

Receptor-mediated endocytosis is the cellular mechanism by which type C receptors of natriuretic peptides exert their clearance function. In the present work, performed in recombinant Chinese hamster ovary cells stably transfected with wild type or mutated human kidney C receptors, we determined net endocytic rates (ER) of C receptor-ligand complexes, lysosomal hydrolysis of ligand (125I-labeled native atrial natriuretic factor, ANF1-28), and receptor recycling. Equilibrium ligand binding, immunocytochemistry, and immunoprecipitation were performed to characterize the transfected receptors. The net ER of recombinant wild type C receptors was approximately 6% of occupied receptors internalized per min, and C receptor-mediated lysosomal hydrolysis of ligand amounted to approximately 250% of specifically bound 125I-ANF1-28/h, with efficient recycling of internalized C receptors to the cell surface. Hypertonic sucrose reduced net ER and lysosomal hydrolysis of 125I-ANF1-28 more than 10-fold, indicating that endocytosis occurred via clathrin-coated pits. Total deletion of the cytoplasmic domain also reduced net ER and lysosomal hydrolysis of 125I-ANF1-28 by almost 10-fold, whereas deletion of the terminal 28 amino acids of the cytoplasmic tail led to a 4-fold reduction in these parameters. Replacement of cytoplasmic domain Tyr508 by Ala, or Tyr508 and Phe538 by Ala, reduced net endocytosis and lysosomal hydrolysis of 125I-ANF1-28 by 40-50%. Replacement of extracellular domain Cys473 by Ala impeded the constitutive formation of homodimers and reduced by approximately 50% the net ER and lysosomal hydrolysis of 125I-ANF1-28. These results demonstrate that the cytoplasmic domain of C receptors, Tyr508 within this domain, and constitutive receptor dimerization are the major molecular determinants of the clearance function of C receptors.

Amino Acid Sequence↗
PubMed1996

Role of atrial natriuretic factor in volume control.

Atrial natriuretic factor (ANF) is a 28 amino acid polypeptide hormone secreted mainly by the heart atria in response to atrial stretch. ANF acts on the kidney to increase sodium excretion and GFR, to antagonize renal vasoconstriction, and to inhibit renin secretion. In the cardiovascular system, ANF antagonizes vasoconstriction, and shifts fluid from the intravascular to the interstitial compartment. In the adrenal gland, ANF is a powerful inhibitor of aldosterone synthesis. ANF participates importantly in the natriuretic response to acute and chronic volume overload. ANF's property of shifting fluid from the vascular to the interstitial compartment acts as a buffering device, guarding against excessive plasma volume expansion in face of an increased total extracellular fluid volume. ANF is also a physiological modulator of GFR, and mediates nephron hyperfiltration and natriuresis when salt excretion is threatened by a reduction in the number of nephrons. Guanylyl cyclase (GCA) receptors mediate the effects of ANF by generating cGMP. Clearance receptors remove ANF from the circulation by receptor-mediated endocytosis, and serve as a hormone buffer system to impede large inappropriate fluctuations in plasma levels of ANF. The specific structure-function-dynamics relationships of these receptors serve to modulate the role of ANF in pressure-volume homeostasis.

Amino Acid Sequence↗
PubMed1994

Conversion of T-kinin to bradykinin by the rat kidney.

Isolated rat kidneys were perfused with T-kinin (TK, Ile-Ser-BK) and bradykinin (BK). HPLC analysis of perfusate samples taken at 2-10 min during the TK perfusion (0.5 nmol/mL initial concentration) showed two peptide peaks, the first one eluting at 14.42 min, the same retention time for standard BK, and the second at 16.20 min, corresponding to that of TK. When BK (0.5 nmol/mL) was perfused, only its corresponding peak was obtained although total BK recovery was reduced quickly, as expected. Using both HPLC analysis and a kinin bioassay on the isolated guinea pig ileum, it was found that 12% of the added TK was converted to BK during the first perfusion cycle (2 min). While the BK recovered (12-14% from the initial TK concentration) was maintained at a similar proportion between the 2nd and the 10th min of perfusion, the rate of TK disappearance, as well as its full recovery from the perfusate, indicated further fragmentation of peptides during kinin perfusion. In the presence of 5 microM DL-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (Mergetpa), an inhibitor of plasma carboxypeptidase N (EC 3.4.17.3), the rate of conversion of TK to BK was not affected. On the other hand, the kinase II inhibitor bradykinin potentiating peptide 9a (BPP9a) increased both the proportion of TK converted to BK and the disappearance rate of TK from the perfusate. In the presence of BPP9a, the rate of BK production increased from 1.5 +/- 0.2 to 7.6 +/- 0.9 nmol/min. Furthermore, the recovery of BK was reduced during the first 2 min of perfusion to 7.6% and the conversion rate to 0.9 nmol/min when TK was perfused into the kidney in the presence of 10 microM bestatin, a known inhibitor of aminopeptidases. These data indicate that in the kidney TK is converted to BK, probably by aminopeptidase M, thus suggesting that BK is, in fact, an additional and functional kinin, inducing physiological and/or pathophysiological effects in the rat kidney in which TK is the main kinin released.

3-Mercaptopropionic Acid↗
PubMed1992

Dynamics of atrial natriuretic factor-guanylate cyclase receptors and receptor-ligand complexes in cultured glomerular mesangial and renomedullary interstitial cells.

The dynamics of the guanylate cyclase receptor of atrial natriuretic factor (GCA-ANF receptor) were investigated in cultured glomerular mesangial and renomedullary interstitial cells from the rat. In these cells, the GCA-ANF receptor did not mediate internalization and lysosomal hydrolysis of 125I-ANF1-28 and did not undergo ligand-induced endocytosis. Glomerular mesangial cells were able, however, to mediate internalization and lysosomal hydrolysis of 125I-ANF1-28 via clearance ANF (C-ANF) receptors and to promote rapid receptor-mediated internalization and lysosomal hydrolysis of 125I-(Sar1) angiotensin II. Radioligand specifically bound to surface GCA-ANF receptors was rapidly dissociated at 37 degrees C (k(off) greater than 0.8 min-1), with a Q10(30-37 degrees C) greater than 6. The dissociation was markedly slower at subphysiological temperatures (Q10(4-30 degrees C), 2-3) or in the presence of 0.5 mM amiloride. The results demonstrate that the GCA-ANF receptor, contrary to C-ANF receptors and most other polypeptide hormone receptors, is a membrane resident protein that does not mediate internalization and lysosomal hydrolysis of ligand. The termination of the interaction of ANF with GCA-ANF receptors results from a physiological process that leads to rapid dissociation of receptor-ligand complexes. The unique dynamics of GCA-ANF receptor-ligand complexes are likely to contribute importantly to stimulus-response homeostasis of ANF.

Amiloride↗
PubMed1992

Renal receptors and effects of atrial natriuretic factor in compensatory renal hypertrophy.

In the present study we investigated the in vivo and in vitro renal responsiveness to ANF, and the adaptation of ANF receptors in compensatory renal hypertrophy in the rat. One week after left nephrectomy (UNx), plasma levels of immunoreactive ANF, blood pressure (MAP), hematocrit (Hct), and urine flow rate (V) were unaltered compared to control (C) rats. Baseline GFR and potassium excretion (UKV) were significantly higher, and sodium excretion (UNaV) tended to be elevated in UNx rats. Administered ANF led to similar dose-related decreases in MAP and increases in Hct in UNx and C rats. However, at each dose of infused ANF, absolute values and the increase in GFR and UNaV were higher in UNx than in C rats. Hypertrophied (H) kidneys were removed from UNx and perfused in vitro to determine distribution and density of ANF receptors, responsiveness to ANF, and receptor-mediated organ clearance of 125I-ANF1-28. The density of ANF receptors in cortex, outer medulla, and papilla of H kidneys was not significantly different from that in C kidneys. In H isolated kidneys, ANF led to dose-related increases in GFR, V, UNaV, and UKV that were indistinguishable (P greater than 0.05) from those in C kidneys. Receptor-mediated organ clearance of 125I-ANF1-28 in isolated H kidneys was 2.8 +/- .02 ml/min, a value not significantly different (P greater than 0.05) from that in C kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Clearance receptor and neutral endopeptidase-mediated metabolism of atrial natriuretic factor.

A novel small linear C-atrial natriuretic factor receptor ligand [C-ANF-(11-15)] and phosphoramidon (PHO) were used to determine the effects of C-ANF receptor blockade alone, or in combination with inhibition of neutral endopeptidase (NEP), on the pharmacokinetics and metabolism of ANF in the rat. C-ANF-(11-15) infusion decreased apparent volume of distribution (Vss) and metabolic clearance rate (MCR) of administered 125I-ANF-(1-28) to one-third of their control values, whereas PHO alone was without effect on these parameters. In combination with C-ANF-(11-15), however, PHO further decreased MCR of 125I-ANF-(1-28) and increased plasma half time by more than threefold. High-performance liquid chromatography analysis revealed that C-ANF-(11-15) inhibited the delayed appearance of free 125I and [125I]monoiodotyrosine but had no effect on the small proportion of NEP metabolites in plasma. The combination of C-ANF-(11-15) and PHO further delayed the appearance of small metabolites, abolished the appearance of NEP metabolites, and markedly prolonged the permanence of intact 125I-ANF-(1-28) in plasma. The results demonstrate that C-ANF receptor blockade by C-ANF-(11-15) impairs clearance and metabolism of ANF, an effect which is synergistically potentiated by concomitant inhibition of NEP. C-ANF-(11-15) alone or in combination with NEP inhibitors may be a potentially useful therapeutic tool in the treatment of cardiovascular and renal diseases.

Animals↗
PubMed1991

DuP 753 is a potent nonpeptide antagonist of angiotensin II receptors in isolated perfused rat kidney and cultured renal cells.

In the present study we investigated the antagonist action of DuP 753 (2-n-butyl-4-chloro-5-hydroxy-methyl-1-[2'-(1H-tetrazol-5-yl)biphe nyl-4-yl) methyl]imidazole, potassium salt) on angiotensin II (AII) binding and vascular effects in the isolated perfused rat kidney. In addition, we determined binding of DuP 753 in cultured glomerular mesangial cells and renomedullary interstitial cells. In the isolated kidney, DuP 753 fully displaced AII from its specific binding sites with high affinity (IC50 = 200 nmol/L) and antagonized the vasoconstrictive effect of AII in a dose-related manner with an ED50 of 170 nmol/L. These effects of DuP 753 were qualitatively similar to those of saralasin and the antagonist effect of DuP 753 on AII-induced renal vasoconstriction was fully overcome by excess AII. DuP 753 had no effect on its own on renal vascular resistance. In cultured glomerular mesangial cells and renomedullary interstitial cells, DuP 753 fully inhibited the specific binding of [125I]-Sar-AII at 1 mumol/L with IC50s of 6.7 and 11 nmol/L for glomerular mesangial cells and renomedullary interstitial cells, respectively. The present results demonstrate that a novel imidazole derivative, DuP 753, is a powerful non-peptide antagonist of angiotensin II receptors in isolated perfused rat kidney and in cultured glomerular mesangial and renomedullary interstitial cells.

Angiotensin Receptor Antagonists↗
PubMed1991

Effects of small C-ANF receptor ligands on plasma levels of atrial natriuretic factor, blood pressure, and renal function in the rat.

In this article, after a very brief review on ANF receptors, we report our study on the effects of small C-ANF receptor ligands in the rat. Two small ligands were synthesized: 2-naphthoxyacetyl-isonipecotyl-rANF11-15-NH2 (5 aa), containing 5 amino acids; and Ala7-rANF8-17-NH2 (10 aa), containing 10 amino acids from the ring structure of ANF1-28. After control periods, 5 aa or 10 aa were infused i.v. at a dose of 10 micrograms.min-1.kg-1 body weight for 70 min in anesthetized rats, followed by a 60-min recovery period. The 5 aa and 10 aa peptides significantly and reversibly increased plasma levels of endogenous immunoreactive ANF by 106 +/- 29 and 52 +/- 24 pg/mL, respectively. Infusion of the 5 aa peptide significantly decreased mean arterial blood pressure from 113 +/- 1 to 100 +/- 3 mmHg (1 mmHg = 133.32 Pa) and increased glomerular filtration rate from 1.6 +/- 0.2 to 2.3 +/- 0.2 mL/min, sodium excretion from 0.6 +/- 0.3 to 3.4 +/- 0.4 mumol/min, and potassium excretion from 0.5 +/- 0.2 to 1.2 +/- 0.2 mumol/min. Similar results were obtained with the 10 aa peptide. The effects of both peptides on blood pressure and sodium excretion persisted throughout the recovery period. The results confirm and extend previous observations showing that C-ANF receptors mediate the removal of ANF from the circulation. The shortening of the minimal peptide length necessary to bind to C-ANF receptors markedly enhances the possibility of developing orally active C-ANF receptor ligands for the treatment of cardiovascular and renal diseases.

Amino Acid Sequence↗
PubMed1991

Half-life, hemodynamic, renal, and hormonal effects of prorenin in cynomolgus monkeys.

Prorenin is found in human plasma, kidneys, and reproductive organs. We investigated the physiological and pharmacokinetic properties of plasma prorenin, and its plasma conversion to active renin, by bolus infusions of human recombinant prorenin (0.5, 2, 20 micrograms; n = 4/dose) into anesthetized male cynomolgus monkeys. The infused prorenin had 3% intrinsic renin activity. Plasma prorenin rose from 61 +/- 6 to 101 +/- 11, 570 +/- 46, and 7,700 +/- 390 ng.ml-1.h-1, respectively, after 5 min. Plasma renin increased to 3% of total renin, angiotensin II increased less than twofold, and aldosterone did not change. Plasma testosterone fell slightly (P less than 0.01). Mean arterial pressure (MAP) fell slowly from 104 +/- 3 to 93 +/- 3 mmHg at 60 min (P less than 0.001). Heart rate, glomerular filtration rate, renal plasma flow, and urinary sodium and potassium excretion were unchanged. For the 2- and 20-micrograms doses, respectively, effective half-life of plasma decay was 47 +/- 4.9 and 109 +/- 21 min (P less than 0.05), apparent volume of distribution was 145 +/- 11 and 166 +/- 35 ml/kg, and metabolic clearance rate was 2.30 +/- 0.44 and 1.08 +/- 0.14 ml.min-1.kg-1 (P less than 0.01). In conclusion, neither the hormonal nor the physiological response to infusion of pharmacologic levels of recombinant human prorenin into monkeys provide evidence for conversion of circulating prorenin to renin. MAP did not increase and actually fell without commensurate effects on renal function. The half-life of recombinant prorenin was similar to that of renin.

Aldosterone↗
PubMed1991

High salt intake increases the vasorelaxant effect of ANF on the isolated perfused rat kidney.

1. The objective of the present study was to determine whether chronic salt load or depletion leads to adaptive changes in kinetics of atrial natriuretic factor (ANF) binding and/or responsiveness to ANF. We measured the equilibrium binding to and the steady-state dose-response effects of ANF1-28 on isolated kidneys from rats kept on a high (H) or low (L) salt diet for 15 days. 2. Twenty-four hour sodium excretion was 5.90 +/- 0.46 mEq for H vs 0.06 +/- 0.01 mEq for L (P less than 0.01). Plasma levels of immunoreactive ANF of H (42.2 +/- 3.9 pg/ml) were not significantly different from those for L (35.2 +/- 5.3 pg/ml). 3. There was no significant differences in distribution, apparent density or affinity of ANF specific binding sites determined in non-filtering isolated kidneys from rats kept on the H or L salt diet. 4. Dose-response curves for the hemodynamic and excretory effects of ANF1-28 in filtering isolated kidneys from rats kept on the H salt diet were not different from those of rats kept on the L salt diet. In contrast, the vasorelaxant response to ANF1-28 in isolated kidneys preconstricted by adding serum from 24-h nephrectomized rats to the perfusate (generation of angiotensin II) was significantly more pronounced in kidneys front rats chronically adapted to the high-salt diet. 5. This effect of ANF may contribute to the increased renal plasma flow and glomerular filtration rate occurring under conditions of chronic salt loading in intact animals.

Animals↗
PubMed1990

Cellular mechanisms of the clearance function of type C receptors of atrial natriuretic factor.

Clearance (C) receptors of atrial natriuretic factor (ANF) have an important role of removing ANF from the circulation. In the present study we investigated the cellular mechanisms of this function. 125I-ANF1-28 specifically bound to C-ANF receptors in cultured bovine vascular smooth muscle cells is internalized by a temperature-dependent process at a rate of 5% occupied receptors/min at 37 degrees C. Internalized 125I-ANF1-28 is rapidly metabolized and released to the medium as [125I]monoiodotyrosine, a process that is reversibly inhibited by NH4Cl (10 mM). Retroendocytosis of receptor-ligand complex is detectable when intracellular accumulation of the ligand is maximized by previous incubation with NH4Cl. In the presence of saturating concentrations of 125I-ANF1-28 when cells are warmed from 4 to 37 degrees C, there is first a decrease and then an almost complete replenishment of surface C-ANF receptors, a phenomenon that is not altered by protein synthesis inhibition with cycloheximide. In the absence of temperature transition, the density of surface C-ANF receptors remains constant, and by 2 h of incubation the amount of ANF hydrolyzed far exceeds the total amount of C-ANF receptors. The total population of surface C-ANF receptors is internalized and recycled every hour, and these processes are constitutive since they also occur in the absence of ligand. Trypsinization and solubilization experiments further indicate that C-ANF receptors are rapidly internalized and recycled to the cell membrane. The results demonstrate that receptor-ligand internalization, extensive receptor recycling, and lysosomal hydrolysis of ANF are the cellular mechanisms by which C-ANF receptors exert their clearance function.

Animals↗
PubMed1990

Endocytosis and lysosomal hydrolysis of proteins in proximal tubules.

The techniques and basic protocols described above can be readily reproduced by investigators with experience in perfusion of isolated nephron segments. They can be modified and adapted by the investigator to address specific issues. In particular, isolated perfused nephron segments have also been successfully used for elucidation of biochemical and morphological aspects of endocytosis and lysosomal hydrolysis of macromolecules, proteins, and polypeptides. The reader is directed to the references cited under Methodological Approaches in this chapter for a description of these techniques. Although studies on the endocytic uptake and metabolism of proteins and polypeptides using isolated perfused nephron segments have made significant inroads in our understanding of these fascinating and important biological processes, much remains to be learned. Hopefully, future uses of the technique will further advance our knowledge in this field.

Absorption↗