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T Maack

Publications and source records attributed to T Maack.

At least 19 recordsLinked to original sources
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↗
PubMed1990

Atrial natriuretic factor receptors in cultured renomedullary interstitial cells.

To gain further insight on the cell types that may mediate the effects of atrial natriuretic factor (ANF) in the renal medulla, we determined the distribution and function of biological (B) and clearance (C) receptors of ANF in renomedullary interstitial cells (RMIC). Studies were performed in the 3rd-17th passages of RMIC obtained from a primary culture of the rat renal medulla. Electron microscopy of the cultured cells showed the typical morphological features of RMIC "in vivo," including prominent lipid droplets. RMIC have a very high density of high-affinity specific binding sites of ANF-(1-28) [23,000 sites/cell; dissociation constant (Kd) = 50 pM]. There was only minimal binding of C-ANF-(4-23) (less than 2,500 sites/cell), a specific ligand of C-ANF receptors. ANF-(1-28) markedly increased guanosine 3',5'-cyclic monophosphate (cGMP) from 1.3 +/- 0.3 to 106 +/- 22 pmol cGMP/10(6) cells [50% effective dosage (ED50) = 1.2 nM]. The effect of ANF-(1-28) on cGMP was nearly additive to that of sodium nitroprusside and was not potentiated or antagonized by C-ANF-(4-23). The density of guanylate cyclase-coupled B-ANF receptors and the ANF-induced increase in cGMP in RMIC are higher than those reported to date in other target cells. This suggests that RMIC may mediate some of the known effects of ANF in the renal medulla.

Animals↗
PubMed1989

Clearance function of type C receptors of atrial natriuretic factor in rats.

The overwhelming majority of atrial natriuretic factor (ANF) receptors in kidney and vascular tissues do not mediate any of the known functional effects of the hormone. To test whether these receptors (C-ANF receptors) function as clearance receptors for circulating ANF-(1-28), we determined the effects of C-ANF-(4-23) [des[Gln18Ser19Gly20Leu21Gly22]rANF-(3-23)-NH2], a specific ligand of C-ANF receptors, on the pharmacokinetics and hydrolysis of 125I-labeled ANF-(1-28) in anesthetized rats. Radioactivity in plasma was characterized by trichloroacetic acid solubility and high-pressure liquid chromatography. C-ANF-(4-23) (1 and 10 micrograms.min-1.kg body wt-1) led to marked dose-dependent increases in initial plasma concentration of administered 125I-ANF-(1-28) and decreases in its volume of distribution at steady state (Vss), metabolic clearance rate (MCR), and appearance of hydrolytic products ([125I]monoiodotyrosine and free 125I) in plasma (Pm). At the highest dose, C-ANF-(4-23) decreased Vss from 97 +/- 12 to 36 +/- 2 ml/100 g body wt, MCR from 50 +/- 4 to 12 +/- 1 ml.min-1.100 g body wt-1, and Pm from 54 +/- 8 to 11 +/- 2% of initial plasma 125I-ANF-(1-28). The data demonstrate that C-ANF receptors are mainly responsible for the very large volume of distribution and fast MCR of ANF in the rat. In this manner, C-ANF receptors are likely to play an important role in the homeostasis of circulating ANF.

Animals↗
PubMed1987

Physiological role of silent receptors of atrial natriuretic factor.

A ring-deleted analog of atrial natriuretic factor--des[Gln18, Ser19, Gly20, Leu21, Gly22] ANF4-23-NH2 (C-ANF4-23)--binds with high affinity to approximately 99% of ANF receptors in the isolated perfused rat kidney. In this preparation, C-ANF4-23 is devoid of detectable renal effects and does not antagonize any of the known renal hemodynamic and natriuretic actions of biologically active ANF1-28. In contrast, both C-ANF4-23 and ANF1-28 increase sodium excretion and decrease blood pressure in intact anesthetized rats. This apparent contradiction is resolved by the finding that the ring-deleted analog markedly increases plasma levels of endogenous immunoreactive ANF in the rat. The results show that the majority of the renal receptors of ANF are biologically silent. This new class of receptors may serve as specific peripheral storage-clearance binding sites, acting as a hormonal buffer system to modulate plasma levels of ANF.

Animals↗
PubMed1987

Binding and functional effects of atrial natriuretic factor in isolated rat kidney.

A new methodological approach was developed to study the relationship between specific binding and dose-response curves of the renal effects of atrial natriuretic factor (ANF) in isolated perfused rat kidneys (IK). IK were perfused with 125I-labeled and unlabeled ANF 1-28 (4 pM to 1 microM) to determine the following: 1) distribution, capacity (Cmax), and apparent affinity (S50) of specific binding of ANF 1-28 in cortex, outer medulla, and papilla and 2) dose-response curves of the effects of ANF 1-28 on renal hemodynamics and excretion of fluid and electrolytes. The kidney had a very high density of high-affinity binding sites for ANF. Cortex had greater than 90% of total binding sites (Cmax = 6.8 pmol/g tissue; S50 = 54 pM), whereas papilla had less than 2% of total binding sites with a 10-fold lower apparent affinity (S50 = 860 pM) than in cortex. ANF-induced increases in glomerular filtration rate and excretion of fluid and electrolytes were detectable at 10-100 pM and maximal effects occurred at 1-10 nM ANF. Below 1 nM there was no dissociation between the renal hemodynamic and natriuretic effects of ANF. There was a close agreement between dose-response and binding curves of ANF to cortex. Results demonstrate that binding site occupancy in kidney cortex and renal effects of ANF occur at near physiological concentrations of the hormone.

Animals↗
PubMed1987

Effects of atrial natriuretic factor on the kidney and the renin-angiotensin-aldosterone system.

ANF is a peptide hormone with peripheral and central effects on several physiologic control systems, which suggests broad involvement in the regulation of intravascular volume and cardiovascular homeostasis. ANF acts directly on the kidney to modulate renal vascular resistance, increase glomerular filtration rate, and decrease inner medullary hypertonicity. These hemodynamic effects act in concert to promote marked natriuresis and diuresis and to inhibit renin secretion by the kidney; the potential role of direct effects on tubular transport and on the juxtaglomerular cells remains to be clarified. ANF also inhibits steroidogenesis, most prominently affecting agonist-induced aldosterone biosynthesis by the adrenal cortex. ANF exerts a smooth muscle relaxant effect on isolated vessels constricted with various hormonal agonists. ANF causes especially pronounced antagonism of the adrenal and vascular actions of angiotensin II and antagonizes the latter peptide's central nervous system effects. Although complex systemic hemodynamic mechanisms are involved, ANF-induced vasorelaxation may contribute to its depressor action, particularly in states characterized by angiotensin II-induced vasoconstriction. Distention of the atria is a major stimulus to ANF release and evokes many responses that are mimicked by ANF infusion. Although ANF is not the sole or even dominant mediator of the responses to atrial distention, available data suggest that it plays a role in the renal and hormonal responses to intravascular volume expansion. Definitive assessment of its physiologic and pathophysiologic significance must await development of specific antagonists, but further studies on the mechanisms of action of ANF at the molecular, cellular, and systemic levels are likely to contribute significantly to our understanding of the complex process of volume regulation and cardiovascular homeostasis.

Animals↗
PubMed1986

Renal vasoconstrictive effect of kinins mediated by B1-kinin receptors.

The nature of the renal vascular actions of kinins, their dependence on prostaglandins and B1-kinin receptor responses were studied in functioning isolated perfused rat kidneys (IK). Lysylbradykinin (LBK), 0.28 and 0.7 microM, transiently decreased and then markedly increased the renal vascular resistance (RVR) in a sustained manner. Bradykinin (BK) at the same doses also had a transient vasorelaxant but not a sustained vasoconstrictive effect. The inactivation of LBK and BK by the IK did not account for the transient nature of their vasorelaxant effect. Indomethacin (5 microM) markedly blunted LBK-induced decrease but not increase in RVR. The B1-kinin receptor agonist desArg9-BK (0.4-1.0 microM) did not decrease RVR but, as LBK, markedly increased RVR in a dose-related manner. The B1-kinin receptor antagonist [Leu8]desArg9-BK had no effect on its own but inhibited the desArg9-BK-induced vasoconstriction in a stoichiometric manner. This antagonist at 4.0 microM also completely abolished the vasoconstrictive effect of 0.7 microM LBK, whereas it potentiated and prolonged its vasorelaxant effect. The results demonstrate that kinins, particularly LBK, have bimodal effects on the renal vascular resistance of the isolated perfused rat kidney. The vasorelaxant effect is at least partly mediated by prostaglandins whereas the vasoconstrictive effect of LBK and/or its renal metabolites has the typical character of a B1-kinin receptor response. It is postulated that B1-kinin receptor responses may be of importance in the generation and/or maintenance of renal vasoconstriction in disease states which lead to renal failure.

Animals↗
PubMed1986

Atrial natriuretic factor increases hematocrit and decreases plasma volume in nephrectomized rats.

To test the hypothesis that ANF increases the efflux of fluid from capillaries we determined the effect of synthetic (1-28) ANF on hematocrit (Hct) and plasma volume (PV) in 24 hr bilaterally nephrectomized rats. Results were compared with those obtained in bilaterally nephrectomized rats receiving saline alone (S) or an infusion of sodium nitroprusside (NP) to produce a similar blood pressure lowering effect as ANF. PV was determined by the volume of distribution of RISA 10 minutes after its i.v. administration. After control periods (C) rats were infused for 40 minutes with saline alone (group A, n = 8), (1-28)ANF, 0.3 micrograms X min-1/kg body wt (group B, n = 9), 1.0 microgram X min-1/kg body wt (group C, n = 8) and NP, 1.0 to 2.0 micrograms X min-1/kg body wt (group D, n = 8). Recovery periods (R) were performed 45 minutes after the experimental periods (E). During E periods, mean arterial blood pressure did not change in group A and fell significantly (p less than 0.01) in the other groups. Group B: C = 89 +/- 4; E = 82 +/- 4 mmHg. Group C: C = 106 +/- 7; E = 92 +/- 7 mmHg. Group D: C = 104 +/- 5; E = 90 +/- 5 mmHg. Neither saline or NP changed Hct, whereas, ANF significantly (p less than 0.01) increased this parameter (Group B: C = 43.4 +/- 0.7; E = 46.3 +/- 0.6% and Group C: C = 44.5 +/- 1.2; E = 47.4 +/- 1.2%). ANF significantly decreased PV (3.86 +/- 0.14 ml/100 gm body wt) as compared to S (4.51 +/- 0.22 ml/100 gm body wt; p less than 0.05) or NP (4.69 +/- 0.11 ml/100 gm body wt; p less than 0.01). The average decrease in PV of 14% corresponded to the average increase in Hct of 7%. Results demonstrate that ANF increases the efflux of fluid from capillaries. This effect explains, at least in part, the ANF-induced decrease in cardiac output and blood pressure in normotensive animals and may play an important role in the homeostatic regulation of plasma volume.

Animals↗