Renal localization and actions of adrenomedullin: a natriuretic peptide

1995 ◽  
Vol 268 (4) ◽  
pp. F657-F663 ◽  
Author(s):  
M. Jougasaki ◽  
C. M. Wei ◽  
L. L. Aarhus ◽  
D. M. Heublein ◽  
S. M. Sandberg ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Collecting Duct ◽  
Plasma Concentrations ◽  
In Vivo Studies ◽  
Sodium Reabsorption ◽  
Contralateral Kidney ◽  
Arterial Blood ◽  
Group I

Adrenomedullin (ADM) is a newly described 52-amino acid peptide originally isolated from extracts of human pheochromocytoma and, more recently, detected in human plasma. Based on the report that ADM mRNA and immunoreactivity are present in the kidney, the current study was designed to determine the renal distribution of ADM by immunohistochemistry and the renal biological actions of ADM. In the immunohistochemical studies, the present investigation demonstrated the localization of ADM in glomeruli, cortical distal tubules, and medullary collecting duct cells of the normal canine kidney. In the in vivo studies, ADM was administered (0.25 ng.kg-1.min-1 in group I and 1, 5, and 25 ng.kg-1.min-1 in group II) intrarenally in normal mongrel dogs with the contralateral kidney receiving only saline vehicle. Intrarenal infusion of ADM resulted in a marked diuretic and natriuretic response, whereas the contralateral kidney showed no renal effects. These significant natriuresis and diuresis in the ADM kidney were associated with increases in glomerular filtration rate and fractional sodium excretion and with a decrease in distal tubular sodium reabsorption. Intrarenal infusion of ADM also caused an increase in mean arterial blood pressure and a decrease in heart rate. Plasma concentrations of atrial natriuretic peptide, renin activity, aldosterone, and guanosine 3',5'-cyclic monophosphate were not changed during the infusion of ADM. The current study demonstrates that ADM is present in renal glomerular and tubular cells and is a potent natriuretic peptide that may play an important role in the regulation of sodium excretion.

scholarly journals ANP-mediated inhibition of distal nephron fractional sodium reabsorption in wild-type and mice overexpressing natriuretic peptide receptor

2010 ◽  
Vol 298 (1) ◽  
pp. F103-F108 ◽  
Author(s):  
Di Zhao ◽  
Kailash N. Pandey ◽  
L. Gabriel Navar
Keyword(s):  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Urinary Sodium Excretion ◽  
Sodium Reabsorption ◽  
Natriuretic Peptide Receptor ◽  
Distal Nephron ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A ◽  
Npr1 Gene

Atrial natriuretic peptide (ANP) elicits natriuresis; however, the relative contributions of proximal and distal nephron segments to the overall ANP-induced natriuresis have remained uncertain. This study was performed to characterize the effects of ANP on distal nephron sodium reabsorption determined after blockade of the two major distal nephron sodium transporters with amiloride (5 μg/g body wt) plus bendroflumethiazide (12 μg/g body wt) in male anesthetized C57/BL6 and natriuretic peptide receptor-A gene (Npr1) targeted four-copy mice. The lower dose of ANP (0.1 ng·g body wt−1·min−1, n = 6) increased distal sodium delivery (DSD, 2.4 ± 0.4 vs. 1.6 ± 0.2 μeq/min, P < 0.05) but did not change fractional reabsorption of DSD compared with control (86.3 ± 2.0 vs. 83.9 ± 3.6%, P > 0.05), thus limiting the magnitude of the natriuresis. In contrast, the higher dose (0.2 ng·g body wt−1·min−1, n = 6) increased DSD (2.8 ± 0.3 μeq/min, P < 0.01) and also decreased fractional reabsorption of DSD (67.4 ± 4.5%, P < 0.01), which markedly augmented the natriuresis. In Npr1 gene-duplicated four-copy mice ( n = 6), the lower dose of ANP increased urinary sodium excretion (0.6 ± 0.1 vs. 0.3 ± 0.1 μeq/min, P < 0.05) and decreased fractional reabsorption of DSD compared with control (72.2 ± 3.4%, P < 0.05) at similar mean arterial pressures (91 ± 6 vs. 92 ± 3 mmHg, P > 0.05). These results provide in vivo evidence that ANP-mediated increases in DSD alone exert modest effects on sodium excretion and that inhibition of fractional reabsorption of distal sodium delivery is requisite for the augmented natriuresis in response to the higher dose of ANP or in Npr1 gene-duplicated mice.

scholarly journals Acute unilateral nephrectomy elicits a specific increase in plasma of peptides derived from the N-terminal region of proopiomelanocortin.

1992 ◽  
Vol 3 (5) ◽  
pp. 1105-1112
Author(s):  
C Qiu ◽  
J P Valentin ◽  
X W Chen ◽  
E Wiedemann ◽  
M H Humphreys
Keyword(s):  
Natriuretic Peptide ◽  
Plasma Concentrations ◽  
Terminal Region ◽  
Unilateral Nephrectomy ◽  
Contralateral Kidney ◽  
Control Value ◽  
Melanocyte Stimulating Hormone ◽  
Reflex Pathways ◽  
Group I ◽  
Specific Increase

Acute unilateral nephrectomy (AUN) causes natriuresis from the contralateral kidney through neurohumoral reflex pathways that involve an increase in the plasma of peptides derived from the N-terminal region of the adrenocorticotropic hormone (ACTH)/beta-endorphin precursor proopiomelanocortin (POMC). To determine the specificity of these humoral changes, the concentrations in plasma of ACTH and two peptides arising from the N-terminal fragment (NTF) of POMC, NTF32-49 and gamma-melanocyte-stimulating hormone (gamma-MSH), and of another natriuretic peptide, atrial natriuretic peptide (ANP), were measured by RIA with highly specific antisera to these epitopes. Group I experiments followed the course of sodium excretion (UNaV) for 120 min after AUN or sham nephrectomy. UNaV more than doubled within 60 min of AUN, and this natriuresis was maintained for the remainder of the experiment, whereas UNaV in sham rats did not change. There was no difference in plasma immunoreactive (ir) ACTH or ir-ANP concentrations between sham and AUN rats 120 min after the procedure, but plasma ir-NTF concentration was double in AUN rats compared with sham (P < 0.03). In Group II experiments, animals were killed 30, 60, 90, or 120 min after AUN and the urinary response related to peptide concentrations in plasma. UNaV rose rapidly after AUN, reaching a maximum value within 45 min that again was double the control value and remained stable for the duration of the experiment, up to 120 min after AUN. There was no significant change in ir-ACTH or ir-ANP at any point after AUN compared with values in sham AUN rats. However, plasma concentrations of both ir-NTF and ir-gamma-MSH were elevated 30 min after AUN and reached values at 120 min that were again double the values in sham rats (P < 0.05 for both).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Phosphodiesterase inhibitors correct resistance to natriuretic peptides in rats with Heymann Nephritis.

1996 ◽  
Vol 7 (4) ◽  
pp. 582-593
Author(s):  
J P Valentin ◽  
W Z Ying ◽  
L A Sechi ◽  
K T Ling ◽  
C Qiu ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Natriuretic Peptide ◽  
Volume Expansion ◽  
Collecting Duct ◽  
Isotonic Saline ◽  
Phosphodiesterase Inhibitors ◽  
Contralateral Kidney ◽  
Heymann Nephritis

Experimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP). The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (VNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruil and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome. Nine to 14 days after Ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min). Thirty min after the onset of the infusion, plasma ANP concentration was increased to the same extent in both normal and nephritic rats, compared with their respective hydropenic controls. Despite this increase, UcGMPV was significantly less in nephritic rats after the saline infusion. Accumulation of cGMP by isolated glomeruil and IMCD cells from nephritic rats after incubation with ANP and RNP was also significantly reduced, compared with normal rats. This difference was not related to differences in either density or affinity of renal ANP receptors, but was abolished when accumulation of cGMP was measured in the presence of 10(-3) M isobutylmethylxanthine or Zaprinast, two different inhibitors of cyclic nucleotide phosphodiesterases (PDE). Infusion of Zaprinast into one renal artery in nephritic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. Furthermore, cGMP-PDE activity was increased in IMCD cell homogenates from nephritic compared with normal rats (388 +/- 32 versus 198 +/- 93 pmol/min per mg protein, P < 0.03). These results indicate that blunted volume expansion natriuresis accompanied by cellular resistance to ANP in vitro occurs in an immunologic model of renal injury. The resistance is not related to an alteration in ANP release or binding to its renal receptors, but is suppressed by PDE inhibitors and is associated with increased renal cGMP. PDE activity, thus suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.

Impaired Natriuretic Response to Atrial Natriuretic Peptide in the Isolated Kidney of Rats with Experimental Cirrhosis

1990 ◽  
Vol 79 (1) ◽  
pp. 67-71 ◽  
Author(s):  
Marios Z. Panos ◽  
Christopher Gove ◽  
John D. Firth ◽  
Anthony E. G. Raine ◽  
John G. G. Ledingham ◽  
...  
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Plasma Concentrations ◽  
Urinary Sodium Excretion ◽  
Sodium Retention ◽  
Kidney Weight ◽  
Experimental Cirrhosis ◽  
Atrial Natriuretic

1. Sodium retention in cirrhosis may be partly attributable to resistance to a putative circulating natriuretic factor. In cirrhosis, plasma concentrations of atrial natriuretic peptide are often increased in the presence of sodium retention. 2. In order to determine whether the kidney of cirrhotic animals may be insensitive to atrial natriuretic peptide, isolated perfused kidneys from six cirrhotic and five control rats were exposed to increasing concentrations of atrial natriuretic peptide. Cirrhosis had been induced by carbon tetrachloride administration. 3. Excretion in vivo of a 2 mmol sodium load, administered by gavage, was impaired in cirrhotic animals for up to 4 h as compared with control animals (4.2 ± 1.9 vs34.9± 13.4% P < 0.05). 4. During perfusion at 110 mmHg in the absence of atrial natriuretic peptide, sodium excretion by isolated kidneys of cirrhotic animals tended to be lower than in control animals, but the difference was not significant (4.93 ± 1.01 vs 8.41 ± 1.48 μmol min−1 g−1 kidney weight, P = 0.09). There was a smaller increase in urinary sodium excretion by the kidneys of cirrhotic rats compared with control rats in the presence of atrial natriuretic peptide at 10, 50 and 200 pmol/l (respectively: 0.06 ± 0.08 vs 1.29 ± 0.35 μmol min−1 g−1 kidney weight, P < 0.02; 0.49 ± 0.08 vs 1.82 ± 0.42 μmol min−1 g−1 kidney weight, P < 0.03; 1.42 ± 0.16 vs 3.23 ± 0.73 μmol min−1 g−1 kidney weight, P < 0.05), but not at 1000 pmol/l. 5. In this animal model of cirrhosis, renal resistance to the natriuretic action of atrial natriuretic peptide at physiological and pathophysiological concentrations may contribute to sodium retention.

Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

2019 ◽  
Vol 19 (1) ◽  
pp. 31-45
Author(s):  
Meena K. Yadav ◽  
Laxmi Tripathi
Keyword(s):  
Anticonvulsant Activity ◽  
Computational Study ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Preclinical Study ◽  
In Vivo Studies ◽  
Maximum Plasma ◽  
Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

scholarly journals Antimalarial herbal drugs: a review of their interactions with conventional antimalarial drugs

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Earnest Oghenesuvwe Erhirhie ◽  
Chidozie Ikegbune ◽  
Anthony Ifeanyi Okeke ◽  
Chukwunonso Chukwudike Onwuzuligbo ◽  
Ngozi Ukamaka Madubuogwu ◽  
...  
Keyword(s):  
Medicinal Plant ◽  
Synergistic Effects ◽  
Plasma Concentrations ◽  
Antimalarial Drugs ◽  
Herbal Remedies ◽  
In Vivo Studies ◽  
Herbal Drugs ◽  
Plant Interactions ◽  
Mice Model

AbstractDevelopment of resistance by malaria parasites to conventional antimalarial drugs has rejuvenated the exploration of herbal medicine as alternatives. Also, the increasing rate of the use of herbal antimalarial remedies in combination with conventional antimalarial drugs (both synthetic and semi-synthetic) has inspired researchers to validate their herb-drug interaction effects. This review evaluated the interaction outcomes between herbal antimalarial drugs in combination with conventional antimalarial drugs. With the aid of electronic databases, Pubmed and Google scholar, articles related to this subject were sourced from English peer reviewed scientific journals published from 2003 to 2020. Search terms used include “antimalarial-herbal drugs interaction”, “antimalarial medicinal plant interactions with conventional antimalarial drugs”, “drug-herbal interactions, “antimalarial drugs and medicinal plants”. Synergistic, antagonistic and none effects were reported among 30 studies reviewed. Among 18 in vivo studies on P. berghei and P. yoelii nigerense infected mice model, 14 showed synergism, 3 showed antagonism and 1 involving three plants showed both effects. Among 9 in-vivo studies involving normal animal (non-infected), 2 showed antagonism, 2 showed synergism and 5 showed none-effects. Two (2) studies on human volunteers and one (1) in vitro quantitative study showed that Garcinia kola reduced plasma concentrations of quinine and halofantrine. Generally, majority of herbal antimalarial drugs showed synergistic effects with CAMDs. Vernonia amygdalina was the most studied plant compared to others. Consequently, herbal remedies that produced synergistic effects with conventional antimalarial drugs may be prospects for standardization and development of antimalarial-medicinal plant combination therapy that could curtail malaria resistance to conventional antimalarial therapies.

Interactions between ADH and prostaglandins in isolated erythrocyte-perfused rat kidney

1987 ◽  
Vol 252 (2) ◽  
pp. F331-F337 ◽  
Author(s):  
W. Lieberthal ◽  
M. L. Vasilevsky ◽  
C. R. Valeri ◽  
N. G. Levinsky
Keyword(s):  
Sodium Excretion ◽  
Rat Kidney ◽  
Urine Osmolality ◽  
Sodium Reabsorption ◽  
Urinary Osmolality ◽  
Hemodynamic Characteristics ◽  
Urinary Concentrating Ability ◽  
Tubular Morphology ◽  
Isolated Kidneys

Interactions between antidiuretic hormone (ADH) and renal prostaglandins in the regulation of sodium reabsorption and urinary concentrating ability were studied in isolated erythrocyte-perfused rat kidneys (IEPK). In this model, hemodynamic characteristics are comparable to those found in vivo, and tubular morphology is preserved throughout the period of perfusion. [Deamino]-D-arginine vasopressin (dDAVP) markedly reduced fractional sodium excretion (FE Na) in the IEPK from 3.5 +/- 0.6 to 0.45 +/- 0.14%. After indomethacin, FE Na fell still further to 0.08 +/- 0.02%. In the absence of dDAVP indomethacin had no effect on sodium excretion; FE Na was 2.4 +/- 0.6% in control and 2.0 +/- 0.4% in indomethacin-treated groups. dDAVP increased urine osmolality in the IEPK to 741 +/- 26 mosmol/kg. When prostaglandin synthesis was blocked with indomethacin, urinary osmolality increased further to 1,180 +/- 94 mosmol/kg. In isolated kidneys perfused without erythrocytes (IPK), dDAVP decreased FENa from 14.5 +/- 1.8% to 9.6 +/- 1.2%; addition of indomethacin had no further effect. dDAVP increased urine osmolality only modestly to 350 +/- 12 mosmol/kg in the IPK and indomethacin did not increase concentrating ability further (342 +/- 7 mosmol/kg). Thus the IEPK (unlike the IPK) can excrete a markedly hypertonic urine in response to ADH. ADH also enhances tubular reabsorption of sodium in the IEPK. Prostaglandins inhibit both these actions of ADH but do not directly affect sodium excretion in the absence of the hormone.

Dexmedetomidine Attenuates the Microcirculatory Derangements Evoked by Experimental Sepsis

2015 ◽  
Vol 122 (3) ◽  
pp. 619-630 ◽  
Author(s):  
Marcos L. Miranda ◽  
Michelle M. Balarini ◽  
Eliete Bouskela
Keyword(s):  
Blood Gases ◽  
Capillary Density ◽  
Sepsis Syndrome ◽  
In Vivo Studies ◽  
Experimental Sepsis ◽  
Leukocyte Rolling ◽  
Capillary Perfusion ◽  
Arterial Blood ◽  
Baseline Values

Abstract Background: Dexmedetomidine, an α-2 adrenergic receptor agonist, has already been used in septic patients although few studies have examined its effects on microcirculatory dysfunction, which may play an important role in perpetuating sepsis syndrome. Therefore, the authors have designed a controlled experimental study to characterize the microcirculatory effects of dexmedetomidine in an endotoxemia rodent model that allows in vivo studies of microcirculation. Methods: After skinfold chamber implantation, 49 golden Syrian hamsters were randomly allocated in five groups: (1) control animals; (2) nonendotoxemic animals treated with saline; (3) nonendotoxemic animals treated with dexmedetomidine (5.0 μg kg−1 h−1); (4) endotoxemic (lipopolysaccharide 1.0 mg/kg) animals treated with saline; and (5) endotoxemic animals treated with dexmedetomidine. Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables and venular leukocyte rolling and adhesion. Mean arterial blood pressure, heart rate, arterial blood gases, and lactate concentrations were also documented. Results: Lipopolysaccharide administration increased leukocyte rolling and adhesion and decreased capillary perfusion. Dexmedetomidine significantly attenuated these responses: compared with endotoxemic animals treated with saline, those treated with dexmedetomidine had less leukocyte rolling (11.8 ± 7.2% vs. 24.3 ± 15.0%; P &lt; 0.05) and adhesion (237 ± 185 vs. 510 ± 363; P &lt; 0.05) and greater functional capillary density (57.4 ± 11.2% of baseline values vs. 45.9 ± 11.2%; P &lt; 0.05) and erythrocyte velocity (68.7 ± 17.6% of baseline values vs. 54.4 ± 14.8%; P &lt; 0.05) at the end of the experiment. Conclusions: Dexmedetomidine decreased lipopolysaccharide-induced leukocyte–endothelial interactions in the hamster skinfold chamber microcirculation. This was accompanied by a significant attenuation of capillary perfusion deficits, suggesting that dexmedetomidine yields beneficial effects on endotoxemic animals’ microcirculation.

Evaluation of Annona muricata (Graviola) leaves activity against experimental trichinellosis: in vitro and in vivo studies

2021 ◽  
Vol 95 ◽  
Author(s):  
E.S. El-Wakil ◽  
H.F. Abdelmaksoud ◽  
T.S. AbouShousha ◽  
M.M.I. Ghallab
Keyword(s):  
Culture Media ◽  
Trichinella Spiralis ◽  
Drug Effects ◽  
In Vivo Studies ◽  
Control Group ◽  
Annona Muricata ◽  
Group I ◽  
Small Intestinal

Abstract Our work aimed to evaluate the possible effect of Annona muricata (Graviola) leaf extract on Trichinella spiralis in in vitro and in vivo studies. Trichinella spiralis worms were isolated from infected mice and transferred to three culture media – group I (with no drugs), group II (contained Graviola) and group III (contained albendazole) – then they were examined using the electron microscope. In the in vivo study, mice were divided into five groups: GI (infected untreated), GII (prophylactically treated with Graviola for seven days before infection), GIII (infected and treated with Graviola), GIV (infected and treated with albendazole) and GV (infected and treated with a combination of Graviola plus albendazole in half doses). Drug effects were assessed by adults and larvae load beside the histopathological small intestinal and muscular changes. A significant reduction of adult and larval counts occurred in treated groups in comparison to the control group. Histopathologically, marked improvement in the small intestinal and muscular changes was observed in treated groups. Also, massive destruction of the cultured adults’ cuticle was detected in both drugs. This study revealed that Graviola leaves have potential activity against trichinellosis, especially in combination with albendazole, and could serve as an adjuvant to anti-trichinellosis drug therapy.

Sign in / Sign up

Export Citation Format

Share Document