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  • 1
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 9, No. 23 ( 2020-12)
    Abstract: Diabetic nephropathy is a common diabetes mellitus complication associated with hypertension, proteinuria, and excretion of urinary plasmin that activates the epithelial sodium channel, ENaC, in vitro . Here we hypothesized that the deletion of plasminogen and amiloride treatment protect against hypertension in diabetes mellitus. Methods and Results Male plasminogen knockout (plasminogen‐deficient [Plg −/− ]) and wild‐type mice were rendered diabetic with streptozotocin. Arterial blood pressure was recorded continuously by indwelling catheters before and during 10 days of angiotensin II infusion (ANGII; 30–60 ng/kg per minute). The effect of amiloride infusion (2 mg/kg per day, 4 days) was tested in wild‐type, diabetic ANGII‐treated mice. Streptozotocin increased plasma and urine glucose concentrations and 24‐hour urine albumin and plasminogen excretion. Diabetic Plg −/− mice displayed larger baseline albuminuria and absence of urine plasminogen. Baseline mean arterial blood pressure did not differ between groups. Although ANGII elevated blood pressure in wild‐type, diabetic wild‐type, and Plg −/− control mice, ANGII did not change blood pressure in diabetic Plg −/− mice. Compared with ANGII infusion alone, wild‐type ANGII‐infused diabetic mice showed blood pressure reduction upon amiloride treatment. There was no difference in plasma renin, ANGII, aldosterone, tissue prorenin receptor, renal inflammation, and fibrosis between groups. Urine from wild‐type mice evoked larger amiloride‐sensitive current than urine from Plg −/− mice with or without diabetes mellitus. Full‐length γ‐ENaC and α‐ENaC subunit abundances were not changed in kidney homogenates, but the 70 kDa γ‐ENaC cleavage product was increased in diabetic versus nondiabetic mice. Conclusions Plasmin promotes hypertension in diabetes mellitus with albuminuria likely through the epithelial sodium channel.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2653953-6
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  • 2
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2013
    In:  Pflügers Archiv - European Journal of Physiology Vol. 465, No. 10 ( 2013-10), p. 1467-1475
    In: Pflügers Archiv - European Journal of Physiology, Springer Science and Business Media LLC, Vol. 465, No. 10 ( 2013-10), p. 1467-1475
    Type of Medium: Online Resource
    ISSN: 0031-6768 , 1432-2013
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2013
    detail.hit.zdb_id: 1463014-X
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 304, No. 10 ( 2013-05-15), p. R899-R907
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 304, No. 10 ( 2013-05-15), p. R899-R907
    Abstract: Experiments were designed to test the hypothesis that cyclooxygenase-2 (COX-2) activity attenuates the blood pressure increase during high NaCl intake by stimulation of endothelial nitric oxide synthase (eNOS)-mediated NO synthesis in the kidney medulla. COX-2 −/− (C57BL6) an COX-2 +/+ mice were fed a diet with 0.004% (low salt, LS) or 4% (high salt, HS) NaCl for 18 days. Arterial blood pressure was recorded continuously using indwelling catheters. Food and water intake and diuresis were measured in metabolic cages. Urine osmolality and excretion of electrolytes, cGMP, cAMP, and NOx were determined, as well as plasma NOx and cGMP. There was a significant dependence of blood pressure on salt intake and genotype: COX-2 −/− exhibited higher blood pressure than COX-2 +/+ both on HS and LS intake. COX-2 +/+ littermates displayed an increase in blood pressure on HS versus LS (102.3 ± 1.1 mmHg vs. 91.9 ± 0.9 mmHg) day and night. The mice exhibited significant blood pressure increases during the awake phase (night) that were larger in COX-2 −/− on HS diet compared with COX-2 +/+ . Water intake, diuresis, Na + , and osmolyte excretions and NOx and cGMP excretions were significantly and similarly elevated with HS in COX-2 −/− and COX-2 +/+ . In summary, C57BL6 mice exhibit a salt intake-dependent increase in arterial blood pressure with increased renal NO production. COX-2 activity has a general lowering effect on arterial blood pressure. COX-2 dampens NaCl-induced increases in arterial blood pressure in the awake phase. In conclusion, COX-2 activity attenuates the changes in nocturnal blood pressure during high salt intake, and COX-2 activity is not necessary for increased renal nitric oxide formation during elevated NaCl intake.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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  • 4
    In: Acta Physiologica, Wiley, Vol. 225, No. 1 ( 2019-01)
    Abstract: The epithelial sodium channel (ENaC) is expressed in cultured endothelial cells and inhibitory coupling to eNOS activity has been proposed. The present study tested the hypothesis that ENaC blockers increase systemic NO‐products and lower blood pressure in patients and mice, depending on eNOS. Methods NO‐products and cGMP were measured in diabetes patient urine and plasma samples before and after amiloride treatment (20‐40 mg for two days, plasma n = 22, urine n = 12 and 5‐10 mg for eight weeks, plasma n = 52, urine n = 55). Indwelling catheters were implanted in the femoral artery and vein in mice for continuous arterial blood pressure and heart rate recordings and infusion. Results Treatment with amiloride for two days increased plasma and urine NO‐products, while plasma cGMP decreased and urinary cGMP was unchanged in patient samples. Eight weeks of treatment with amiloride did not alter NO‐products and cGMP. In mice, amiloride boli of 5, 50, and 500 µg/kg lowered heart rate and arterial blood pressure significantly and acutely. Benzamil had no effect on pressure and raised heart rate. In hypertensive eNOS −/− and L‐NAME‐treated mice, amiloride lowered blood pressure significantly. L‐NAME infusion significantly decreased NO‐products in plasma; amiloride and eNOS‐deletion had no effect. An acetylcholine bolus resulted in acute blood pressure drop that was attenuated in eNOS −/− and L‐NAME mice. ENaC subunit expressions were not detected consistently in human and mouse arteries and endothelial cells. Conclusion Amiloride has an acute hypotensive action not dependent on ENaC and eNOS and likely related to the heart.
    Type of Medium: Online Resource
    ISSN: 1748-1708 , 1748-1716
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2617148-X
    detail.hit.zdb_id: 2219379-0
    SSG: 12
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