We studied the changes in systemic and regional hemodynamics (using the radioactive microsphere technique) and catecholamine levels produced by propranolol in conscious semi-restrained intact or nephrectomized rats. Blood pressure increased by 17 +/- 2 and 32 +/- 2 mmHg in intact and anephric rats respectively, total peripheral vascular resistance by 61.5% and 176.5%, heart rate decreased by 23% and 35% respectively, cardiac index decreased by 35% and 57%, and stroke volume index by 14% and 30%. All changes were significantly more pronounced in anephric rats (p less than 0.05). Baseline norepinephrine, epinephrine, and dopamine were significantly higher in anephric versus intact animals and did not change significantly after B-blockade except for norepinephrine of the anephric rats which decreased. After B-blockade regional blood flows in most organs (including coronary flow) decreased in proportion to the diminished cardiac index except for brain flow which decreased by only 12% in intact and 25% in anephric animals. Local vascular resistances increased concomitantly and these changes were far more pronounced in the absence of kidneys. Thus, anephric state exacerbates all systemic and regional hemodynamic alterations caused by B-blockade in the rat.
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Nat Commun
February 2021
Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.
Murine animal models from genetically modified pluripotent stem cells (PSCs) are essential for functional genomics and biomedical research, which require germline transmission for the establishment of colonies. However, the quality of PSCs, and donor-host cell competition in chimeras often present strong barriers for germline transmission. Here, we report efficient germline transmission of recalcitrant PSCs via blastocyst complementation, a method to compensate for missing tissues or organs in genetically modified animals via blastocyst injection of PSCs.
View Article and Find Full Text PDFEndocr Metab Immune Disord Drug Targets
September 2021
Department of Pathology, School of Veterinary Medicine, Ankara University, Ankara, Turkey.
Background: Extrarenal 1α,25-dihydroxyvitamin D3 (1,25-D) locally produced by immune cells plays crucial roles in the regulation of the immune system. However, in vivo status of extrarenal 1,25-D and 25-hydroxyvitamin D (25-D) in acute inflammatory conditions are unknown.
Objective: The aim of this study was to determine the extrarenal 1,25-D level in circulation in bilaterally nephrectomized rats, induced by low-dose lipopolysaccharide (LPS).
Nat Commun
February 2019
Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, 444-8787, Aichi, Japan.
Regeneration of human kidneys in animal models would help combat the severe shortage of donors in transplantation therapy. Previously, we demonstrated by interspecific blastocyst complementation between mouse and rats, generation of pluripotent stem cell (PSC)-derived functional pancreas, in apancreatic Pdx1 mutant mice. We, however, were unable to obtain rat PSC-derived kidneys in anephric Sall1 mutant mice, likely due to the poor contribution of rat PSCs to the mouse metanephric mesenchyme, a nephron progenitor.
View Article and Find Full Text PDFKnowledge of clearance plays a key role in the development of new drug entities, especially in the development of improved analogues for treatment of chronic conditions. Improved pharmacokinetic properties can be used to increase dosing interval and thereby improve patient compliance. This will lead to improved treatment outcome or decreased risk of treatment failure when treating chronic conditions.
View Article and Find Full Text PDFJ Am Soc Nephrol
January 2016
Departments of Internal Medicine, Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; Physiology, and
αKlotho is a multifunctional protein highly expressed in the kidney. Soluble αKlotho is released through cleavage of the extracellular domain from membrane αKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating αKlotho production and handling is incompletely understood, however.
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