ABSTRACT
The renal outer medullary potassium (ROMK) channel mediates potassium recycling and facilitates sodium reabsorption through the Na+/K+/2Cl- cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Evidence from the phenotype of humans and rodents with functional ROMK deficiency supports the contention that selective ROMK inhibitors (ROMKi) will represent a novel diuretic with potential of therapeutic benefit for hypertension. ROMKi have recently been synthesized by Merck & Co, Inc. The present studies were designed to examine the effects of ROMKi B on systemic hemodynamics, renal function and structure, and vascular function in Dahl salt-sensitive rats. Four experimental groups-control, high-salt diet alone; ROMKi B 3 mg·kg-1·d-1; ROMKi B 10 mg·kg-1·d-1; and hydrochlorothiazide 25 mg·kg-1·d-1-were included in prophylactic (from week 1 to week 9 on high-salt diet) and therapeutic studies (from week 5 to week 9 on high-salt diet), respectively. ROMKi B produced sustained blood pressure reduction and improved renal and vascular function and histological alterations induced by a high-salt diet. ROMKi B was superior to hydrochlorothiazide at reducing blood pressure. Furthermore, ROMKi B provided beneficial effects on both the plasma lipid profile and bone mineral density. Chronic ROMK inhibition not only prevented but also reversed the development of hypertension and end-organ damage in Dahl salt-sensitive rats. Our findings suggest a potential utility of ROMKi B as a novel antihypertensive agent, particularly for the treatment of the salt-sensitive hypertension patient population.
Subject(s)
Acute Kidney Injury/prevention & control , Blood Pressure , Hypertension/prevention & control , Kidney Medulla/metabolism , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Acute Kidney Injury/metabolism , Acute Kidney Injury/physiopathology , Animals , Biomarkers/urine , Disease Models, Animal , Glomerular Filtration Rate , Hypertension/metabolism , Kidney Medulla/drug effects , Potassium Channels, Inwardly Rectifying/metabolism , Rats , Rats, Inbred DahlABSTRACT
The renal outer medullary potassium channel (ROMK, KCNJ1) mediates potassium recycling and facilitates sodium reabsorption through the Na(+)/K(+)/2Cl(-) cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Human genetic studies indicate that ROMK homozygous loss-of-function mutations cause type II Bartter syndrome, featuring polyuria, renal salt wasting, and hypotension; humans heterozygous for ROMK mutations identified in the Framingham Heart Study have reduced blood pressure. ROMK null mice recapitulate many of the features of type II Bartter syndrome. We have generated an ROMK knockout rat model in Dahl salt-sensitive background by using zinc finger nuclease technology and investigated the effects of knocking out ROMK on systemic and renal hemodynamics and kidney histology in the Dahl salt-sensitive rats. The ROMK(-/-) pups recapitulated features identified in the ROMK null mice. The ROMK(+/-) rats, when challenged with a 4% salt diet, exhibited a reduced blood pressure compared with their ROMK(+/+) littermates. More importantly, when challenged with an 8% salt diet, the Dahl salt-sensitive rats with 50% less ROMK expression showed increased protection from salt-induced blood pressure elevation and signs of protection from renal injury. Our findings in ROMK knockout Dahl salt-sensitive rats, together with the previous reports in humans and mice, underscore a critical role of ROMK in blood pressure regulation.
Subject(s)
Blood Pressure , Potassium Channels, Inwardly Rectifying/physiology , Animals , Female , Heterozygote , Kidney/physiology , Male , Phenotype , Potassium Channels, Inwardly Rectifying/genetics , Rats , Rats, Inbred Dahl , Sodium-Potassium-Chloride Symporters/physiology , Solute Carrier Family 12, Member 1ABSTRACT
We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension.
Subject(s)
Hypertension, Renal/drug therapy , Mineralocorticoid Receptor Antagonists , Mineralocorticoid Receptor Antagonists/pharmacology , Sodium Chloride, Dietary/pharmacology , Spironolactone/analogs & derivatives , Aldosterone/blood , Animals , Blood Pressure/drug effects , Chronic Disease , Creatinine/blood , Disease Models, Animal , Disease Progression , Electrolytes/blood , Eplerenone , Heart Rate/drug effects , Hypertension, Renal/pathology , Hypertension, Renal/physiopathology , Kidney/drug effects , Kidney/pathology , Kidney/physiology , Male , Mineralocorticoid Receptor Antagonists/blood , Organ Size , Rats , Rats, Inbred Dahl , Receptors, Mineralocorticoid/physiology , Spironolactone/blood , Spironolactone/pharmacologySubject(s)
Data Collection/methods , Documentation/methods , Evidence-Based Medicine/methods , Nursing Research/methods , Postanesthesia Nursing/methods , Vocabulary, Controlled , Databases as Topic , Humans , Internet , Nursing Assessment/methods , Nursing Diagnosis , Nursing Records , Outcome Assessment, Health Care , Patient Care Planning , Research DesignABSTRACT
Functional interleuin-8 (IL-8) receptors (IL-8RA and IL-8RB: CXCR1 and CXCR2, respectively) have been described in human, monkey, dog, rabbit, and guinea pig. Although three IL-8R homologues have been found in rat, only one of these, rat CXCR2, appears to be functional based on responsiveness to ligands. Similarly, CXC chemokines induce biological responses through the murine homolog of CXCR2, but the identification of functional rodent CXCR1 homologues has remained elusive. We have identified and characterized the mouse CXCR1 homologue (mCXCR1). Murine CXCR1 shares 68 and 88% amino acid identity with its human and rat counterparts, respectively. Similar to the tissue distribution pattern of rat CXCR1, we found murine CXCR1 mRNA expression predominantly in lung, stomach, bone marrow, and leukocyte-rich tissues. In contrast to previous reports, we determined that mCXCR1 is a functional receptor. We show predominant engagement of this receptor by mouse GCP-2/CXCL6, human GCP-2, and IL-8/CXCL8 by binding, stimulation of GTPgammaS exchange, and chemotaxis of mCXCR1-transfected cells. Furthermore, murine CXCR1 is not responsive to the human CXCR2 ligands ENA-78/CXCL5, NAP-2/CXCL7, GRO-alpha, -beta, -gamma/CXCL1-3, or rat CINC-1-3. In addition, we show concomitant elevation of mCXCR1 and its proposed major ligand, GCP-2, positively correlated with paw swelling in murine collagen-induced arthritis. This report represents the first description of a functional CXCR1-like receptor in rodents.
Subject(s)
Chemokines, CXC/metabolism , Interleukin-8/metabolism , Receptors, Interleukin-8A/genetics , Receptors, Interleukin-8A/physiology , Amino Acid Sequence , Animals , Arthritis, Experimental/metabolism , Chemokine CXCL6 , Cloning, Molecular , Collagen/metabolism , Disease Models, Animal , Humans , Mice , Molecular Sequence Data , RNA, Messenger/metabolism , Rats , Sequence Homology, Amino AcidABSTRACT
The Post Anesthesia Care Unit (PACU) visitation program of Memorial Sloan-Kettering Cancer Center needed revision. The process was disorganized, visits were unescorted, and nurses and physicians were resistant. A committee was formed with the goal of developing a new unit philosophy and improving the overall process. Committee steps included reviewing the literature, educating staff about the benefits of visitation, empowering nurses to incorporate family visitation into patient care, and providing family education. As a result, staff attitudes changed, and nurses now contact the family within 90 minutes of the patient's arrival to the PACU to develop an individualized visitation plan. Morale is high, and nurses take pride in meeting the needs of patients and families.
Subject(s)
Family Nursing/organization & administration , Postoperative Care/nursing , Recovery Room/organization & administration , Visitors to Patients , Cancer Care Facilities , Humans , New York City , Organizational Innovation , Outcome Assessment, Health Care , Postanesthesia Nursing/organization & administration , Professional Staff CommitteesABSTRACT
The focus of this work was on the relation between grammatical gender and categorization. In one set of studies, monolingual English-, Spanish-, French-, and German-speaking children and adults assigned male and female voices to inanimate objects. Results from Spanish and French speakers indicated effects of grammatical gender on classification; results from German speakers did not. A connectionist model simulated the contradicting findings. The connectionist networks were also used to investigate which aspect of grammatical gender was responsible for the different pattern of findings. The predictions from the connectionist simulations were supported by the results from an artificial language-learning task. The results from this work demonstrate how connectionist networks can be used to identify the differences between languages that affect categorization.
Subject(s)
Cognition , Cross-Cultural Comparison , Language , Linguistics , Adult , Child , Child, Preschool , Concept Formation , Humans , Language Development , Models, PsychologicalABSTRACT
Las personas infectadas por el virus immunodeficiencia humana frecuentemente tienen manifestaciones clínicas de disfunción del sistema nervioso central. Esto puede ser envolvimiento primario o procesos secundários como infecciones o tumores. El trabajo que presentamos es un resumen corto de las manifestaciones radiológicas de afectación del sistema nervioso central en pacientes con SIDA según se ve en CT o MRI. Incluimos los hallazgos radiológicos de encefalitis por HIV-1, toxoplasmosis, linfoma primario del SNC, cryptococcosis, histoplasmosis, encefalitis por CMV, virus de herpes y varicella. Esperamos que este trabajo ayude en el manejo del paciente con SIDA
