The actions of angiotensin II on type 1 (AT₁) and type 2 (AT₂) receptor subtypes are important for normal kidney development before birth. This study investigated the effect of AT₁ receptor antagonism on renal growth and growth regulators in fetal sheep during late gestation. From 125 days of gestation (term 145±2 days), chronically catheterised sheep fetuses were infused intravenously for 5 days with either an AT₁-specific receptor antagonist (GR138950, 2-4 mg/kg per day, n=5) or saline (0.9% NaCl, n=5). Blockade of the AT₁ receptor decreased arterial blood oxygenation and pH and increased blood pCO₂, haemoglobin and lactate, and plasma cortisol and IGF-II. Blood glucose and plasma thyroid hormones and IGF-I were unchanged between the treatment groups. On the 5th day of infusion, the kidneys of the GR-treated fetuses were lighter than those of the control fetuses, both in absolute and relative terms, and were smaller in transverse cross-sectional width and cortical thickness. In the GR-infused fetuses, renal AT₂ receptor protein concentration and glomerular density were significantly greater than in the saline-infused fetuses. Blockade of the AT₁ receptor had no effect on relative cortical thickness, fractional or mean glomerular volumes, or renal protein levels of the AT₁ receptor, IGF type 1 receptor, insulin receptor or protein kinase C ζ. Therefore, in the ovine fetus, AT₁ receptor antagonism causes increased renal protein expression of the AT₂ receptor subtype, which, combined with inhibition of AT₁ receptor activity, may be partly responsible for growth retardation of the developing kidney.

01 Jul 2008·Pharmaceutical ResearchQ3 · MEDICINE

Evaluation of Direct Transport Pathways of Glycine Receptor Antagonists and an Angiotensin Antagonist from the Nasal Cavity to the Central Nervous System in the Rat Model

Q3 · MEDICINE

Article

Author: Kevin D. Read ; Susan T. Fayinka ; Lisbeth Illum ; Joanne Whetstone ; Stanley S. Davis ; Stuart T. Charlton

PURPOSEThe aim of this study was to investigate and quantify drug movement to the brain via the neuro-olfactory system after intranasal dosing of four model drugs; three glycine receptor antagonists and one angiotensin antagonist.METHODSThe drugs were dosed to rats via intranasal or intravenous administration, after which a quantitative method for tissue distribution was utilised to determine drug distribution to the olfactory lobes, brain sections and the blood over 30 min. Autoradiography was used to visualise and quantify drug distribution throughout the brain and in the CSF. Micro-autoradiography was used to examine drug distribution throughout the olfactory nerve apparatus.RESULTSThe three glycine receptor antagonist compounds were transported to the CNS to differing degrees although they had similar molecular structures and similar physicochemical characteristics. All three compounds were shown to exploit a direct route of transport from nose to brain with Direct Transport Percentages (DTP) of 99.99%, 96.71% and 51.95%, respectively, although for the last molecule a major part of the brain content originated from systemic transport across the BBB. Intranasal administration of GR138950 resulted in over 3.5 times more drug in the olfactory lobes at 1 min post-dose compared to intravenous administration; and 5 times more drug was delivered to the olfactory lobes over 30 min. Micro-autoradiography showed that GR138950 could be found throughout the olfactory nerve apparatus. Autoradiography illustrated drug distribution throughout the brain and CSF, with drug concentrations in the CSF being equal or higher than in the brain tissue. It was determined that approximately 0.8% of the administered dose moved into the brain and CSF via the olfactory pathway over 30 min.CONCLUSIONSIntranasal administration resulted in greater delivery of the model drugs to the olfactory lobes and brain as compared to intravenous dosing. It is proposed that the drug moved through the neuro-olfactory system, primarily via paracellular pathways.

01 Jun 2007·International Journal of PharmaceuticsQ2 · MEDICINE

Nasal administration of an angiotensin antagonist in the rat model: Effect of bioadhesive formulations on the distribution of drugs to the systemic and central nervous systems

Q2 · MEDICINE

Article

Author: L. Illum ; S.S. Davis ; S.T. Charlton

The effect of bioadhesive formulations on the direct transport of an angiotensin antagonist drug ((14)C-GR138950) from the nasal cavity to the central nervous system was evaluated in a rat model. Three different bioadhesive polymer formulations (3% pectin LM-5, 1.0% pectin LM-12 and 0.5% chitosan G210) containing the drug were administered nasally to rats by inserting a dosing cannula 7mm into the nasal cavity after which the plasma and brain tissue levels were measured. It was found that the polymer formulations provided significantly higher plasma levels and significantly lower brain tissue levels of drug than a control, in the form of a simple drug solution. Changing the depth of insertion of the cannula from 7 to 15mm, in order to reach the olfactory region in the nasal cavity significantly decreased plasma levels and significantly increased brain tissue levels of drug for the two formulations studied (1.0% pectin LM-12 and a simple drug solution). There was no significant difference between the drug availability for the bioadhesive formulation and the control in the brain when the longer cannula was used for administration. It is suggested that the conventional rat model is not suitable for evaluation of the effects of bioadhesive formulations in nose-to-brain delivery.

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