Development and Validation of a Rat Model for Examining the AT1 and ETA Receptor-Blocking Activity of Dual AT1 and ETA Receptor Blockers
| Autor: | Ram Gupta, Deepa Joshi, Anookh Mohanan |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Endothelin receptor type A Angiotensin II receptor type 1 Chemistry Biological activity Pharmacology Angiotensin II Endocrinology Losartan Internal medicine Renin–angiotensin system cardiovascular system Internal Medicine medicine Cardiology and Cardiovascular Medicine Endothelin receptor Receptor hormones hormone substitutes and hormone antagonists circulatory and respiratory physiology medicine.drug |
| Zdroj: | High Blood Pressure & Cardiovascular Prevention. 16:39-45 |
| ISSN: | 1120-9879 |
| DOI: | 10.2165/00151642-200916020-00002 |
| Popis: | Background: Hypertension is a multifactorial disease, with angiotensin II (Ang II) as the established target of pharmacological intervention. However, there has been increasing interest in the biological effects of other vasoactive peptides such as endothelin (ET). A separate estimation of activity for the dual angiotensin type-1 (AT1) and endothelin type-A (ETA) receptor blocker mediated through individual AT1 and ETA receptors is important as there is evidence demonstrating an interaction between the renin-angiotensin and ET systems. Objective: An appropriate animal model to separate out and individually measure the AT1 and ETA receptor-blocking activity of the dual-action molecules is required for the screening of therapeutic agents that would target the renin-angiotensin and ET systems together. The objective of this study is to validate such an animal model. Methods: In anesthetized male Sprague Dawley rats, isolation of AT1 receptor-blocking activity was validated with losartan (a selective AT1 receptor blocker) by measuring reversal of the pressor effect of exogenously administered Ang II in the presence of maximal blockade of endogenous ETA receptors. Similarly, measurement of isolated ETA receptor-blocking activity was validated with ZD1611 (selective ETA receptor blocker), by measuring the reversal of exogenously administered big ET-1 pressor response in the presence of maximal blockade of endogenous AT1 receptors. The model was validated finally with BMS346567, a dual AT1 and ETA receptor blocker. Results: A dose-dependent fall in mean blood pressure upon losartan or ZD1611 infusion was observed when endogenous ETA or AT1 receptors were blocked. Similar results were obtained using BMS346567 in both models. Conclusions: A model was developed and validated for screening pharmacological activity of dual AT1 and ETA receptor blockers on each target in isolation without the influence of an interacting pathway. |
| Databáze: | OpenAIRE |
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