The response to arachidonic acid before and after non-steroidal anti-inflammatory drugs in normotensive and hypertensive rats


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Abstract

ObjectiveTo establish equivalent doses of four non-steroidal anti-inflammatory drugs (NSAID) in normotensive and hypertensive rats using inhibition of the fall in blood pressure produced by the injection of arachidonic acid as the measure of equivalence.DesignAn experimental study using two rat models of hypertension and their normotensive controls.MethodsTwo rat models of hypertension (spontaneously hypertensive rats and two-kidney, one clip rats) and their normotensive controls were studied. The change in blood pressure after intravenous injection of arachidonic acid was measured in anaesthetized rats. Blood pressure was measured from a carotid artery cannula, attached to a pen-recorder. Dose-response curves for the effect of arachidonic acid were established in each type of rat, then the effects of different doses of four NSAID (indomethacin, piroxicam, naproxen and sulindac) on these responses were measured.ResultsArachidonic acid produced a dose-dependent fall in blood pressure in all rats. However, both types of hypertensive rats sustained a larger fall in blood pressure for a given dose of arachidonic acid than did the normotensive controls. Doses of NSAID were found that inhibited this response in Wistar rats. However, the doses of NSAID that were equivalent in normotensive rats were not equivalent in either type of hypertensive rat; indomethacin had a greater inhibitory effect. As far as could be established, this was not due to differences in the metabolism of the NSAID between normotensive and hypertensive rats.ConclusionsThe arachidonic acid response can be used as a method of establishing equivalent doses of NSAID in normotensive and hypertensive rats. Hypertensive rats appear to be more sensitive to the effects of arachidonic acid than normotensive rats, independent of the model of hypertension. Doses of NSAID that are equivalent in normotensive rats are not equivalent in hypertensive rats. Indomethacin is more effective in attenuating the effect of arachidonic acid, possibly due to actions other than inhibition of cyclo-oxygenase.

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