Abstract
It was suggested that prostaglandins which are synthesized by cyclooxygenase (COX) enzymes contribute to the actions of angiotensin-converting enzyme (ACE) inhibition and angiotensin AT1 receptor antagonism and there is an interaction between ACE signaling pathway and COX enzymes. We aim to investigate the role of COX enzymes in the effects of losartan, an angiotensin II (Ang II) receptor antagonist or lisinopril, an ACE inhibitor, on the contractions of rat thoracic aorta in isolated tissue bath. Responses of losartan (10-6, 10-5, 10-4 M), lisinopril (10-6, 10-5, 10-4 M), and non-selective COX inhibitor dipyrone (10-4, 7 × 10-4, 2 × 10-3 M) alone to the contractions induced by phenylephrine (Phe) (10-7 M), potassium chloride (KCl) (6 × 10-2 M), Ang II (10-8 M) and responses of losartan or lisinopril in combination with dipyrone to the contractions induced by Phe or KCl were recorded. When used alone, dipyrone and losartan inhibited Phe, KCl, and Ang II-induced contractions, whereas lisinopril inhibited only Phe and Ang II-induced contractions. Inhibition of COX enzymes (COX-3, COX-3 + COX-1, COX-1+ COX-2 + COX-3 by dipyrone 10-4, 7 × 10-4, 2 × 10-3 M, respectively) augmented the relaxant effects of losartan or lisinopril. Also, dipyrone potentiated the effect of lisinopril on KCl-induced contractions. We suggest that dipyrone increases the smooth-muscle relaxing effects of losartan or lisinopril and that COX enzyme inhibition may have a role in the enhancement of this relaxation.
Highlights
Angiotensin II (Ang II) regulates and maintains physiological vascular tone and function
Most of the effects of angiotensin II (Ang II) are associated with the AT1 receptors, and Ang II generates contraction by activating AT1 receptors which are selectively blocked by AT1 receptor antagonists [2]
Cyclooxygenase (COX) enzymes which are inhibited by non-steroidal anti-inflammatory drugs (NSAIDs) catalyze the rate-limiting step of prostanoid synthesis [6]
Summary
Angiotensin II (Ang II) regulates and maintains physiological vascular tone and function. The antihypertensive effect elicited by ACE inhibition is reported to involve a reduction in the levels of Ang II, an increase in tissue kinin concentrations, as well as the release of nitric oxide and prostanoids [4]. Prostanoids are considered as important cardiovascular regulatory mediators They play significant actions for controlling physiological vascular tonus, renin release, and blood pressure [5]. It was reported that COX-1 is constitutive and responsible for the generation of prostaglandins which mediate a number of physiological effects, whereas COX-2 is induced in multiple tissues in conditions such as inflammation [8]. COX-2-mediated prostanoid production is responsible for the regulation of vascular functions and physiologic and pathophysiologic processes, such as renal hemodynamics, control of blood pressure, and endothelial thromboresistance [11]. There is not enough data on the clinical relevance of COX-3 in humans [12]
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