Acetaminophen, phenacetin and dipyrone do not modulate pressor responses to arachidonic Acid or to pressor agents.

In contrast to nonsteroidal anti-inflammatory drugs (NSAIDs), the nonopioid analgesics phenacetin, acetaminophen and dipyrone exhibit weak anti-inflammatory properties. An explanation for this difference in pharmacologic activity was provided by the recent discovery of a new cyclooxygenase isoform, cyclooxygenase (COX)-3, that is reported to be inhibited by phenacetin, acetaminophen and dipyrone. However, COX-3 was found to be a spliced variant of COX-1 and renamed COX-1b. Although recent studies provide evidence for the existence of this new COX isoform, it is uncertain whether this COX-3 (COX-1b) isoform, or putative acetaminophen-sensitive pathway, plays a role in the generation of vasoactive prostaglandins. NSAIDs increase systemic blood pressure by inhibiting the formation of vasodilator prostanoids. Angiotensin II, norepinephrine and other vasoconstrictor agents have been reported to release prostaglandins. It is possible that this acetaminophen-sensitive pathway also modulates pressor responses to these vasoconstrictor agents. Therefore, the purpose of the present study was to determine whether this acetaminophen-sensitive pathway plays a role in the generation of vasoactive products of arachidonic acid or in the modulation of vasoconstrictor responses in the pulmonary and systemic vascular bed of the intact-chest rat. In the present study, the nonopioid analgesics did not attenuate changes in pulmonary or systemic arterial pressure in response to injections of the prostanoid precursor, arachidonic acid, to the thromboxane A(2) mimic, U46619, or to angiotensin II or norepinephrine. The results of the present study do not provide evidence in support of a role of a functional COX-3 (COX-1b) isoform, or an acetaminophen-sensitive pathway, in the generation of vasoactive prostanoids or in the modulation of responses to vasoconstrictor hormones in the intact-chest rat.

Differential effects of losartan and candesartan on vasoconstrictor responses in the rat.

Losartan has been reported to have inhibitory effects on thromboxane (TP) receptor-mediated responses. In the present study, the effects of 2 nonpeptide angiotensin II (AT1) receptor antagonists, losartan and candesartan, on responses to angiotensin II, the thromboxane A2 mimic, U46619, and norepinephrine were investigated and compared in the pulmonary and systemic vascular beds of the intact-chest rat. In this study, intravenous injections of angiotensin II, U46619, and norepinephrine produced dose-related increases in pulmonary and systemic arterial pressure. Losartan and candesartan, in the doses studied, decreased or abolished responses to angiotensin II. Losartan, but not candesartan, and only in a higher dose, produced small, but statistically significant, reductions in pressor responses to U46619 and to norepinephrine in the pulmonary and systemic vascular beds. Furthermore, losartan significantly reduced arachidonic acid-induced platelet aggregation, whereas candesartan had no effect. Pressor responses to angiotensin II were not changed by thromboxane and alpha-adrenergic receptor antagonists, or by cyclooxygenase and NO synthase inhibitors. These results show that losartan and candesartan are potent selective AT1 receptor antagonists in the pulmonary and systemic vascular beds and that losartan can attenuate thromboxane and alpha-adrenergic responses when administered at a high dose, whereas candesartan in the highest dose studied had no effect on responses to U46619 or to norepinephrine. The present data show that the effects of losartan and candesartan on vasoconstrictor responses are different and that pulmonary and systemic pressor responses to angiotensin II are not modulated or mediated by the release of cyclooxygenase products, activation of TP receptors, or the release of NO in the anesthetized rat.