(5Z)-carbacyclin displays agonist-antagonist properties on prostacyclin-receptors in platelets and vascular myocytes.

(5E)- and (5Z)-carbacyclin are chemically stable analogues of prostacyclin (PGI2), which mimic PGI2 actions. In particular, they inhibit platelet aggregation and relax vascular smooth muscle, through the activation of adenylate cyclase (AC) being, however, less potent than PGI2. The characteristics of AC activity modulation by the two isomeric carbacyclins in membranes of human platelets and of myocytes cultured from rabbit mesenteric artery have been investigated. In human platelet membranes, both carbacyclins stimulated AC activity with the same efficacy as PGE1 and PGI2; in addition, these two prostaglandins inhibited the aggregation of human and rabbit platelets to the same extent as PGE1. On the contrary, in myocytes (5Z)-carbacyclin fails to produce the same degree of stimulation of AC elicited by PGI2, (5E)-carbacyclin and PGE1, nor does it induce the maximal relaxation of rabbit mesenteric artery attained with the other prostaglandins. (5Z)-carbacyclin is also able to antagonize the activation of AC by PGE1, PGI2 or (5E)-carbacyclin, acting therefore as a partial agonist. In conclusion, (5Z)-carbacyclin is a full agonist at the platelet level both in human and rabbit, thus excluding possible interspecies differences, but it is a partial agonist on myocytes. Therefore, (5Z)-carbacyclin appears to discriminate between PGI2 -receptors in the two target cells.

(5Z)-carbacyclin discriminates between prostacyclin-receptors coupled to adenylate cyclase in vascular smooth muscle and platelets.

(5E)- and (5Z)-carbacyclin are prostacyclin (PGI2) analogues endowed with antiaggregating and vasodilator properties, which stimulate adenylate cyclase activity in membranes from human platelets and cultured myocytes from rabbit mesenteric artery. In platelets they display the same efficacy as prostaglandin E1 (PGE1), and hence PGI2 both as activators of adenylate cyclase and as inhibitors of aggregation. In contrast, in vascular smooth muscle cells (5Z)-carbacyclin fails to produce the same degree of stimulation of the enzyme as PGI2, (5E)-carbacyclin and PGE1, nor does it induce the maximal relaxation of the mesenteric artery as do the other prostaglandins. (5Z)-carbacyclin is also able to antagonize the activation of adenylate cyclase and the relaxation elicited by PGE1 or PGI2 in the mesenteric artery, and therefore it displays partial agonist properties in these cells. We conclude that the receptors for PGI2 coupled to adenylate cyclase in platelets and vascular smooth muscle cells are different from each other, because (5Z)-carbacyclin can discriminate between them, being a partial agonist at myocyte but not at platelet level.

Quantitative determination of 6-keto-PGF1 alpha released by rat aorta: comparison of mass fragmentography and high resolution gas chromatography with electron capture detection.

Mass fragmentography (MF) and high resolution gas chromatography with electron capture detection (HRGC-ECD) were used for measuring 6-keto-PGF1 alpha, the stable hydrolysis product of prostacyclin (PGI2) released by fresh rings of rat aorta, incubated in the absence of the precursors arachidonic acid or prostaglandin endoperoxide (PGH2). The incubation medium was acidified, extracted, chromatographed on silicic acid column and derivatized. Comparable results were obtained analyzing each sample by MF and HRGC-ECD. Both methods proved to be suitable in terms of sensitivity and specificity for the measurement of 6-keto-PGF1 alpha produce by individual rat aortae.