Norepinephrine-stimulated vascular prostacyclin synthesis. Receptor-dependent calcium channels control prostaglandin synthesis

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Abstract
Norepinephrine-stimulated prostacyclin synthesis was studied in rat aortic rings by measuring 6-keto-prostaglandin F1α (6-keto-PGF1α) by radioimmunoassay. Norepinephrine (10−6 M) results in a 10- to 20-fold increase in 6-keto-PGF1α synthesis by rat aortic rings (54 ± 11 to 437 ± 260 pg∙mg wet weight−1∙20 min−1). The maximal stimulation of 6-keto-PGF1α synthesis was observed with a norepinephrine concentration of 10−5 M at a mean effective concentration (EC50) of 9.5 ± 3.2 × 10−7 M which is similar to the contractile response (Emax = 10−5 M, EC50 = 6.5 ± 1.8 × 10−7 M). Potassium chloride (30 mM), although causing a similar maximal contractile response as 10−6 M norepinephrine, did not increase 6-keto-PGF1α synthesis. Norepinephrine-stimulated 6-keto-PGF1α synthesis was dependent upon extracellular calcium. Norepinephrine stimulation in Ca2+-free medium did not lead to a significant increase in 6-keto-PGF1α synthesis. However, on the introduction of Ca2+, 6-keto-PGF1α synthesis was restored to its initial level. Phentolamine (10−6 M) (an α-adrenergic antagonist) and trifluroperazine (2.5 × 10−4 M) (a calmodulin inhibitor) completely inhibited norepinephrine-stimulated 6-keto-PGF1α synthesis, whereas verapamil 3 × 10−6 M (a calcium channel blocking drug) only partially inhibited synthesis (control, 74 ± 12; norepinephrine, 437 ± 260; norepinephrine + verapamil, 123 ± 8 pg∙mg wet weight−1∙20 min−1). Norepinephrine-stimulated prostacyclin synthesis is probably α-receptor mediated and appears to depend upon the opening of receptor-operated Ca2+ channels. The operation of potential-dependent Ca2+ channels (by 30 mM KCl) in contrast, although known to be associated with an increase of intracellular Ca2+, does not stimulate PG synthesis.