Further evidence implicating a cytochrome P-450-mediated reaction in the contractile tension of the lamb ductus arteriosus.

Abstract

The authors have recently provided evidence implicating the cytochrome P-450 system in the generation of contractile tension of the ductus arteriosus. To confirm this possibility, carbon monoxide (CO/O2 ratio, 0.27) and cytochrome P-450 inhibitors [4-phenylimidazole; 14-isocyano,15-(methoxymethyleneoxy)-5Z,8Z,11 Z-eicosatrienoic acid; 9-hydroxyellipticine; alpha-naphthoflavone] were tested on the isolated ductus arteriosus from mature fetal lambs equilibrated at low (4-26 mm Hg) or high (229-694 mm Hg) O2 partial pressure (PO2). Carbon monoxide completely relaxed intact vessel wall preparations and preparations consisting of only the muscle. Carbon monoxide relaxation was reversed by illumination with monochromatic light and the peak for the photoactivated contraction occurred at 450 nm. 4-Phenylimidazole (100 and 1,000 microM) was also a relaxant agent, and its action was manifest at both low and high PO2. Unlike 4-phenylimidazole, the isonitrile compound (5 microM) and 9-hydroxyellipticine (10 and 100 microM) were relaxant only at low PO2 and were also less potent. At the same PO2, alpha-naphthoflavone (10 microM) barely reduced ductal tension. Treatment of the ductus with either a combination of superoxide dismutase (60 or 150 U/ml) and catalase (40 or 1,000 U/ml) or mannitol alone (80 mM) failed to alter the steady-state tone at low PO2 and the contractile response to O2. Arachidonic acid was tested on tissues pretreated with the dual cyclooxygenase and lipoxygenase inhibitor, BW755C (10 microM), and produced a weak relaxation at a concentration of 1 microM or higher. 5,6-Epoxytrienoic acid relaxed the untreated tissue, and its action was abolished by indomethacin (2.8 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Sildenafil Reverses O2 Constriction of the Rabbit Ductus Arteriosus by Inhibiting Type 5 Phosphodiesterase and Activating BKCa Channels

“…This suggests that mediators other than NO may stimulate sGC, increasing cGMP in the DA. Indeed, carbon monoxide has been shown to stimulate sGC and increase cGMP in various vascular beds, including the DA (18,19).…”

Relaxant Effects of Carbon Monoxide Compared with Nitric Oxide in Pulmonary and Systemic Vessels of Newborn Piglets

“…Several mechanisms have been proposed to explain the vasorelaxation induced by CO and NO (17) including not only activation of sGC (11) but also stimulation of K ϩ channels (17,27) or inhibition of the cytochrome P450 monooxygenase (28,29). Hussain et al (30) have shown that ODQ completely abolished relaxation of rabbit aortic rings induced by CO, whereas only a partial attenuation of NO-induced relaxation was achieved.…”

Pharmacological and Clinical Aspects of Heme Oxygenase

“…In support of HO-1-mediated vasodilation, inhibition of HO activity increased blood pressure in spontaneously hypertensive rats (SHR) (Ndisang and Wang, 2002). The vasodilator effect of CO in various vessels may be due to a CO-mediated decrease in the cytochrome P450-dependent generation of vasoconstrictors (Coceani et al, 1988;Wang, 1998). Cytochrome P450 metabolizes arachidonic acid to the very potent vasoconstrictor, 20-HETE Schwartzman et al, 1996).…”