RESUMEN
We have recently shown that a cytochrome P-450-based mechanism is important for the generation of contractile tension by the ductus arteriosus and have now examined whether the same mechanism operates in the ductus venosus. Carbon monoxide (CO/O2 ratio, 0.27) and cytochrome P-450 inhibitors [metyrapone; 4-phenylimidazole; 14-isocyano, 15-(methoxymethyleneoxy)-5Z,8Z,11Z- eicosatrienoic acid; alpha-naphthoflavone] were tested in vitro on the ductus venosus sphincter from mature fetal lambs. Each preparation was precontracted with indomethacin (2.8 x 10(-6) M). Carbon monoxide completely relaxed the ductus, and its action was reversed by illumination with monochromatic light. Peak photocontraction occurred at 450 nm. With the exception of alpha-naphthoflavone, all cytochrome P-450 inhibitors were also relaxant agents. Alpha-naphthoflavone (the sole type I inhibitor tested) produced instead a modest contraction that was often transient. Relaxation brought about by both carbon monoxide and drugs was fully reversed by the thromboxane A2 analog 9,11-epithio-11,12-methano-thromboxane A2 and by excess potassium (55 mM). Carbon monoxide was equally effective in the intact ductus and the ductus denuded of endothelium, whereas cytochrome P-450 inhibitors were marginally less effective in the latter preparation. These findings indicate that the ductus venosus sphincter, like the ductus arteriosus, relies on an intramural cytochrome P-450 mechanism to develop its contractile tone. The actual constrictor remains to be characterized in both vessels.
Asunto(s)
Sistema Enzimático del Citocromo P-450/fisiología , Vasoconstricción , Venas/embriología , Animales , Monóxido de Carbono/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Conducto Arterial/fisiología , Femenino , Luz , Metirapona/farmacología , Embarazo , Ovinos , Venas/fisiologíaRESUMEN
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)
Asunto(s)
Sistema Enzimático del Citocromo P-450/fisiología , Conducto Arterial/fisiología , Ovinos/fisiología , Animales , Ácido Araquidónico , Ácidos Araquidónicos/farmacología , Monóxido de Carbono/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Radicales Libres , Contracción Muscular , Músculo Liso Vascular/fisiologíaRESUMEN
Octopamine, the phenol analogue of noradrenaline, is a neurosecretory product found in many vertebrate and invertebrate species. In the American lobster, octopamine produces an increase in muscular tension during activation of the motor nerve and may induce spontaneous contractions at concentrations of 10(-7) M (refs 1,2). In the lobster, postsynaptic mechanisms, including a change in Ca2+ conductance of the muscle membrane, are thought to be responsible for potentiation of contraction. In contrast, studies on insects have implicated both pre- and postsynaptic effects: for example, O'Shea and Evans reported that neuromuscular transmission in the locust leg extensor muscle is modulated by octopamine released from a specific neurosecretory neurone which acts on high-affinity octopamine receptors located both on the muscle and on excitatory nerve terminals. The presynaptic receptors mediate an increase in frequency of spontaneous miniature postsynaptic potentials recorded in the muscle. In view of the apparent discrepancy between insect and crustacean results, we have re-examined the effects of octopamine on neuromuscular transmission in a crustacean muscle and report here that enhanced postsynaptic potentials produced by very low levels of octopamine (10(-10) -10(-7) M) are largely attributable to a presynaptic effect which increases quantal release of transmitter. Also, this effect is more pronounced and longer lasting when octopamine is applied to active neuromuscular preparations. This system provides a model for selective consolidation of active synapses by neurohormonal mechanisms. Such an effect could be of general significance in the nervous system, as it would provide a mechanism for selective neurohormonal regulation and strengthening of pathways used during specific activities.