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)
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.
Our previous studies implicate a cytochrome P-450-based mechanism in the constrictor response of the ductus arteriosus to oxygen. The present experiments were conducted on saponin-skinned strips of ductal muscle from mature fetal lambs to determine the location, sarcolemmal versus intracellular, of this cytochrome and to obtain a better insight into the sequence of events underlying the action of oxygen. Skinned preparations contracted to free Ca2+ over the range between 0.1 and 5-10 microM (pCa 7 to 5). In contrast, oxygen (PO2, 608-690 Torr; 1 Torr = 133.3 Pa) had no significant effect, both in the absence and presence of 10 microM calcium. Carbon monoxide, tested as pure CO or a CO-O2 mixture (ratio 0.28), did not relax preparations maximally contracted with calcium. These findings indicate that oxygen exerts its effect on the plasma membrane of ductus muscle cells and that a membrane-bound cytochrome P-450 mechanism likely functions as the signal transducer for oxygen in the formation of a constrictor agent.
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