The effects of dopamine, serotonin and influences associated with meconium on lung liquid production in in vitro lungs from fetal guinea pigs (cavia porcellus)

Lungs from near term fetal guinea pigs (58-67 days of gestation) were supported in vitro for three hours; lung liquid production was monitored by a dye dilution technique. 42 preparations (61 + 1 days of gestation, 81.9 ± 9.5 g (SD) body weight) were used to study the effects of dopamine placed in the outer saline for the middle hour. At concentrations of 10⁻⁷ and 10⁻⁶ M , dopamine produced significant reductions of fluid production; at 10⁻⁵ M, there was complete arrest of production. Dopamine, at 10⁻⁴ M , produced fluid reabsorption. The linear log concentration response curve (r=0.99) showed a theoretical threshold at 1.7 x 10⁻⁹ M dopamine. Responses from dopamine involved dopaminergic receptors, since they were abolished by haloperidol (10⁻⁵ M) (n=24), a non-specific dopamine antagonist. Activation was through D₂ receptors, since responses were abolished by 10⁻⁵ M domperidone (D₂-receptor antagonist) (n=24), but unaffected by 10⁻⁵ M SCH 23390 (D₁-receptor antagonist) (n=24). Reductions by dopamine were resistant to amiloride (IO⁻⁶, 10⁻⁵ and IO⁻⁴ M) (n=66) and benzamil (10⁻⁵ M) (n=24). 36 preparations (61 ± 1 days of gestation, 77.7 + 11.5 g (SD) body weight) treated with serotonin showed about 50% reduction in fluid (10⁻⁷, 10⁻⁶ and 10⁻⁵ M). Below 10⁻⁷ M serotonin, there was a linear log concentration response curve (r=0.98), and the line of best fit suggested a theoretical threshold of 5 x IO⁻⁹ M . Preparations from 10 more mature fetuses, (65 ± 1 days of gestation, 126.2 + 13.2 g (SD) body weight) showed significantly greater responses. Maximal responses at 10⁻⁷ M involved serotonergic receptors since they were eliminated by the general serotonin antagonist, cyproheptadine (10⁻⁶ M) (n=24). In addition, 10⁻⁶ M amiloride abolished effects by serotonin (n=24). 6 untreated lungs from meconium-stained fetuses produced lung fluid consistently throughout 3 hours of incubation. However, rates of lactate production throughout experimentation were higher than rates produced by untreated, meconium-free fetuses. This suggested that these meconium-influenced lungs have increased their glycolytic metabolism to support normal fluid production. Twelve meconium-free preparations treated with 10⁻³ M 2,4-dinitrophenol (DNP) showed strong reabsorptions, and total loss of lactate increased by 3.8-fold during treatment. These reabsorptions resembled those produced after 2 x 10⁻⁴ M DNP; however, total lactate loss during treatment with 2 x 10⁻⁴ M DNP only doubled. This suggested that reabsorptions can operate on mainly glycolytic processes. In contrast, twelve lungs taken from meconium-stained fetuses and treated with 2 x 10⁻⁴ M DNP showed no change in fluid production; however, lactate production again doubled. It appeared that these lungs, although already showing above average glycolytic activity, were still capable of increasing it. Failure to reabsorb fluid may be due to a disruption in the link between metabolic processes and the reabsorptive mechanism. These studies suggest that lungs from meconium-stained fetuses have differences concerning fluid production and reabsorption processes. Furthermore, in the guinea pig, dopamine may play a role in reducing lung fluid production or initiating reabsorption close to birth, but by processes other than Na+ transport. Serotonin can slow lung liquid production or cause reabsorption; the effect increases close to term and is due to activation of amiloride-sensitive Na+ channels.Science, Faculty ofZoology, Department ofGraduat