Prostanoids counterbalance the bronchoconstrictor activity of endothelin-1 in pigs.

In 12 anaesthetized spontaneously breathing pigs divided into two groups of six animals we evaluated the respiratory and haemodynamic responses to endothelin-1 (ET-1) administered by aerosol (200 pmol x kg(-1) in 1 ml of saline solution). In the first group (control group), the responses to ET-1 were evaluated before and after the blocking of endogenous nitric oxide (NO) by NG-nitro-L-arginine methyl ester (L-NAME 5 mg x kg(-1), i.v.). In the second group (indomethacin-pretreated group), the experimental protocol was similar to that of the control group, but the responses were evaluated after the blocking of endogenous prostanoids by indomethacin (3 mg x kg(-1), i.v.). Results show that in the control group ET-1 administered before and after L-NAME did not change compliance (Crs) or resistances (Rrs) of the respiratory system. In indomethacin-pretreated pigs, ET-1 significantly increased Rrs and decreased Crs. This constrictor effect appearing only during the block of arachidonic acid metabolites showed that ET-1 activity can be counterbalanced by a release of dilator prostanoids. In this group after L-NAME pretreatment ET-1 did not alter the mechanical properties of the respiratory system, suggesting an involvement of other bronchodilator mechanisms. In the control group, aerosol administered ET-1 increased mean systemic (MAP) and pulmonary (MPAP) arterial pressures, while when ET-1 was administered after L-NAME pretreatment, MPAP decreased. In the indomethacin-pretreated group, the peptide did not modify MAP, but caused an early decrease in MPAP when administered after L-NAME. Therefore, our results show that ET-1 caused a bronchoconstrictor effect only in indomethacin-pretreated pigs and suggest that the intrinsic constrictor activity of the peptide can be modulated especially by the release of dilator prostanoids.

Cardiovascular responses to glibenclamide during endotoxaemia in the pig.

The effects of blockading the ATP-sensitive potassium channel (K+ATP channels) on endotoxin-induced vascular derangements was studied. Escherichia coli endotoxin was infused (20 micrograms/kg per h) intravenously for 180 min into anaesthetized, mechanically ventilated, indomethacin-treated pigs. After 150 min of endotoxaemia, glibenclamide (a K+ ATP channel blocker) was infused intravenously at 2 mg/kg per min for 5 min. The cardiovascular parameters were recorded before (control), every 30 min up to 150 min during endotoxaemia, and then at 5, 15 and 30 min after administration of glibenclamide. Infusion of endotoxin reduced the systemic arterial pressure to 60.6% +/- 3.7% (p < 0.01) and increased the pulmonary arterial pressure by 75.9% +/- 11.0% (p < 0.01) of the control values. Within 5 min, infusion of glibenclamide transiently but significantly reversed the systemic hypotension by raising the systemic vascular resistance, whereas the increased pulmonary arterial pressure was further augmented. Glibenclamide infusion did not influence the cardiac output. Within 30 min, the cardiovascular parameters had returned to the values induced by endotoxin, except for the systemic vascular resistance. Infusion of glibenclamide into normal pigs did not change the systemic pressure or resistance, but the pulmonary pressure and resistance were augmented transiently. These data suggest that, in pigs, the ATP-sensitive K+ channels may be one factor playing a role in the vascular changes due to endotoxaemia, especially in the systemic circulation.

The effects of glibenclamide, a blocker of K+ ATP-sensitive potassium channels, on diaphragmatic fatigue during endotoxaemia in pigs.

An in vivo porcine model of endotoxaemia was used to study the effects of glibenclamide, a K+ ATP-sensitive potassium channel blocker. Escherichia coli lipopolysaccharides (LPS, 70 micrograms/kg, i.v., as a bolus) were infused into anaesthetized, mechanically ventilated, indomethacin-treated pigs. After 120 min of endotoxaemia, glibenclamide was administered (10 mg/kg, i.v., over 5 min) to half the pigs. The strength at different frequencies of stimulation (10, 20, 30, 50 Hz, 20 V,) 1 s) and the endurance capacity (10 Hz, 20 V, 30 s) of the diaphragm were evaluated after 120 min of endotoxaemia and 5, 10, 20 and 30 min after drug infusion. Glibenclamide transiently increased the blood pressure without changing the decreased cardiac output and at the same time further impaired the diaphragmatic activity. The reduced ability of the diaphragm to generate force in response to different electrical stimulations was shown by a significant reduction in strength. The endurance index decreased 5 min after glibenclamide infusion, returning to the pre-glibenclamide values by 150 min. These results indicate that glibenclamide modifies the activity of vascular smooth muscle and of the diaphragm.

Inhaled Nitric Oxide Counterbalances ET-1 Dependent Pulmonary Hypertension and Bronchoconstriction in the Pig.

In anaesthetized, paralysed, ventilated pigs the ability of inhaled nitric oxide (80 ppm in 0(2)) to reduce the haemodynamic and respiratory effects of endothelin-1 administration (200 pmol/kg, i.v.) was evaluated. The mechanical properties of the respiratory system were evaluated by the rapid airway occlusion technique. The overall respiratory resistance, the interrupter resistance and the additional resistance that reflects the viscoelastic properties of tissues and the inequality of the time constant within the system were also evaluated. The results show that inhaled nitric oxide can act as a selective pulmonary vasodilator and as a bronchodilator to counteract the vasoconstrictor and bronchoconstrictor activity of endothelin-1. In the pig, nitric oxide inhaled at 80 ppm for 6 mitt reduced the changes in respiratory-, interrupter- and additional resistance due to endothelin-1 administration without significantly changing the static and dynamic elastance of the respiratory system.

Inhaled Nitric Oxide Reverses Vascular and Respiratory Effects of ET-1 and PAF in Pigs.

In anaesthetized paralysed, mechanically ventilated pigs, the vascular and respiratory effects of 80 ppm nitric oxide (NO) inhaled for 6 min were evaluated. To evoke different levels of smooth muscle contraction ET-1 or PAF, mediators involved in pulmonary disorders, were used. In control conditions, inhaled NO caused selective pulmonary vasodilatation without affecting respiratory resistances. This pulmonary vascular activity influenced the distensibility of the respiratory system and decreased inspiratory work. ET-1 administration significantly increased pulmonary arterial pressure and modestly changed mechanical properties of the respiratory system, while PAF caused potent vasoconstriction and bronchoconstriction associated with a marked change in volume-pressure relationship. In both cases, the changes in vascular and mechanical properties of the respiratory system increased inspiratory work. The vascular and respiratory activities of inhaled NO were correlated with preconstriction levels. The data show that the combination of vascular and respiratory effects improves pulmonary function, suggesting that inhalation of NO is a possible therapeutic approach for obstructive and inflammatory pulmonary diseases.

Comparison of vascular and respiratory effects of endothelin-1 in the pig.

The haemodynamic and respiratory responses caused by i.v. administration of endothelin-1 (ET-1) (20-100 pmol/kg) were studied in anaesthetized spontaneously breathing pigs. Intravenous bolus administration of synthetic ET-1 (40-100 pmol/kg) caused a transient decrease followed by a long-lasting increase in mean pulmonary arterial pressure and dose dependent vasoconstriction both in the systemic and pulmonary circulations. The effect on pulmonary arterial pressure was biphasic, with an initial transient fall followed by a long-lasting dose dependent increase. A biphasic response of the systemic mean arterial pressure was demonstrated only at a high dose of ET-1 (100 pmol/kg). ET-1 administration did not significantly change breathing pattern or phasic vagal input, but caused a significant decrease in passive compliance. Passive resistances or active compliance and resistances of the respiratory system were not modified. These results suggest that in the pig ET-1 is a more potent constrictor of vascular than of bronchial smooth muscle. The vasoconstrictor activity was greater in the pulmonary than the systemic circulations.

Inspiratory timing regulation of PGF2 alpha in newborn pigs.

In intact and vagotomized anesthetized, spontaneously breathing piglets, we investigated the regulation of inspiratory timing evoked by i.v. administration of prostaglandin (PG) F2 alpha. The inspiratory time was evaluated from the flow trace as an index of mechanical inspiratory time (Ti) and from costal and crural diaphragmatic EMG (TiEMG) as an index of neural inspiratory time. Our results under control conditions showed that TiEMG was shorter than Ti. Vagotomy abolished the difference, inducing a change in the power spectrum without modifying the centroid frequency (Cf). PGF2 alpha lengthened TiEMG, causing a postinspiratory diaphragmatic discharge to appear, while mechanical inspiratory time decreased significantly. Postvagotomy i.v. administration of PGF2 alpha did not cause any significant changes in inspiratory time and did not evoke the postinspiratory discharge. The i.v. administration of PGF2 alpha before and after vagotomy did not change the centroid frequency in spite of recruitment of new motor units synchronized with those that are active under control conditions.

PAF and the role of the vagus nerve in the breathing pattern of the pig.

In 14 anesthetized, spontaneously breathing pigs we examined the changes in breathing pattern, in respiratory mechanics and in systemic and pulmonary vascular parameters after i.v. PAF administration. In another 3 pigs, the effects of PAF were also examined after bilateral vagotomy. In intact pigs, PAF induces apnea, bronchoconstriction, pulmonary hypertension and systemic hypotension. Our results also show that administration of PAF alters the phasic vagal activity, modifying the slope of VT vs TI and TE vs TI relationships and the TI0/TI ratio. These effects and apnea are vagus-dependent. The central excitatory timing effect of PAF on inspiratory duration (TI0) was correlated with a decrease in passive compliance but not with active compliance. We postulate that the activation by vagal input strengthens the mechanisms that counteract the bronchoconstrictor effect of PAF.