Circulatory responses to endothelin-1 and nitric oxide with special reference to endotoxin shock and nitric oxide inhalation.

1. In patients with sepsis syndrome, plasma levels of ET-LI and NA were elevated. In the porcine endotoxin shock model, plasma ET-1-L1 levels were also elevated and increased plasma levels of NA, A and NPY-LI indicated enhanced sympatho-adrenal activation. 2. ET-1 infusion in healthy human subjects to arterial plasma levels of ET-1-LI below or similar to those seen in patients with sepsis syndrome, induced a fall in splanchnic and renal blood flow, indicating that circulating ET-1-LI at levels seen in sepsis syndrome, have vasoactive effects. 3. In man, ET-1-LI was extracted in the pulmonary, splanchnic, renal and skeletal muscle vascular beds, but not in the cerebral circulation. The pulmonary circulation eliminated almost half of the administered ET-1. Apart from an initial short half-life of plasma ET-1-LI (1-2 min) after infusion, a prolonged presence of slightly elevated plasma ET-1-LI may have contributed to the long-lasting vasoconstrictor effect of the peptide in lung, splanchnic and renal circulations. In contrast, signs of vasodilation were present in the cerebral and skeletal muscle circulations, indicating net ETB receptor activation in these vascular beds. In the pig, upon infusion of similar doses of ET-1, the vascular response was slightly smaller than that in man while the pulmonary fractional extraction of ET-1-LI was similar in both species. At high levels of ET-1-LI the extraction capacity in the pig lung was saturated. Pretreatment with diclofenac did not significantly change the cardiovascular response to ET-1 nor plasma levels of ET-1-LI or the disappearance rate of ET-1-LI after infusion. 4. In the pig, pretreatment with diclofenac led to a more stable haemodynamic course during endotoxin infusion. Further, it abolished the first peak in the biphasic increase in PAP and PVR seen in endotoxin controls, indicating participation of products from the cyclooxygenase pathway in both the pulmonary hypertension and systemic hypotension seen in endotoxin shock. The increase in arterial plasma levels of ET-1-LI was delayed but not reduced by diclofenac whereas the activation of the sympathetic nervous system was attenuated. 5. A low dose of inhaled NO (10 ppm) markedly reduced the second, more prolonged phase of pulmonary hypertension during endotoxaemia. No signs of tachyphylaxis was seen during 2.5 h of NO inhalation, and upon cessation a rapid (within 15 min) elevation of PAP and PVR was seen. The effect was selective to the lung circulation.(ABSTRACT TRUNCATED AT 400 WORDS)