REGIONAL EFFECTS AND CLEARANCE OF ENDOTHELIN-1 ACROSS PULMONARY AND SPLANCHNIC CIRCULATION

To determine the impact of i.v. endothelin-1 on systemic, pulmonary and splanchnic circulation, as well as the peptide's regional clearance, hepatic venous and right heart catheterization was performed in healthy volunteers. During the peptide's continuous i.v. administration (0.4 pmol x kg-1 x min-1, 60 min) its plasma concentration rose from 2.1 +/- 0.5 to 9.5 +/- 5.3 pmol/l (pulmonary artery), from 2.1 +/- 0.9 to 5.0 +/- 1.6 pmol/l (femoral artery), and from 1.5 +/- 0.6 to 2.9 +/- 1.2 pmol/l (hepatic vein). This was accompanied by an increase in mean systolic arterial pressure from 127 +/- 14 to 131 +/- 12 mmHg (P < 0.05). Concomitantly, cardiac output and heart rate decreased from 7.0 +/- 1.1 to 5.8 +/- 1.0 1/min and from 63 +/- 6 to 56 +/- 5 beats/min, respectively, while total vascular resistance increased from 964 +/- 273 to 1204 +/- 338 dyn x cm x s-5 (P < 0.01). No major changes in pulmonary circulation were observed, while splanchnic vascular resistance increased from 4472 +/- 1056 to 5361 +/- 1420 dyn x cm x s-5 (P < 0.01) and estimated hepatic blood flow decreased from 1403 +/- 218 to 1218 +/- 219 ml min-1 (P < 0.01). During endothelin-1 infusion the pulmonary vascular bed accounted for approximately 53% of the peptide's overall disposal. Since the splanchnic area receives blood previously cleared during passage across the pulmonary vascular bed and the splanchnic plasma flow represented only 25 to 30% of the pulmonary plasma flow, the absolute amount of endothelin-1 disposed in the splanchnic region represented only about 3%. However, the regional fractional extraction rates were comparable (mean splanchnic fractional extraction: 35.5 +/- 21%; mean pulmonary fractional extraction: 49.2 +/- 14.9%), and thereby indicate a potentially similar efficacy of the pulmonary and splanchnic vascular bed to extract endothelin-1. In conclusion we showed pulmonary clearance to be a main cause of the short half-life of endothelin-1 in man. Furthermore, the hemodynamic changes induced by the slight increases in regional concentrations of endothelin-1 provide evidence for a role of endothelin-1 in the regulation of circulation under (patho-) physiological conditions.