Biochemical and functional characterization of endothelin peptides with special reference to vascular effects.
1. Detection of ET-LI in porcine and human tissues in the present study revealed the presence of high levels in blood vessels, heart, airways, kidney, placenta, amnion and umbilical vessels. ET-1 was the predominant form in both porcine and human tissues, while evidence for additional occurrence of ET-3 was obtained in the porcine kidney and spinal cord. No evidence for presence of VIC or ET-2 was obtained in the studied porcine or human tissues. Immunohistochemical techniques revealed the presence of ET-LI in the amniotic membrane cells as well as in vascular endothelial cells. 2. Transient release of ET-LI from the porcine spleen was observed during endotoxin infusion and after a 2 min period of asphyxia. During endotoxin administration plasma ET-LI increased progressively and the presence of both ET-1 and big ET-1 in the plasma was shown. Short term sympatho-adrenal activation did not evoke ET-release, however. In man, high levels of ET-LI, indicating release, were observed in the amniotic fluid and umbilical plasma at birth. 3. Specific, high affinity ET receptors were demonstrated in human and porcine tissues. One main characteristic for ET binding was the extremely slow dissociation rate. The ET-1 selective ETA receptor was predominant in the porcine spleen and renal artery as well as in the human heart and umbilical arteries, whereas the ETB receptor predominated in the porcine renal medulla and the spinal cord and the human placenta. In the porcine and human lung a mixed population of ETA and ETB receptors seemed to be present. ET-1 but not ET-3 increased IP turnover in the spleen, while both ET-1 and ET-3 was effective in the lung, suggesting the same second messenger system for both receptor subtypes. Neither ET-1 nor ET-3 was observed to have any effect on the adenylate cyclase system. 4. ET-1 was extremely potent as a vasoconstrictor in the porcine kidney and spleen in vivo, while the effect in the femoral vascular bed was less pronounced. ET-3 was considerably less potent than ET-1 as vasoconstrictor in the kidney and the spleen. However, ET-1 and ET-3 acted equipotently as vasodilators in the bronchial circulation, suggesting opposite vascular effects in the different vascular beds. Big ET-1 caused only minor vasoconstriction. ET-1 was a potent constrictor agent of human coronary, pulmonary and umbilical vessels as well as of human bronchi in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)
Hemsén
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A
Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
D000595:Amino Acid Sequence; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000378:metabolism; D019332:Endothelin-1; D016232:Endothelins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007295:Inositol Phosphates / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000502:physiology; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011863:Radioimmunoassay; D011956:Receptors, Cell Surface / Q000378:metabolism; D017466:Receptors, Endothelin; D013552:Swine
D019332:Endothelin-1; D016232:Endothelins; D007295:Inositol Phosphates; D009478:Neuropeptide Y; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D017466:Receptors, Endothelin; D000242:Cyclic AMP; D009638:Norepinephrine