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Endothelin (ET-21) induced a sustained contraction of rat thoracic aortae (EC,, = 2.65 x 10-n' M) in vitro, and caused a potent pressor effect in vivo after intravenous administration to rats. In contrast, the precursor deduced from porcine cDNA coding ET-21 (PET-39) had 1Wfold less contractile activity in vitro (EC,, = 3.26 x 1O-s M), and so did the precursor from human cDNA (hET-38) (EC, = 1.48 x 108 M). However, both PET-39 and hET-38 caused almost the same dose-dependent pressor effects as ET-21 in vivo. After intravenous bolus injection at 1 nmol/kg, ET-21 caused an initial transient drop of the arterial pressure, and then induced a gradual pressor effect. On the other hand, hET-38 caused only a gradual rise of the arterial pressure. There may be different mechanism(s) for ET-21 and hET-38 which induce changes in the arterial pressure in vivo.

Endothelin (ET) is a potent vasoconstrictor/ pressor peptide consisting of 21 amino acid residues isolated from the cultures of porcine aortic endothelial cells1}. Analysis of a human genomic library reveals three forms of ET (ET-1, ET-2 and ET-3) which have more than 70% homology with one another2). In various organs, high affinity and specific receptors for ET have been found3). They have been distinguished as receptors ETA and ETB4-5). ET-1 exhibits potent and long-lasting vasoconstrictive activity in vivo and in vitro1"1, as a result of binding to the ETAreceptor. In the course of our screening program for ET-1 binding inhibitors from microorganisms, we isolated asterric acid (Fig. 1, 1) as an active substance from the culture filtrate of a fungus, Aspergillus sp. Asterric acid had been reported as a metabolite of a fungus6'7). We have shown that it has the property of inhibiting ET-1 binding to the ETA receptor of A10 cells8).The fungus was cultivated on a rotary shaker at 25°C for 7 days in 500-ml Erlenmeyer flasks each containing 100ml ofKl5 medium which consists of 2% malt extract, 2% glucose, 0.1% peptone and 0.1% agar.

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1 In the present study, we investigated the relationship between relaxation and guanosine 3':5'-cyclic monophosphate (cyclic GMP) formation induced by KRN2391, compared with those induced by nicorandil and nitroglycerin, in the coronary artery of the pig. 2 KRN2391 (10-8-3 x 10-5 M), nicorandil (10-8-3 x 10-4 M) and nitroglycerin (10-9-10-5 M) antagonized the contraction caused by 25 mM KCI in a concentration-dependent manner. 3 The concentration-relaxation curves for KRN2391, nicorandil and nitroglycerin shifted rightward in the presence of methylene blue (10-5 M).4 KRN2391 (10-6 M), nicorandil (10-4 M) and nitroglycerin (10-6 M) induced an increase in cyclic GMP. 5 The magnitude of the shift of the concentration-relaxation curve caused by methylene blue and the increase in cyclic GMP with KRN2391 were lower than those with nicorandil and nitroglycerin. 6 The adenosine 3':5'-cyclic monophosphate (cyclic AMP) level was not increased by KRN2391 even at a concentration that produced full relaxation. 7 The present results suggest that KRN2391-induced relaxation in the coronary artery of the pig is partly due to the increase in cyclic GMP formation through the stimulation of guanylate cyclase.