Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor.

Abstract

Endothelin releases prostacyclin and thromboxane A2 from guinea pig or rat isolated lungs and endothelium-derived relaxing factor in the perfused mesentery of the rat. Endothelin is also substantially removed by the pulmonary circulation of the rat in vitro and in vivo and by guinea pig lungs in vitro. In the rat, the effects of endothelin on the blood pressure vary from pressor (in pithed rats) to purely depressor in anesthetized rats where the resting blood pressure is high. It therefore 4ias the characteristics of a local pressor hormone, rather than a circulating one.The endothelial cell (EC) is known to release vasoactive substances such as prostacyclin (PGI2) (1) and endotheliumderived relaxing factor (EDRF) (2), recently identified as nitric oxide (3). Release of endothelium-dependent vasoconstrictor factors has been observed in response to various chemical and physical stimuli such as norepinephrine (4), thrombin (4), hypoxia (5, 6), increased transmural pressure (7), and mechanical stretch (8).Masaki and his colleagues (9) have recently characterized from cultures of porcine aortic ECs a 21-amino acid peptide, which they called endothelin (ET). In the chemically denervated rat, porcine ET is the most potent pressor substance yet described, with a long duration of action. They suggested that ET directly activates dihydropyridine-sensitive calcium channels.We report here that apart from its vasoconstrictor activity, ET can release potent vasodilator substances such as PGI2 and EDRF and is also removed by the pulmonary circulation.MATERIALS AND METHODS Superfusion Bioassay. Spiral strips of de-endothelialized vascular smooth muscle from the rabbit (mesenteric artery, celiac artery, carotid artery, aorta, jugular vein, mesenteric vein) and other smooth muscle preparations (guinea pig trachea, guinea pig ileum, rat stomach strip, rabbit duodenum) were mounted in a cascade (10) and superfused at 5 ml-min-1 with Krebs-Ringer solution containing indomethacin (5.6 ,M). Agonists such as ET (1-50 pmol), bradykinin(1-10 pmol), substance P (1-10 pmol), and angiotensin 11 (1-10 pmol) were injected over the assay tissues.Isolated Lungs. Male Dunkin-Hartley guinea pigs (300-400 g) or male Wistar rats (200-300 g) were anesthetized with sodium pentobarbital (Sagatal, 70 ,umol kg-', i.v.) and a thoracotomy was performed. The pulmonary artery and the trachea were cannulated and the lungs were removed and placed in a warm chamber. The lungs were perfused at S ml-min-' via the pulmonary artery with oxygenated (95% 02/ 5% CO2) and warmed (370C) Krebs-Ringer solution (11). The lungs were left to stabilize for 30 min and ET was infused for 3 min at a flow rate of 0.1 ml-min-' to achieve a final concentration of 1 or 10 nM. The effluent from lungs was collected and analyzed by RIA for 6-oxoprostaglandin F1l (6-oxo-PGF1,) and thromboxane (TX) B2 as measures of prostacyclin and TXA2 release (12). The removal of ET was calculated by comparing the contractions of the assay tissues in response to infusions of ET directly over...

Structure‐activity relationship in vasoconstrictor effects of sarafotoxins andendothelin‐1

“…The vasoconstrictor effect of ET-I was in accordance with the results reported by Godfraind et al [8], Warner et al [9,10] and Walder et al [9,1 I]. In rat thoracic aorta, the contractile activity was ET-l > SRTb > SRTa > SRTc at lower concentrations, but SRTb > ET-l > SRTa > SRTc at higher concentrations.…”

Specific receptors for endothelin‐3 in cultured bovine endothelial cells and its cellular mechanism of action

“…Furthermore, De Nucci et al have reported that ET-1 induces transient depressor response in isolated perfused rat mesenteries mediated by the release of EDRF [6]. A subsequent study by the same group has shown that ET-3 is far more potent than ET-1 in vasodilating perfused rat mesenteries [3], suggesting that ET-3 functions as a vasodilator rather than a vasoconstrictor.…”

Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels

“…On the other hand, endothelial ET B receptors have been demonstrated to play a dual role. They can induce vasodilation through the release of nitric oxide and prostacyclin [9], but can also cause the release of the potent pulmonary vasoconstrictor thromboxane A 2 [10].…”