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...

Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginlne orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angjotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164±6 mm Hg at 4-6 weeks, compared with 108±3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125±6 mm Hg, still elevated compared with rats receiving losartan alone (98±3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfuslon, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomerull. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension. Activation of the renin-angiotensin system may account, at least in part, for the vasoconstrictor activity after such inhibition. (Hypertension 1992^0:298-303) KEY WORDS • endothelium-derived relaxing factor • kidney • hypertension, malignant • blood pressure • nitric oxide • rat studies T he endothelium releases a labile, diffusable vasorelaxing substance that has been termed endothelium-derived relaxing factor (EDRF). 1Recent observations have suggested that a major portion of the vascular effects of EDRF can be attributed to nitric oxide (NO). inhibition of NO biosynthesis. 4-67 These observations indicate that local release of NO in the microcirculation may occur on a continuous basis, thus modulating the effects of local and circulating vasoconstrictors and helping to finely regulate blood pressure and organ blood flow. In addition, micropuncture studies have suggested that angiotensin II (Ang II) may account for some of the renal microcirculatory alterations associated with acute NO inhibition. 6If NO exerts a tonic vasorelaxing effect on the microcirculation, its persistent inhibition might lead to the predominance of vasoconstrictor agents, resulting in arterial hypertension similar to that observed after chronic infusion of Ang II, 8 norepinephrine, 9 or thromboxane. 10 Recently, Gardiner and coworkers" demonstrated a marked blood pressure elevation in Brattleboro rats receiving ...

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Background and purpose:Obesity is associated with deterioration in asthma outcomes. Although airways eosinophil accumulation is characteristic of lung allergic diseases, little is known about the influence of obesity on the allergic eosinophil trafficking from bone marrow to lung tissues, and recruitment to airways lumen. Here, we have assessed the effects of diet-induced obesity on allergic eosinophilic inflammation in mice, examining eosinophil trafficking from bone marrow to airways, and production of TH1/TH2 cytokines. Experimental approach: C57BL/6 mice fed for 10 weeks with standard chow or high-fat diet were sensitized and challenged with ovalbumin. At 24-96 h post-ovalbumin challenge, bronchoalveolar lavage (BAL) fluid, lung tissue and bone marrow were examined. Key results: The high-fat-fed mice exhibited increased body weight and epididymal fat, glucose intolerance and alterations in lipid profile compared with the lean mice. Obesity markedly elevated serum leptin and lowered adiponectin levels. Ovalbumin challenge in obese mice promoted a markedly higher eosinophil accumulation in bone marrow and connective tissue surrounding the bronchial and bronchiolar segments. Eosinophil number in BAL fluid of obese mice was lower at 24 and 48 h. Levels of interleukin (IL)-5, eotaxin, tumour necrosis factor-a and IL-10 in BAL fluid of obese mice were significantly higher than in lean mice. Conclusions and implications: Diet-induced obesity enhanced eosinophil trafficking from bone marrow to lung tissues, and delayed their transit through the airway epithelium into the airway lumen. Consequently, eosinophils remain longer in lung peribronchiolar segments due to overproduction of TH1/TH2 cytokines and chemokines.