Effects of endothelin on porcine coronary arterial strips.
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Endothelin, a novel endothelium derived 21-residue vasoconstrictor peptide synthesized by Peninsula Laboratories, provoked a concentration-dependent contraction of porcine coronary arterial strips. EC50 value for endothelin was 14 +/- SD 4 nmol/L (n = 6), and significantly lower than the values for 5-hydroxytryptamine (5-HT, 0.28 +/- 0.07 mumol/L, n = 6) and 15-methyl-prostaglandin F2 alpha (15-methyl-PGF2 alpha, 4 +/- 3 mumol/L, n = 7). The maximal increase in tension caused by endothelin was 5.4 +/- 1.1 g, being much greater than that induced by 5-HT (3.7 +/- 0.8 g, P less than 0.05) and 15-methyl-PGF2 alpha (3.7 +/- 0.6 g, P less than 0.01). The changes in tension provoked by endothelin (2-20 nmol/L) were attenuated significantly after pretreated with tetrodotoxin (TTX, 30 mumol/L, P less than 0.05 or 0.01). The results suggest that endothelin is one of the most potent vasoconstrictive agents, and its action is partially related to voltage-sensitive Na+ channel in the cell membrane. (+info)
The contributions of adrenal hormones, hemodynamic factors, and the endotoxin-related stress reaction to stable prostaglandin analog-induced peripheral lymphopenia and neutrophilia.
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Stable prostaglandin analogs are known to induce lymphopenia and neutrophilia in a dose-dependent fashion after subcutaneous injection in rats. The purpose of the present investigation is to determine whether the prostaglandin-induced changes in circulating leukocytes might be secondary to hypotension with the ensuing release of adrenal hormones. The adrenal medullary catecholamine epinephrine was found to induce neutrophilia in both intact and adrenalectomized rats, and the glucocorticosteroid analog dexamethasone induced a profound lymphopenia in rats as reported by previous investigators. A stable analog of PGF2 alpha (15-S-15-methyl PGF2 alpha; M-PGF2 alpha) at the dose of 1 mg/kg induced marked systemic hypotension 1 h after injection, with lymphopenia and neutrophilia 6 h after injection. The non-prostanoid hypotensive agent captopril, at a dose of 63 mg/kg, induced a hypotension of similar magnitude and kinetics to that induced by prostaglandin. Captopril also induced lymphopenia and neutrophilia at 6 h, although the neutrophilia was of lesser magnitude than that induced by prostaglandins. The prostaglandin-induced lymphopenia was found to be mediated, at least in part, by the hypotension-induced release of adrenal hormones, as evidenced by the abrogation of lymphopenia in prostaglandin-treated adrenalectomized rats. Captopril-treated adrenalectomized rats, however, did develop a significant lymphopenia, suggesting that hypotension can result in lymphopenia even in adrenalectomized rats. The M-PGF2 alpha-induced neutrophilia in adrenalectomized rats, by comparison to captopril-induced neutrophilia in adrenalectomized rats, was greater than the neutrophilia expected as the result of hypotension alone. Indeed, the M-PGF2 alpha-induced neutrophilia in adrenalectomized rats was greater than the captopril-induced neutrophilia in sham-adrenalectomized rats. Thus, a portion of the neutrophilia induced by M-PGF2 alpha in intact rats may be mediated through adrenal-independent, hemodynamic-independent mechanisms. The possibility that M-PGF2 alpha might be inducing neutrophilia via an endotoxin-like stress reaction was investigated by examining changes in circulating white blood cells in intact and adrenalectomized C3H/HeN (endotoxin-sensitive) and C3H/HeJ (endotoxin-resistant) mice after prostaglandin administration. No quantitative differences in the prostaglandin-induced neutrophilia were noted in C3H/HeJ mice as compared to the C3H/HeN mice.(ABSTRACT TRUNCATED AT 400 WORDS) (+info)
Stable analogs of prostaglandins E1 and F2 alpha ameliorate the proteinuria of aminonucleoside-of-puromycin nephrosis in Lewis rats.
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Prostaglandins have been implicated by previous investigators in the pathogenesis of the nephrotic syndrome. A single subcutaneous injection of 1 mg/kg of stable analogs of prostaglandins E1 or F2 alpha (15[S]-15-methyl -PGE1 [M-PGE1] and -PGF2 alpha [M-PGF2 alpha]) was found in the present study to dramatically decrease proteinuria on Day 10 of puromycin aminonucleoside (PAN) nephrosis in Lewis rats. The decrease in proteinuria was mediated at least in part by a decrease in glomerular filtration rate (GFR), as quantitated by inulin clearances in nephrotic control and prostaglandin-treated rats. M-PGE1, moderately, and M-PGF2 alpha, to a lesser degree, also decreased the GFR in normal rats. Interestingly, the GFR was dramatically decreased in nephrotic as compared with nonnephrotic control rats, which suggests that PAN nephrosis may not be an ideal experimental model for human minimal change nephrosis in which the GFR is usually not severely compromised. The prostaglandin-induced decrease in GFR in both nephrotic and normal rats was coincident with a drop in systemic blood pressure. Nephrotic rats, however, had a slightly higher baseline blood pressure than normals, and the hypotensive effects of both prostaglandins were much less in nephrotic than in normal rats. The decrease in proteinuria was not related to a cytoprotective effect, as indicated by the failure of daily doses of 5 micrograms/kg M-PGE1 to reduce proteinuria 6, 8, or 10 days after injection of puromycin aminonucleoside. The similar antiproteinuric effects of prostaglandin synthesis inhibitors and of pharmacologic doses of prostaglandins are somewhat paradoxical but are reminiscent of the similarly paradoxical mutual antiinflammatory effects of these agents. The high doses of prostaglandins required to reduce proteinuria as well as their reduction of blood pressure and GFR will limit their clinical usefulness in the nephrotic syndrome. (+info)
Effects of endothelin-1 on isolated uterine horns in estrogen-primed and pregnant mice.
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Mouse uterine horns from 4 states (estrogen-primed and early-, mid-, and late-pregnancy) were used to study the effect of endothelin-1 (ET) vs carboprost (Car) and oxytocin (Oxy). In K(+)-Krebs (KCl 40 mmol.L-1) solution, ET (1-300 nmol.L-1), Car (0.002-20 mumol.L-1), and Oxy (0.6-60 nmol.L-1) evoked concentration-dependent increases in tension of the uterine horns from 4 different states. Emax for ET were 1.12 +/- 0.26, 1.27 +/- 0.18, and 1.49 +/- 0.13 g in early-, mid-, and late-pregnancies, respectively. Emax for Car in mid- was twice that in late-pregnancy, whereas Emax for Oxy in late- was thrice that in mid-pregnancy. EC50 for ET were 9.6, 5.8, and 6.3 nmol.L-1 in early-, mid-, and late-pregnancies, respectively, and were only 2% to 7% of that for Car and 3-15 times of that for Oxy in various gravid stages. The results suggest that the contractile activity of pregnant mouse uterus to ET is more potent than that of Car while slightly weaker than that of Oxy. (+info)