dinoprost and sapropterin

Nitric oxide (NO)-mediated smooth muscle relaxation causes penile erections. The endothelial NO synthase (eNOS) coenzyme tetrahydrobiopterin (BH4) converts eNOS-mediated catalytic activity from oxygen radical to NO production, improving endothelial function and vascular smooth muscle relaxation.. Using quantitative immunohistochemistry, 8-isoprostane and nitrotyrosine concentrations were compared in cavernosal tissue from 17 potent and 7 impotent men, and the effect of single oral doses of BH4 on penile rigidity and tumescence was investigated. The pharmacodynamic effect of single oral doses of BH4 on penile rigidity and tumescence was investigated in a randomized, placebo-controlled, double-blind cross-over fashion in 18 patients with erectile dysfunction (ED) while receiving visual sexual stimulation.. 8-Isoprostane content in endothelium and smooth muscle was significantly higher in impotent patient samples; the level of nitrotyrosine was unchanged in ED patients. Relative to placebo, a single dose of 200 mg BH4 led to a mean increase in duration of > 60% penile rigidity (33.5 min [95% confidence interval (CI): 13.1-49.3] at base and 29.4 min [95% CI: 8.9-42.2] at tip). A 500-mg dose increased the relative duration of > 60% penile rigidity by 36.1 min (95% CI: 16.3-51.8) at the base and 33.7 min (95% CI: 11.4-43.9) at the tip. Treatments were well tolerated.. BH4 treatment is suggested to switch eNOS catalytic activity from super-oxide to NO formation, leading to a reduced formation of free radical reaction product 8-isoprostane without alteration of nitrotyrosine. The observed results make BH4 a suitable candidate as an ED treatment through reconstitution of altered catalytic activity of the eNOS.

Topics: Adolescent; Adult; Aged; Biopterins; Cross-Over Studies; Dinoprost; Double-Blind Method; Erectile Dysfunction; Humans; Immunohistochemistry; In Vitro Techniques; Male; Middle Aged; Muscle, Smooth, Vascular; Nitric Oxide; Penile Erection; Penis; Tyrosine

In the liver, eNOS appears to have a central role in protecting against ischemia/reperfusion (I/R) injury. We hypothesized that tetrahydrobiopterin (BH4) would protect livers subjected to I/R injury by coupling with eNOS.. Chinese Kun Ming (KM) mice were subjected to 60 min of 70% hepatic ischemia 30 min after the administration of BH4 or saline. After reperfusion, survival was evaluated. The histologic appearance and ALT, BH4, nitrite/nitrate, 8-isoprostane, and eNOS protein expression levels were measured.. The 1-wk survival rate was 66.67% in the BH4 group and 33.33% in the saline group. The serum ALT values in the BH4 group 1, 3, 6, 12, and 24 h after reperfusion were significantly lower than those of the saline group. A histologic examination of the liver revealed only a small necrotic area in the BH4 group as opposed to massive necrosis in the saline group. The percentage values of the hepatic necrotic area 24 h after reperfusion were significantly less for the BH4 group than for the saline group. The nitrite/nitrate levels in the liver tissue were significantly increased by ~2-fold in the BH4 group compared with the saline group. The free radical indicator 8-isoprostane was reduced approximately 50% in the BH4 group compared with the saline group. Western blotting showed that the level of eNOS protein between the groups was not significantly different.. BH4 significantly improved the survival rate by reducing liver failure. This was supported by the histologic findings, and the mechanism was explored. According to the results, we suggest that BH4 prevents liver damage from I/R injury by attenuating reactive oxygen species and increasing NO synthesis, and might provide a novel and promising therapeutic option for preventing I/R injury.

Topics: Alanine Transaminase; Animals; Biopterins; Delayed Graft Function; Dinoprost; Liver; Liver Diseases; Liver Transplantation; Mice; Mice, Inbred Strains; Nitrates; Nitric Oxide Synthase Type III; Reperfusion Injury; Superoxides; Vitamin B 12

Cysteinyl leukotrienes (cysLT) are pro-inflammatory and vasoactive products suspected to be involved in the regulation of vascular tone and blood pressure in hypertension.. We investigated, in spontaneously hypertensive rats (SHR), the involvement of cysLT in the in-vivo regulation of blood pressure and the in-vitro endothelium-dependent contraction to acetylcholine in isolated aorta.. SHR and Wistar-Kyoto rats (WKY) were orally treated for 3 weeks with either the cysLT biosynthesis inhibitor MK-886 (0.1 mg/ml) or vehicle. After mean arterial blood pressure (MABP) measurement, aortic ring preparations were removed from all groups of animals, and contractions and relaxations were monitored subsequent to stimulation with acetylcholine.. MABP was higher in SHR. Chronic treatment with MK-886 did not alter MABP in either SHR or WKY. In the presence of the N-nitro-L-arginine (L-NA, 100 micromol/l), and on prostaglandin F2alpha (PGF2alpha)-induced tone, acetylcholine evoked concentration-dependent contractions in intact aortic rings from SHR only. Pretreatment with either MK-886 (10 micromol/l), the 5-lipoxygenase (5-LO) inhibitor AA861 (10 micromol/l), or the cysLT1 receptor antagonist MK571 (1 micromol/l) reduced (P < 0.05) acetylcholine-induced contractions in intact aortic rings from SHR only. Acetylcholine-induced contractions were weaker (P < 0.01) in SHR chronically treated with MK-886 than in SHR. In the presence of L-NA, leukotriene (LT) D4 induced greater (P < 0.05) concentration-dependent contractions in aortic rings from SHR than from WKY. MK571 abolished LTD4-evoked contractions.. These data suggested that 5-LO-derived products, through the activation of cysLT1 receptors, could be involved in the endothelium-dependent contraction to acetylcholine in aorta from SHR but not in the regulation of MABP in SHR.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Arachidonate 5-Lipoxygenase; Benzoquinones; Biopterins; Blood Pressure; Body Weight; Dinoprost; Endothelium, Vascular; Hypertension; Indoles; Leukotriene D4; Lipoxygenase Inhibitors; Male; Membrane Proteins; Nitroarginine; Propionates; Quinolines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Leukotriene; Vasoconstriction

Coronary endothelial dysfunction after heart transplantation is predictive of cardiac allograft vasculopathy. Immunosuppressive drugs, particularly cyclosporine may contribute to this dysfunction by a direct effect. Tetrahydrobiopterin (BH(4)) is a potent antioxidant and an essential cofactor of nitric oxide biosynthesis. The purpose of this study was to investigate whether BH(4) could reverse the endothelial dysfunction induced by cyclosporine.. A previously described in vitro model of drug incubation in Krebs-bicarbonate solution (4 degrees C, 48 hours) of porcine epicardial coronary arteries was used. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10(-4) mol/L) in the presence or absence of 6-methyltetrahydropterin (MH(4) [0.1 mol/L], a BH(4) analog) to assess its effect on the cyclosporine-induced endothelial dysfunction.. The average doses of PGF2(alpha) required to attain 50% of the maximal contraction to KCl was significantly lower (P < .001) in the cyclosporine group (8.6 +/- 1.94 x 10(-6) mol/L) compared to the control group (24.8 +/- 5.2 x 10(-6) mol/L). Exposure to cyclosporine induced a significant decrease in endothelium-dependent relaxations to serotonin (5HT) (% E(max) [5HT]: 77% +/- 4%; P < .05). Addition of MH(4) significantly reversed this impaired response (% E(max) [5HT]: 62% +/- 4%; P < .05). No alterations of relaxation were observed with bradykinin in both groups. Endothelium-independent relaxations to sodium nitroprussiate were fully preserved.. These results suggest a significant protective role of BH(4) on coronary endothelial function following exposure to cyclosporine, which could reduce the incidence of endothelial dysfunction and cardiac allograft vasculopathy following cardiac transplantation.

Topics: Animals; Antioxidants; Biopterins; Coronary Vessels; Cyclosporine; Dinoprost; Endothelium, Vascular; In Vitro Techniques; Muscle Contraction; Swine

In intrapulmonary arteries cultured under hypoxic conditions (5% oxygen) for 7 days, endothelium-dependent relaxation and cGMP accumulation induced by substance P were decreased as compared to those of a normoxic control (20% oxygen). In rabbit mesenteric arteries exposed to chronic hypoxia, however, endothelial dysfunction was not observed. Furthermore, in endothelium-denuded pulmonary arteries exposed to hypoxia, neither relaxation nor cGMP accumulation due to sodium nitroprusside differed from those of the normoxic control. Hypoxia did not change the mRNA expression of endothelial NO synthase (eNOS), the protein expression of eNOS or the eNOS regulatory protein caveolin-1 as assessed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) or whole-mount immunostaining. Morphological study revealed atrophy of endothelial cells and condensation of the eNOS protein in many cells. These results suggest that chronic hypoxia impaired NO-mediated arterial relaxation without changing either the eNOS protein expression or the NO-sensitivity of smooth muscle cells in pulmonary arteries. Changes in cell structure and organization may be involved in endothelial dysfunction.

Topics: Animals; Arginine; Biopterins; Caveolin 1; Caveolins; Cyclic GMP; Dinoprost; Dose-Response Relationship, Drug; Endothelium, Vascular; Hypoxia; Ionomycin; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroprusside; Organ Culture Techniques; Pulmonary Artery; Rabbits; RNA, Messenger; Substance P; Superoxide Dismutase; Vasoconstriction; Vasodilation; Vasodilator Agents