Hiroshi Asano

Prostaglandin H2 as an endothelium-derived contracting factor and its interaction with endothelium-derived nitric oxide.

The possibility that prostaglandin H2 is an endothelium-derived contracting factor (EDCF) was evaluated in rings of thoracic aorta of spontaneously hypertensive rats (SHR). When the aortic rings were contracted with norepinephrine (10(-7) mol/l) and treated with acetylcholine (10(-5) mol/l), a relaxant response with a peak after approximately 1 min and a contractile response with a peak after approximately 7 min were observed. When these rings were pretreated with a thromboxane A2/prostaglandin H2 receptor antagonist (ONO-3708), the later contractile response was clearly inhibited and only a sustained relaxant response was observed. This relaxant response was completely inhibited by pretreatment with an inhibitor of nitric oxide production (N-nitroarginine methylester; NNM). When aortic rings in the basal condition were treated with NNM and then with acetylcholine, a contractile response with a peak after 7 min was observed, but this reaction was completely inhibited by pretreatment with ONO-3708. The rate of 6-keto-prostaglandin F1 alpha production showed a peak of 1.4 x 10(-6) mol/l per min per tissue, 2-4 min after administration of acetylcholine. With exogenous prostaglandin H2 (5 x 10(-7) mol/l), a peak contraction was observed after approximately 4 min, the degree and pattern of which were similar to that induced by acetylcholine. Endogenous prostaglandin H2 is considered to be produced by the aortic rings in an amount sufficient to induce vascular contraction within 30 s, and the pattern of this contraction induced by acetylcholine resembles that induced by exogenous prostaglandin H2. These findings most strongly suggest that prostaglandin H2 is an EDCF.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Prostaglandin H2 as an Endothelium-Derived Contracting Factor in Diabetic State

This study investigated the possible involvement of prostaglandin H2, an acetylcholine-induced endothelium-derived contracting factor in rat aorta, in the development of abnormality of the vasculature in diabetes. Rings of thoracic aorta were prepared from control Wistar-Kyoto and STZ-induced diabetic rats to examine the changes in isometric tension. In 10−7 M norepinephrine-precontracted rings, acetylcholine induced relaxations, which were significantly impaired in diabetic rats. Inhibition of thromboxane A2-prostaglandin H2 receptors with ONO-3708 (10−6) M) prevented the development of the impairment of relaxation in diabetic rats. Thromboxane A2 synthesis inhibition with OKY-046 (10−5 M) did not affect the acetylcholine-induced relaxation in both control and diabetic rats. In aortic rings under resting tension, acetylcholine induced a contraction that was greater in diabetic than control rats, when the nitric oxide production was inhibited by NGxs-nitro-L-arginine methylester (10−4 M). This acetylcholine-induced contraction was observed only in the rings with intact endothelium and was completely abolished by ONO-3708 (10−6 M). The concentration of 6-keto-prostaglandin F1α in the solution bathing diabetic rat aortic rings increased significantly after acetylcholine (10−5 M) administration. Prostacyclin (10−9 · 10−6 M) did not induce contractions at all. Prostacyclin is unlikely to mediate contractions because of its low contractile potency. These findings suggest that the impairment of acetylcholine-induced relaxation in the diabetic state is not caused by the diminished production of an endothelium-derived relaxing factor or nitric oxide but rather by the increased endothelium-derived contracting factor or prostaglandin H2, which may be responsible for abnormalities of the vasculature in diabetes.

Correlation with blood pressure of the acetylcholine-induced endothelium-derived contracting factor in the rat aorta.

To examine a relation between the production of acetylcholine-induced endothelium-derived contracting factor and an increase in blood pressure, endothelium-dependent contraction and relaxation were evaluated by measuring the isometric tension of aortic rings from spontaneously hypertensive rats and Wistar-Kyoto rats at 5, 10, 20, and 30 weeks of age. In norepinephrine-precontracted rings, acetylcholine (10(-8) to 10(-5) M)-induced relaxations diminished at the doses of 10(-6) to 10(-5) M in both strains except at 5 weeks of age. Treatment with a thromboxane A2/prostaglandin H2 antagonist (ONO-3708) prevented this reduction in acetylcholine-induced relaxations in both strains and induced dose-dependent relaxations, which were completely inhibited by treatment with a nitric oxide inhibitor, NG-nitro-L-arginine methyl ester. In aorta treated with NG-nitro-L-arginine methyl ester without precontraction, acetylcholine induced dose-dependent contractions, which were greater in spontaneously hypertensive rats than in Wistar-Kyoto rats. These acetylcholine-induced contractions, which were observed only in rings with endothelium, were completely inhibited by treatment with ONO-3708 but not with a thromboxane A2 synthetase inhibitor (OKY-046). There was a statistically significant correlation between the acetylcholine-induced contractions and blood pressure. Release of 6-ketoprostaglandin F1 alpha by acetylcholine from the aorta was greater in spontaneously hypertensive rats. In vivo administration of another thromboxane A2/prostaglandin H2 antagonist (ONO-8809) (10 or 30 micrograms per body per day) for 3 weeks (5-8 weeks of age) did not affect blood pressure in either rat strain.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin H2 as an endothelium-derived contracting factor modulates endothelin-1-induced contraction

Objective To investigate the possible involvement of prostaglandin H2, an endothelium-derived contracting factor in the rat aorta, in the development of the contraction induced by endothelin-1 Methods The aortic rings from spontaneously hypertensive rats (SHR) were prepared, and the changes of isometric tension of these rings developed by endothelin-1 were recorded with or without the treatment of several inhibitors or an antagonist. The concentrations of prostaglandins and thromboxane B2 in the bath solution with the rings contracted by endothelin-1 were measured by radioimmunoassay. The effects of a thromboxane A2/prostaglandin H2 receptor antagonist (ONO-3708) on endothelin-1-induced contraction were compared in SHR and Wistar-Kyoto (WKY) rats Results Indomethacin (10-5mol/l) and ONO-3708 (10-6mol/l) significantly diminished endothelin-1 (3×10-8mol/l)-induced contractions in the aortic rings from SHR with but not without endothelium. The thromboxane A2 synthetase inhibitors OKY-046 (10-5 mol/l) and RS-5186 (10-5mol/l) did not attenuate the contractions either with or without endothelium. Endothelin-1 significantly increased the release of 6-keto-prostaglandin F1α, which is the metabolite of prostaglandin I2 and its precursor prostaglandin H2, from rings with endothelium of SHR, but the concentration of thromboxane B2 from aortic rings was unchanged. In the rings without endothelium the endothelin-1-induced release of 6-keto-prostaglandin F1α was also observed. The half-maximal effective concentration of endothelin-1 for rings from SHR was shifted to the right by ONO-3708, but that of WKY rats was not changed, and significantly greater amounts of 6-keto-prostaglandin F1α were released in the rings from SHR than in those from WKY rats by endothelin-1 Conclusions Endothelin-1 induced the release of prostaglandin H2 from endothelial cells in the rat aorta, the effect being greater in the hypertensive state. The released prostaglandin H2, an endothelium-derived contracting factor, modulated the vasoconstriction that is induced by endothelin-1, another endothelium-derived contracting factor, in addition to the direct vasoconstrictive action of endothelin-1 on vascular smooth muscle

Comparison of Frequency of Radial Artery Occlusion After 4Fr Versus 6Fr Transradial Coronary Intervention (from the Novel Angioplasty USIng Coronary Accessor Trial)

The frequency of radial artery occlusion was compared between patients receiving 4Fr versus 6Fr transradial coronary interventions (TRIs) in an open-label randomized trial (ClinicalTrials.gov identifier: NCT00815997). The primary outcome measure was radial artery occlusion on the day after TRI. The secondary outcome measures were the procedural success, major advanced cardiac events, access site-related complications, procedural times, fluoroscopy times, and contrast dye usage. A total of 160 patients were included. The procedure was successful in 79 of 80 patients (99%) in both groups. Whereas the 4Fr group showed no access site-related complications, the 6Fr developed 5 (6%), including 3 radial artery occlusions and 2 bleedings (1 radial artery perforation and 1 massive hematoma; p = 0.02). Although the radial artery occlusion rate was lower in the 4Fr versus the 6Fr groups, the difference was not significant (0% vs 4%, p = 0.08). The mean hemostasis time was significantly shorter in the 4Fr than in the 6Fr groups (237 ± 105 vs 320 ± 238 minutes, p = 0.007). In conclusion, these findings suggest that 4Fr TRI may become a less invasive alternative to 6Fr TRI in treating coronary artery diseases.

Diagnosis of right ventricular infarction by overlap images of simultaneous dual emission computed tomography using technetium-99m pyrophosphate and thallium-201

The validity of dual energy single-photon emission computed tomography (SPECT) with technetium-99m pyrophosphate (Tc-99m PPi) and thallium-201 for the diagnosis of right ventricular (RV) infarction, and the clinical features of RV infarction, were investigated in 190 patients with acute myocardial infarction. Diagnosis of RV infarction was performed by Tc-99m PPi accumulation in the RV myocardium on thallium-201 and Tc-99m PPi over-lay images at the dual SPECT with simultaneous imaging taken 2 to 9 days after the onset of myocardial infarction. Thirty RV infarctions were found among the 190 patients with left ventricular infarction (15.8%): 29 (97%) in association with the inferior and 1 (3%) with the lateral infarction. Tc-99m PPi accumulation was mostly observed in the posterior wall of the right ventricle. A total occlusion or a severe stenosis of the right coronary artery was demonstrated angiographically in 92% of the patients with RV infarction. The prevalence of RV infarctions was significantly lower in patients who achieved successful early reperfusion than in those who did not (26.7 vs 68.4%, respectively, p < 0.01). However, a successful early reperfusion therapy could not significantly decrease the rate of RV involvement in patients without significant collateral flow (p < 0.01). Thus, dual isotope SPECT with Tc-99m PPi and thallium-201 can be used as a reliable method for the diagnosis of RV infarction.

Measurement of Anti-Factor Xa Activity in Patients on Apixaban for Non-Valvular Atrial Fibrillation

BACKGROUND Chromogenic anti-factor Xa activity (AXA) assay is reported to be the most appropriate method to measure the pharmacodynamics of apixaban, but the distribution of AXA in non-valvular atrial fibrillation (NVAF) patients on apixaban therapy has not been fully elucidated. METHODSANDRESULTS Steady-state trough and peak AXA were measured in 124 NVAF patients taking apixaban. In 25 patients, baseline, first peak, and trough AXA were also examined, and were 0.01±0.02 IU/ml, 0.83±0.43 IU/ml, and 0.34±0.17 IU/ml, respectively. First trough AXA was significantly lower than steady-state trough AXA, although it was significantly higher than baseline (P<0.0001). Similarly, first peak AXA was significantly lower than steady-state peak AXA (P<0.0001). In 124 patients, steady-state peak AXA was significantly higher in the 5-mg b.i.d. group than in the 2.5-mg b.i.d. group (2.05±0.73 IU/ml vs. 1.51±0.65 IU/ml, respectively; P<0.001), although there was no significant difference in trough AXA. Other than dose, age and serum creatinine were significantly related to both trough and peak AXA. CONCLUSIONS The distribution of AXA in Japanese NVAF patients on apixaban therapy in daily clinical practice both in the acute and steady-state phase was measured. In patients taking apixaban, measurement of AXA clearly showed the pharmacodynamic profile of this drug.

Enalapril reduces the enhanced 1,2-diacylglycerol content and RNA synthesis in spontaneously hypertensive rat hearts before established hypertension

There is evidence that cardiac hypertrophy in spontaneously hypertensive rats (SHR) occurs before the development of hypertension. 1,2-Diacylglycerol, which is thought to be a second messenger activating protein kinase C, is also produced in excess in SHR hearts at 4 weeks of age, before established hypertension. We determined myocardial 1,2-diacylglycerol content in SHR with and without prazosin and enalapril from 3 to 4 weeks of age. Hearts from untreated SHR had greater RNA and DNA synthesis and greater relative weights at 4 weeks of age than those from Wistar-Kyoto (WKY) rats. There was no difference in triglyceride content or phospholipid species between WKY rats and untreated SHR, except for a higher cholesterol content in SHR. Treatment of SHR with enalapril, but not prazosin, lowered not only 1,2-diacylglycerol content but also RNA synthesis to the levels of WKY rats. Moreover, fatty acids involved in 1,2-diacylglycerol were altered by enalapril despite the lack of a difference between WKY rats and untreated SHR. Prazosin did not have any effect on 1,2-diacylglycerol fatty acid composition. Enalapril may decrease cardiac hypertrophy in SHR by lowering myocardial 1,2-diacylglycerol production.

Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non-valvular atrial fibrillation

Dabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non‐valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co‐administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug‐drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated.

Distribution of Anti-Factor Xa Activity in Patients on Edoxaban Therapy for Non-Valvular Atrial Fibrillation.

BACKGROUND The distribution of anti-factor Xa activity (AXA) values in non-valvular atrial fibrillation (NVAF) patients on edoxaban therapy has not been fully elucidated. METHODSANDRESULTS The steady-state trough and peak AXA values were measured in 66 NVAF patients. The trough AXA value did not differ significantly between the 60-mg and the 30-mg OD groups (0.17±0.13 IU/ml vs. 0.12±0.11 IU/ml, respectively; P=0.17). Similarly, the peak AXA value did not differ significantly between the 2 groups (1.45±0.81 IU/ml vs. 1.25±0.48 IU/ml, respectively; P=0.26). CONCLUSIONS Recommended dosing should be followed for sufficient efficacy of edoxaban. (Circ J 2016; 80: 745-747).