Yoshihito Nakashima

Nitroglycerin-induced aortic relaxation mediated by calcium-activated potassium channel is markedly diminished in hypertensive rats.

Nitroglycerin (NTG), a nitric oxide (NO) donor, is considered to relax vascular smooth muscle by stimulating soluble guanylate cyclase, which in turn increases cyclic GMP (cGMP) level. Recently it became evident that NO-induced vasodilatation is also mediated by stimulating Ca-activated K (K(Ca)) channels directly and/or indirectly through cGMP. We, therefore, tried to investigate the possible involvement or the alteration of K(Ca) channels in the mechanism of vasodilation induced by NTG in physiological and pathological conditions. Using rings prepared from thoracic aortas of spontaneously hypertensive rats (SHR) and those of age-matched Wistar-Kyoto rats (WKY), we studied changes in isometric tension of the rings in response to NTG to evaluate effects of a soluble guanylate cyclase inhibitor methylene blue (MB), and a specific blocker of K(Ca) channel charybdotoxin (CTX). Rings from WKY and SHR precontracted with norepinephrine showed similar aortic relaxation to NTG. MB markedly suppressed the NTG-induced relaxation in both strains, leaving about 30% of MB-resistant relaxation. CTX nearly completely eliminated this MB-resistant relaxation in WHY but did not affect this relaxation in SHR. These results suggest that NTG-induced vasorelaxation is mediated through i) cGMP-dependent and ii) cGM P-independent K(Ca) channel involving mechanisms, the latter may be diminished or virtually eliminated in hypertensive state.

Role of K+ channels in EDHF-dependent relaxation induced by acetylcholine in canine coronary artery

SummaryTo identify the K+ channels responsible for endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation, we studied the effects of various K+ channel blockers on acetylcholine-induced relaxation, which persists even in the presence of both an inhibitor of nitric oxide synthase and that of cyclooxygenase, in canine coronary artery rings. A nonselective K+ channel blocker, tetrabutylammonium (TBA), a large and intermediate conductance Ca2+-activated K+ channel blocker, charybdotoxin (CTX), and a voltage-dependent K+ channel blocker, 4-aminopyridine (4-AP), significantly inhibited this residual relaxation. A combined treatment with CTX and 4-AP almost completely blocked the relaxation. Neither a large (iberiotoxin) nor a small (apamin) conductance Ca2+-activated K+ channel blocker blocked the relaxation. We also investigated effects of K+ channel blockers on basal tone to determine whether or not EDHF is involved in regulating basal tone. TBA and CTX substantially raised basal tone to a greater degree in endothelium-intact preparations than in endothelium-denuded preparations. These results indicate that EDHF may exert its relaxing action through intermediate conductance Ca2+-activated and voltage-dependent K+ channels in canine coronary arteries. In addition, EDHF may play a role in maintaining basal vascular tone.

Mechanisms of hypoxic coronary vasodilatation in isolated perfused rat hearts

We pharmacologically investigated the potential involvement of nitric oxide (NO), prostacyclin, adenosine, adenosine triphosphate (ATP)-sensitive K (K(ATP)) channel opening and Ca2+-activated K (K(Ca)) channel opening in coronary vasodilatation during 15 min of hypoxia in isolated rat hearts perfused at a constant pressure of 70 mm Hg. The coronary flow suppressed by 10(-4) M Nomega-nitro-L-arginine methyl ester (L-NAME), which corresponds to the NO-dependent flow, decreased to almost zero during hypoxia. In contrast, the NO-dependent coronary flow amounted to approximately 40% of the total coronary flow during normoxia. The suppression of coronary flow by 10(-5) M 8-phenyltheophylline (8-PT), which corresponds to the adenosine-dependent flow, was remarkable in the middle and the late phases of a 15-min hypoxia. The coronary flow suppressed by 2 x 10(-6) M glibenclamide, which corresponds to the K(ATP) channel opening-dependent flow, depended on the agents added to the perfusate. However, there was a marked increase in coronary flow in the early phase of hypoxia in the heart perfused with the combination of 8-PT, 10(-2) M tetraethylammonium (TEA) and L-NAME. During hypoxia, the coronary flow suppressed by TEA, which corresponds mainly to the K(Ca) channel opening-dependent flow, also depended on the agents added to the perfusate. However, during reoxygenation, there was a transient significant increase in any combination of the agents. Our study suggests that hypoxia almost completely inhibits NO production, and that K(ATP) channel opening immediately after hypoxia and subsequent enhanced adenosine production cause a marked hypoxic coronary vasodilatation. It also suggests that K(Ca) channel opening causes vasodilatation during reoxygenation.

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.

Clinical usefulness of measuring prothrombin time and soluble fibrin levels in Japanese patients with atrial fibrillation receiving rivaroxaban

BACKGROUND Rivaroxaban is currently used to prevent stroke in patients with atrial fibrillation. Measuring coagulation function may help clinicians to understand the effects of this drug and the associated risk of bleeding. METHODS AND RESULTS Rivaroxaban was given to 136 patients with non-valvular atrial fibrillation. Mean age was 74.5±9.0 years (men: 63.2%) and mean CHADS2 score (±SD) was 1.8±1.2. Prothrombin times (PTs) and plasma soluble fibrin (SF) levels were examined in 84 out of 136 patients at baseline and at least 2 weeks thereafter. In 48 patients we were able to collect blood at exact times, namely just before and 3h after rivaroxaban administration, corresponding to the trough and peak concentrations. Mean peak PT in 48 patients was 17.1±3.6s and median peak SF level was 1.46μg/mL. Multiple regression analysis showed that female sex, high brain natriuretic peptide, and high dose were independent factors prolonging the peak PT. Patients with peak PTs ≥20s experienced significantly more bleeding events. Among 29 of 46 patients newly treated with rivaroxaban without any previous anticoagulant, we examined coagulation function at the exact trough and peak times. In 29 patients, peak PT was significantly more prolonged than the baseline or trough PT (p<0.001 for both), whereas trough PT was comparable to the baseline PT. In contrast, both trough and peak SF levels in these newly treated patients were significantly reduced than at baseline (p=0.003 and p<0.001, respectively). CONCLUSIONS In Japanese patients with non-valvular atrial fibrillation receiving rivaroxaban, a prolonged peak PT (≥20s) could indicate increased risk of bleeding, and both trough and peak SF levels were reduced relative to baseline. PT and SF are both valuable measures of coagulation status in patients receiving rivaroxaban, regardless of prior anticoagulant history.

Monitoring of anti-Xa activity and factors related to bleeding events: A study in Japanese patients with nonvalvular atrial fibrillation receiving rivaroxaban

BACKGROUND Anti-Xa activity (AXA) in patients with nonvalvular atrial fibrillation (NVAF) and relationship to bleeding events remains unclear. METHODS We evaluated AXA in 94 patients at both trough and peak rivaroxaban concentrations. Rivaroxaban dosage was determined according to creatinine clearance (CrCl): 10 and 15mg once daily for patients with CrCl 15-49 and CrCl ≥50mL/min, respectively. AXA value distribution and its association with bleeding events were examined in enrolled subjects. RESULTS The mean peak AXA level was significantly higher than the mean trough level (1.98±0.81 vs. 0.16±0.15IU/mL; p<0.001). The peak AXA level significantly differed among patients with CrCl 15-29, 30-49, 50-79, and ≥80mL/min (2.51±0.83, 1.72±0.76, 2.05±0.82, and 1.66±0.51IU/mL, respectively; p=0.004). Major and non-major clinically relevant bleeding events occurred in 22 patients (23.4% and 14.6% per year, respectively). The mean peak AXA level was significantly higher in patients who experienced bleeding events than in those who did not (2.40±0.70 vs. 1.84±0.80IU/mL; p=0.001). A Cox multivariate analysis showed that the peak AXA level was independently related to the incidence of major and non-major clinically relevant bleeding events (p=0.012). Cumulative bleeding rates were significantly higher in patients with high peak AXA levels (p<0.001). CONCLUSION Peak AXA level was an independent predictor for bleeding events in Japanese NVAF patients receiving rivaroxaban.

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.

Use of sodium–glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long‐term use of SGLT2 inhibitors in older patients with diabetes.

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).

Recurrent Hemoptysis due to Aortobronchopulmonary Fistula of False Aortic Aneurysm Associated with Repair of Rupture of the Sinus of Valsalva.

A 54-year-old man presented with recurrent hemoptysis of one year duration. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a saccular aneurysm of the ascending aorta. The aneurysm was intraoperatively found to have formed on the superior surface of the site of aortotomy suture placed during previous repair of rupture of the sinus of Valsalva and to have a fistulous communication to the lung. CT and MRI were very useful in the diagnosis of the aneurysm as the cause of hemoptysis.