Effects Of Nipradilol Research Articles

Relative importance of calcium-activated potassium channels in nipradilol-induced aortic relaxation in rats.

Nipradilol (CAS 81486-22-8), a vasodilatory beta-blocker, has been shown to dilate smaller vessels than nitroglycerin does, and the vasodilative effects of nipradilol have been reported to be less mediated by cyclic GMP (guanosine monophosphate) than those of nitroglycerin. To test the hypothesis that cyclic GMP-independent potassium channels have a larger role in nipradilol-induced aortic relaxation than cyclic GMP-dependent mechanisms, the effects of a potassium channel blocker, tetraethylammonium (TEA, CAS 56-34-8), and of a guanylate cyclase inhibitor, methylene blue (MB, CAS 61-73-4), on nipradilol-induced aortic relaxation were investigated and compared with those on nitroglycerin-induced aortic relaxation in isolated rat aortic rings. Relaxation response was expressed as percent relaxation, which is a percentage of the tension developed by 10(-7) mol/l norepinephrine. Nitroglycerin and nipradilol similarly relaxed the aortic ring in a concentration-dependent manner (10(-9)-10(-4) mol/l). In contrast, desnitronipradilol, a nipradilol analogue which has no nitroxy group, induced almost no aortic relaxation. TEA at 10(-3) mol/l, which is selective for calcium-activated potassium channels, inhibited the aortic relaxation induced by nipradilol (10(-5) mol/l) to a significantly greater extent than that induced by nitroglycerin (10(-5) mol/l) (% relaxation: 30.0 +/- 6.8 vs. 51.1 +/- 6.1%, p < 0.05). MB (10(-5) mol/l) suppressed the relaxation by nitroglycerin slightly but not significantly more than that by nipradilol. (% relaxation: 54.7 +/- 9.9 vs. 64.6 +/- 5.7%). The combination of TEA and MB almost completely eliminated the relaxation induced by nipradilol as well as by nitroglycerin. Thus, cyclic GMP-independent calcium activated potassium channels may be more involved in the aortic relaxation by nipradilol than that by nitroglycerin in rats.

Retrobulbar Hemodynamic Effects of Nipradilol in Normal and Normal-Tension Glaucoma Eyes

Purpose. To investigate the effects of nipradilol on retrobulbar hemodynamics. Methods. We investigated normal and normal-tension glaucoma (NTG) eyes. Topical nipradilol (one eye) and placebo eye drops (fellow eye) were instilled for 1 week in volunteers. Nipradilol was also instilled in NTG patients. Ultrasound color Doppler imaging for the posterior vessels was performed before, 2 hr, 1 week (for normal), and at 4 weeks (for NTG). Results. In normal eyes, there were significant decreases in the resistance index (RI) for the temporal short posterior ciliary arteries (PCA) at 2 hr and for the ophthalmic arteries at 1 week. There were no significant changes in the placebo-treated eyes. In the NTG eyes, there was a significant decrease in the RI for the central retinal artery, nasal, and temporal PCA at 2 hr and 4 weeks. Conclusion. Short-term observations found that nipradilol increased the ocular blood flow in normal and NTG eyes.

Effects of Nipradilol on Alpha-Adrenoceptor Function in Ocular Arteries

The effects of nipradilol, a drug used in the treatment of glaucoma, on the contractions induced by noradrenaline and phenylephrine in isolated dog central retinal, external and internal ophthalmic arteries and pig ciliary arteries were investigated. In dog ocular arteries treated with oxyhemoglobin (1.6 × 10^–5 mol/l) to adsorb nitric oxide, noradrenaline (2 × 10^–8 to 10^–5 mol/l) produced a concentration-related contraction which was markedly inhibited by prazosin but not by yohimbine. Nipradilol (10^–9 to 10^–7 mol/l) slightly but significantly inhibited the noradrenaline-induced contraction in a concentration-related manner, but the inhibitory potency and efficacy were much less than those of prazosin. However, nipradilol inhibited the phenylephrine-induced contraction with a similar PA₂ value of prazosin. In pig ciliary arteries treated with oxyhemoglobin, noradrenaline-induced contraction was slightly inhibited by prazosin but markedly inhibited by yohimbine. Nipradilol, similarly to timolol, did not inhibit, but rather tended to potentiate, the contraction elicited by noradrenaline. The contraction induced by phenylephrine was significantly inhibited by prazosin and nipradilol. It is concluded that nipradilol acts as an α₁-adrenoceptor antagonist (but not as an α₂-adrenoceptor antagonist) in the ocular arteries, which may partially explain its ocular-pressure-lowering mechanism. Taken together with the results of our previous studies, the potencies of the nipradilol-induced vascular actions in ocular arteries are found to be in the following order: β-adrenoceptor inhibition > α₁-adrenoceptor inhibition ≒ direct vasodilation via a release of nitric oxide.

Effect of nipradilol on silent myocardial ischemia and heart rate variability in chronic stable angina.

Silent myocardial ischemic episodes as well as decreased heart rate variability (HRV) indices are associated with an unfavorable outcome in patients with coronary artery disease. Nipradilol, which is a nonselective beta-adrenergic and nitrate-like vasodilator anti-anginal agent developed in Japan, may ameliorate silent myocardial ischemia, while it also improves exercise tolerance and HRV indices in patients with chronic stable angina. To investigate the effect of nipradilol (6 mg daily) on silent myocardial ischemic episodes and HRV indices, and to study its effect on the relationship between them, 24 patients with chronic stable angina underwent exercise treadmill testing and a 24-hour ambulatory electrocardiogram (ECG). The study protocol utilized a single blind, 4-week placebo-controlled design. The HRV indices from ambulatory ECG included mean RR (ms), SDNN (ms), SDANN (ms), SD (ms), rMSSD (ms), pNN50 (%); frequency analysis of HRV consisted of total (ms, 0.01-1.00 Hz), low (ms, 0.04-0.15 Hz) and high (ms, 0.15-0.40 Hz) components. Nipradilol significantly decreased the mean heart rate at submaximal and maximal exercise and the mean pressure rate product at submaximal and maximal exercise. It significantly improved exercise-induced maximal ST segment depression from -1.7 +/- 0.6 mm to -1.1 +/- 0.7 mm (p < 0.05). Silent myocardial ischemic episodes recorded during the 24-hour ambulatory ECG significantly decreased after nipradilol administration. Nipradilol also significantly influenced several HRV indices as well as the relationship between silent myocardial ischemic episodes and the HRV indices. Nipradilol significantly increased SD, rMSSD, pNN50, total spectra, low frequency spectra and high frequency spectra. In addition, nipradilol significantly decreased the LF/HF ratio from 1.7 (1.5-2.0) to 1.5 (1.3-1.8). These effects of nipradilol on HRV indices concomitantly occurred with the reduction in silent myocardial ischemic episodes. Nipradilol was found to effectively improve the episodes of silent myocardial ischemia as well as exercise-induced ischemia probably due to its beta-blocking properties and not nitrate-like actions. In addition, nipradilol also had a favorable effect on the HRV indices.

Effects of Nipradilol, a Nitric Oxide-Releasing β -Adrenoceptor Blocking Agent, on Phosphoenolpyruvate Carboxykinase Gene Transcription in a Rat Hepatoma Cell Line

Effects of nipradilol, a β-adrenoceptor blocker with a nitroxy moiety, on phosphoenolpyruvate carboxykinase (PEPCK) gene transcription were examined using a rat hepatoma cell line, H4IIE cells. Dexamethasone was employed as an enhancer of PEPCK gene transcription. Nipradilol, but not timolol (a β-blocker without a nitroxy moiety), attenuated PEPCK gene transcription both in the control and the dexamethasone-treated cells. The effects of nipradilol were eradicated by methylene blue (an inhibitor of cellular guanylate cyclase). Nipradilol is a unique β-blocker that suppresses PEPCK gene transcription in hepatocytes likely through liberation of nitric oxide and resultant activation of guanylate cyclase.

The effect of nipradilol, an a-ß blocker, on retinal blood flow in healthy volunteers

Purpose. To study the effects of topically applied nipradilol, an a-ß blocker recently developed in Japan as an ocular hypotensive drug, on retinal blood flow (RBF) in healthy volunteers. Methods. Seven healthy volunteers (mean age, 33 years) underwent measurement of RBF using a newly developed stabilized laser Doppler velocimetry system. In a double-blind trial, retinal arterial blood flow, intraocular pressure (IOP), and blood pressure (BP) were measured before and after the instillation of nipradilol or saline every hour for 5 hours. Results. Retinal arterial blood flow and the diameter of the retinal artery significantly (p < 0.05) increased at 4 hours after instillation in nipradilol-treated eyes. Retinal blood velocity did not change significantly. Nipradilol evoked a significant (p < 0.05) bilateral decrease in IOP. Mean BP decreased significantly (p < 0.05) 3 hours after instillation. Ocular perfusion pressure (OPP), calculated from the mean BP and IOP, did not change significantly during the study. Conclusion. Topical nipradilol significantly increased retinal arterial blood flow in healthy volunteers, not through a secondary effect dependent on a change in OPP, but likely through the vasodilatory action of the drug.

The Effect of Nipradilol on the Isoproterenol-Induced Depression of Contractions in the Cat Soleus Muscle

The effect of nipradilol on the isoproterelol-induced depression of contractions of the soleus muscle of the anesthetized cats was studied. Isoproterenol (0.3 μg/kg) injected intravenously decreased the tension and degree of fusion of incomplete tetanic contractions of the soleus muscle of the anesthetized cats. The effect of isoproterenol was blocked by nipradilol (≧3 μg/kg), desnitro-nipradilol (≧10 μg/kg) and propranolol (≧10 μg/kg), but not by nitroglycerin (10-100 μg/kg). Nipradilol (30 μg/kg) and desnitro-nipradilol (300 μg/kg) almost completely antagonized the depressor effects of isoproterenol. These results coupled with evidence that nipradilol does not penetrate the blood-brain barrier indicate that nipradilol exerts an anti-tremor action by blocking peripheral β2-adrenoceptors.

The effect of nipradilol on the isoproterenol-induced depression of contractions in the cat soleus muscle.

The effect of nipradilol on the isoproterelol-induced depression of contractions of the soleus muscle of the anesthetized cats was studied. Isoproterenol (0.3 microg/kg) injected intravenously decreased the tension and degree of fusion of incomplete tetanic contractions of the soleus muscle of the anesthetized cats. The effect of isoproterenol was blocked by nipradilol (> or = 3 microg/kg), desnitro-nipradilol (> or = 10 microg/kg) and propranolol (> or = 10 microg/kg), but not by nitroglycerin (10-100 microg/kg). Nipradilol (30 microg/kg) and desnitronipradilol (300 microg/kg) almost completely antagonized the depressor effects of isoproterenol. These results coupled with evidence that nipradilol does not penetrate the blood-brain barrier indicate that nipradilol exerts an anti-tremor action by blocking peripheral beta2-adrenoceptors.

本態性高血圧症患者に対するＮｉｐｒａｄｉｌｏｌおよびＢａｒｎｉｄｉｐｉｎｅのインスリン抵抗性および脂質に対する影響

本態性高血圧症患者に対するＮｉｐｒａｄｉｌｏｌおよびＢａｒｎｉｄｉｐｉｎｅのインスリン抵抗性および脂質に対する影響

Chronic Therapy with Nipradilol, a β-Adrenergic Blocker, Attenuated Left Ventricular Remodeling Following Myocardial Infarction in Rats

We determined whether chronic treatment with nipradilol, a β-blocker with vasodilating action, reduces left ventricular cavity dilation (LV remodeling) following myocardial infarction and improves cardiac performance. Myocardial infarction was produced by coronary artery ligation in 16-week-old female rats and then the rats were treated for 3–4 months with nipradilol (10 mg/kg/day) or vehicle (0.5°7o carboxymethylcellulose). The effect of nipradilol on LV remodeling was evaluated by assessing the left ventricular end-diastolic volume index (LVEDVI) and passive pressure-volume relation curve. Since LVEDVI depends on the infarct size, LVEDVI was compared between the vehicle- and nipradilol-treated rats with similar infarct size (10-40°7o). At 3–4 months after myocardial infarct production, the left ventricular end-diastolic volume index in the vehicle-treated rats with myocardial infarction was significantly increased, compared with that in the sham-operated rats without infarction. The nipradilol-treated rats had a significantly smaller left ventricular volume index than the vehicle-treated rats (2.04±0.16 ml/kg in the vehicle-treated group vs 1.36±0.10 ml/kg in the nipradilol-treated group, P<0.01). The maximum cardiac index achieved by volume loading as an index of cardiac performance was significantly greater in the nipradilol group than the vehicle group (254.5± 12.6 ml/min kg in the vehicle group vs 347.9±20.2 ml/min kg in the nipradilol group, P <0.01). These results suggest that chronic treatment of nipradilol attenuated left ventricular cavity dilation after myocardial infarction and improved cardiac performance.

Chronic therapy with nipradilol, a beta-adrenergic blocker, attenuated left ventricular remodeling following myocardial infarction in rats.

We determined whether chronic treatment with nipradilol, a beta-blocker with vasodilating action, reduces left ventricular cavity dilation (LV remodeling) following myocardial infarction and improves cardiac performance. Myocardial infarction was produced by coronary artery ligation in 16-week-old female rats and then the rats were treated for 3-4 months with nipradilol (10 mg/kg/day) or vehicle (0.5% carboxymethylcellulose). The effect of nipradilol on LV remodeling was evaluated by assessing the left ventricular end-diastolic volume index (LVEDVI) and passive pressure-volume relation curve. Since LVEDVI depends on the infarct size, LVEDVI was compared between the vehicle- and nipradilol-treated rats with similar infarct size (10-40%). At 3-4 months after myocardial infarct production, the left ventricular end-diastolic volume index in the vehicle-treated rats with myocardial infarction was significantly increased, compared with that in the sham-operated rats without infarction. The nipradilol-treated rats had a significantly smaller left ventricular volume index than the vehicle-treated rats (2.04 +/- 0.16 ml/kg in the vehicle-treated group vs 1.36 +/- 0.10 ml/kg in the nipradilol-treated group, P < 0.01). The maximum cardiac index achieved by volume loading as an index of cardiac performance was significantly greater in the nipradilol group than the vehicle group (254.5 +/- 12.6 ml/min kg in the vehicle group vs 347.9 +/- 20.2 ml/min kg in the nipradilol group, P < 0.01). These results suggest that chronic treatment of nipradilol attenuated left ventricular cavity dilation after myocardial infarction and improved cardiac performance.

Some effects of nipradilol, a β‐antagonist possessing a nitroxy group, on smooth muscle of the pig coronary artery

1. The effects of nipradilol, a beta-adrenoceptor antagonist which possesses a nitroxy group, on cytosolic Ca2+ concentration ([Ca2+]i), and on tension development were simultaneously measured by front-surface fluorometry and fura-2-loaded strips in the proximal portion of pig coronary arteries. 2. Nipradilol reduced in a concentration-dependent manner both the [Ca2+]i and tension, irrespective of whether the strips were unstimulated or exposed to either high K+ or histamine containing solutions. However, both in the case of contractions induced by high K+-depolarization and histamine stimulation, for a given [Ca2+]i elevation the tension which developed in the presence of nipradilol was smaller than that generated in its absence, so that the [Ca2+]i-tension curves during the contraction were shifted to the right. 3. In the absence of extracellular Ca2+, the [Ca2+]i elevation due to the release of Ca2+ from histamine-sensitive store was inhibited by nipradilol. Nipradilol had no effect on the [Ca2+]i elevation due to the release of Ca2+ from caffeine-sensitive stores; however, it did inhibit the caffeine-induced increase in tension. A derivative of nipradilol, which lacked a nitroxy molecule (Nip(-N)), had no effect on the [Ca2+]i and tension elevated by histamine or caffeine in the absence of extracellular Ca2+. 4. The beta-adrenoceptor agonist, isoprenaline, reduced [Ca2+]i tension when applied to steady state contractions induced by high K+, or at the peak level of tension to histamine. The reduction of [Ca2+]i and tension induced by isoprenaline was inhibited by Nip(-N) in a concentration-dependent manner and nipradilol inhibited the isoprenaline-induced relaxation with bell-shaped concentration-response curves. At lower concentrations, nipradilol acted as a beta-blocker, the IC50- value being smaller than that of Nip(-N), and at higher concentrations, it acted as a nitrovasodilator. 5. Thus, it is suggested that, at lower concentrations, nipradilol, an antianginal drug, acts as a beta-adrenoceptor antagonist. At higher concentrations, it relaxes the proximal portion of the coronary artery by directly reducing [Ca2+]i and the Ca2+-sensitivity of the myofilaments, apparently due to the presence of the nitroxy molecule.

Canine retinal arterial and arteriolar dilatation induced by nipradilol, a possible glaucoma therapeutic.

The effects of nipradilol, an ocular hypotensive drug, on isolated canine retinal central arteries and on retinal arterioles in vivo were investigated. Nipradilol (10(-9) to 10(-5) mol/l) produced a dose-related relaxation of the arterial strips contracted with prostaglandin F2 alpha which was not influenced by timolol or indometacin. The median effective concentration of this drug was five times that of glycerol trinitrate (GTN). The nipradilol-induced relaxation in the endothelium-intact strips was not influenced by NG-nitro-L-arginine, a nitric oxide synthase inhibitor, but was abolished by oxyhemoglobin and methylene blue. Treatment with high concentrations of sodium nitroprusside abolished the response to nipradilol, as observed with that to GTN. Retinal arterial strips responded to isoproterenol with a slight relaxation which was depressed by nipradilol. In anesthetized dogs, intra-arterial injections of nipradilol dilated the retinal arterioles in the ocular fundus; the dilator potency was approximately one fifth that of GTN. It is concluded that nipradilol dilates canine retinal arteries in vitro and arterioles in vivo, possibly due to activation of soluble guanylate cyclase and increased production of cyclic guanosine monophosphate that are associated with nitric oxide liberated from the molecule itself in the tissue but not derived from the endothelium and perivascular nerve. Beta adrenoceptor blocking action was determined in the retinal artery.

本態性高血圧症患者に対するニプラジロールのインスリン抵抗性および脂質に対する影響

本態性高血圧症患者に対するニプラジロールのインスリン抵抗性および脂質に対する影響

労作狭心症における自律神経系の日内変動に対するＮｉｐｒａｄｉｌｏｌの効果

労作狭心症における自律神経系の日内変動に対するＮｉｐｒａｄｉｌｏｌの効果

ニプラジロールの抗狭心症作用機序の検討

ニプラジロールの抗狭心症作用機序の検討

安定労作性狭心症例の運動負荷試験及び無症候性心筋虚血発作に及ぼすｎｉｐｒａｄｉｌｏｌの影響

安定労作性狭心症例の運動負荷試験及び無症候性心筋虚血発作に及ぼすｎｉｐｒａｄｉｌｏｌの影響

P-122 - Effects of nipradilol on cytosolic calcium concentration and tension development in Isolated coronary artery of the pig

P-122 - Effects of nipradilol on cytosolic calcium concentration and tension development in Isolated coronary artery of the pig

本態性高血圧症に対するｎｉｐｒａｄｉｌｏｌの左室心筋重量および拡張機能に及ぼす効果

本態性高血圧症に対するｎｉｐｒａｄｉｌｏｌの左室心筋重量および拡張機能に及ぼす効果

２４時間血圧日内変動からみたニプラジロール（ハイパジール）の降圧効果 周期共分散分析法による判定

２４時間血圧日内変動からみたニプラジロール（ハイパジール）の降圧効果 周期共分散分析法による判定