Yuri Takano

Azelnidipine, unique calcium channel blocker could prevent stress-induced cardiac dysfunction like α·β blocker

BACKGROUND We have reported that α and β adrenergic blockers could protect against emotional stress-induced cardiac dysfunction. Azelnidipine is a unique calcium blocker which does not increase heart rate. The purpose of this study is to evaluate the effect of azelnidipine to prevent stress-induced cardiac dysfunction. METHODS AND RESULTS Rats premedicated with azelnidipine (0.3 mg/kg), labetalol (3 mg/kg), or vehicle, were restrained for 30 min (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) by echocardiography, blood pressure, and heart rate at the end of IMO and every 10 min for 60 min after IMO. During IMO, FAC in the labetalol group was significantly lower than that in the other two groups. At 20 min after IMO, FAC in the azelnidipine or labetalol group was significantly higher than that in the vehicle group (86 ± 9%, 73 ± 5% vs. 56 ± 11%, p<0.05). During IMO, mean blood pressure in the azelnidipine or labetalol group was significantly lower than that in the vehicle group (107 ± 5 mmHg, 106 ± 17 mmHg vs. 124 ± 5 mmHg, p<0.05). CONCLUSION Acute administration of azelnidipine could prevent a sudden drop of cardiac function after acute stress like IMO. Azelnidipine might have a protective effect on stress-induced cardiac dysfunction like α and β adrenergic blockers.

Acute effects of beta-blocker with intrinsic sympathomimetic activity on stress-induced cardiac dysfunction in rats

BACKGROUND We have reported that α and β adrenergic blockers could protect against emotional stress-induced cardiac dysfunction but those protective effects of β adrenergic blockers with intrinsic sympathomimetic activity (ISA), such as celiprolol, are unknown. The purpose of this study is to evaluate whether ISA could relate with this protective effect. METHODS AND RESULTS Rats medicated with celiprolol (8 mg/kg), metoprolol (4 mg/kg), or vehicle, were restrained for 30 min (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) using an echocardiography (SONOS5500) with s12 probe (frequency: 5-12 MHz, frame rate: 120 Hz) at the end of IMO and every 10 min for 1h. During IMO, FAC in rats with a premedication of metoprolol was lower than in those with a premedication of vehicle or celiprolol. At 20 min after IMO, FAC in rats with a premedication of celiprolol was significantly higher than that with a premedication of metoprolol or vehicle (84 ± 9% vs. 65 ± 3% or 60 ± 7%, p<0.05). At 60 min after IMO, FAC in rats with a premedication of vehicle or celiprolol recovered, but FAC in rats with a premedication of metoprolol did not. CONCLUSION Acute premedication with celiprolol could prevent a sudden drop of cardiac function after acute stress such as IMO. ISA might have an important role in preventing stress-induced cardiac dysfunction.

M-002 AMLODIPINE COULD PREVENT CARDIAC DYSFUNCTION AFTER EMOTIONAL STRESS

Background We have reported that &agr; and &bgr; blocker protects against emotional stress-induced cardiac dysfunction but protective effects of other antihypertensive drug is unknown. The purpose of this study is to evaluate the effect of a calcium antagonist, amlodipine to prevent stress induced cardiac dysfunction compared with an angiotensin II receptor blocker, olmesartan medoxomil. Methods Rats premedicated with amlodipine, olmesartan or vehicle, were restrained for 30 minutes (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) and blood pressure at the end of IMO and every 10 min for 60 minutes. Results At 20 minutes after IMO, FAC inan amlodipine group was significantly higher than that in other groups. At 60 minutes after IMO, FAC was no significant differences among the three groups. At the end of IMO, BP in an amlodipine and an olmesartan group was lower than BP in a vehicle group. After IMO stress, BP inan olmesartan group was significantly lower than BP in a vehicle group, but BP inan amlodipine group was not significantly difference with other groups. Conclusion Amlodipine could have preventive effects on cardiac dysfunction after acute emotional stress, which might not relate with decreased BP. Figure. No caption available.

V-004 COMBINATION EFFECTS OF TADALAFIL AND CITRULLINE TO PREVENT WORSENING MONOCROTALINE–INDUCED PULMONARY HYPERTENSION IN RATS

Background Tadalafil, phosphodiesterase5 (PDE5) inhibitor, was reported to have a therapeutic effect on pulmonary hypertension (PH) and citrulline is an amino acid to dilate arteries as a mild NO donor. Combination effects of tadalafil and citrulline has been unknown. The aim of this study is to evaluate the combination effects of tadalafil and citrulline on monocrotaline (MCT) -induced PH in rats. Methods We used 4-week-old male SD rats which developed PH from about 7-week old by 5-times subcutaneous injection of MCT. We evaluated heart function by echocardiography before and after 6 times administration per two weeks of saline, tadalafil alone, citrullin alone and tadalafil and citrullin. Results The survival rate of tadalafil and citrullin administration was 91.7%, which was higher than other groups (a tadalafil alone: 58.3%, a citrullin alone: 50%, a saline: 33.3%). The ratios of right to left ventricular end-diastolic area in a tadalafil alone, a citrullin alone and a tadalafil and citrullin group were significantly lower than those in a saline group (1.97+0.60, 2.10 + 1.17, 2.02 + 0.93 vs 3.07 + 0.76). However, those ratios among three groups were almost same. Conclusion Combination therapy of tadalafil and citrullinecould be useful to prevent deterioration of PH.

J-012 BACKGROUND OF BENZODIAZEPINE PRESCRIPTION IN PATIENTS WITH HYPERTENSION

Background Sleep disorder or anxiety is well associated with lifestyle-related diseases, such as hypertension. In recent years, patients prescribed benzodiazepine for sleep or anxiety disorder, increased and many of them could not quit medication. However, there were few studies to investigate the relationship between hypertension and insomnia or anxiety. The aim of this study is to investigate the background of benzodiazepine prescriptions in patients with hypertension Methods We analyzed the database of the consecutive patients taking antihypertensive medications (n = 4421, male: 2442, female: 1979) in the Osaka university hospital and analyzed the background of patients taking benzodiazepine. Results Ratio of hypertensive patients taking benzodiazepine increased concomitant with age, especially those ratios in female patients were higher than those in male patients from 40 to 80 years-old (p < 0.0001). Ratio of female hypertensive patients taking benzodiazepine increased concomitant with number of antihypertensive prescriptions. Ratios of hypertensive patients taking benzodiazepine were related with types of antihypertensive medication in a specific age and gender. Conclusions Gender and age might be related with benzodiazepine prescriptions in patients with hypertension. Moreover, some antihypertensive medications might relate with benzodiazepine prescription in a specific age and gender. Those results might contribute to reduce benzodiazepine prescriptions in patients with hypertension.

W-001 BACKGROUND OF UNSTABLE HYPERTENSION WITH MENTAL DISORDER

Background Patients with mental diseases such as depression or anxiety are often accompanied with hypertension. These patients who have many indefinite complaints, such as headache, dizziness, palpitation and so on, might visit several clinics and have many unnecessary examinations. And those patients often visit hypertension clinic due to unstable high blood pressure. Methods We studied 18 male patients (average age: 56 years old) with hypertension who experienced unscheduled or emergency consultation due to high blood pressure within 3 months. Also those patients suffered from depression or anxiety and were treated with selective serotonin reuptake inhibitors (SSRI) and beta blocker in a male menopausal clinic. We studied the medical history in those patients. Results Systolic and diastolic blood pressure in those patients decreased from 156 + 14 and 90 + 10 mmHg to 125 + 10 and 77 + 6 mmHg after treatment. About 6 months later, 11 patients discontinue and other patients decreased antihypertensive medications. Patients consulted many clinical departments such as internal medicine (100%), ophthalmology (61%), otolaryngology (50%), urology (44%) and orthopedics (39%), and had many examinations, such as brain CT (61%), brain MRI (44%), ECG (89%), echocardiography (28%), chest CT (28%), abdominal echo (61%), abdominal CT (22%), abdominal MRI (17%) and endoscopy (50%) within past two years. Conclusions Patients with unstable hypertension, who frequently consult many doctors and had many examinations, might have mental disorder. Combination therapy of SSRI and beta blocker could be effective to treat patients with unstable hypertension.

AZELNIDIPINE, UNIQUE CALCIUM CHANNEL ANTAGONIST COULD PREVENT STRESS INDUCED CARDIAC DYSFUNCTION LIKE ALPHA AND BETA BLOCKER: PP.1.32

Background and Purpose: We have reported that α and βblocker, such as labetalol, protects against emotional stress-induced cardiac dysfunction but protective effects of other antihypertensive drug, such as calcium antagonist is unknown. Azelnidipine is a unique calcium antagonist which does not increase heart rate. The purpose of this study is to evaluate the effect of azelnidipine to prevent stress induced cardiac dysfunction. Methods: Rats premedicated with azelnidipine (0.3 mg/kg), labetalol (3 mg/kg) or vehicle, were restrained for 30 minutes (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) using SONOS5500 (Philips) with s12 probe (frequency: 5–12 MHz, frame rate: 120 Hz) at the end of IMO and every 10 min for 60 minutes. Results: During IMO, FAC with labetalol was significantly lower than that with azelnidipine or vehicle. At 20 minutes after IMO, FAC with azelnidipine or labetalol was significantly higher than that with vehicle (84±9% vs. 73±5%, 60±7%, p < 0.05). During IMO, BP with azelnidipine or labetalol was significantly lower than that with vehicle (107±5mmHg, 114±4mmHg, vs 126±2mmHg, p < 0.05). During study, HR with labetalol was significantly lower than that with azelnidipine or vehicle. Conclusion: Acute administration of azelnidipine, could prevent a sudden drop of cardiac function after acute stress like IMO. Azelnidipine might have a protective effect on stress induced cardiac dysfunction like α and β blocker. Figure 1. No caption available.

ACUTE EFFECTS OF BETA-BLOCKER WITH INTRINSIC SYMPATHOMIMETIC ACTIVITY ON STRESS-INDUCED CARDIAC DYSFUNCTION IN A RAT: ECHOCARDIOGRAPHIC OBSERVATION: PP.1.30

Background and Purpose: We have reported that α and β blocker protects against emotional stress-induced cardiac dysfunction, but only β blocker, such as metprolol, does not. The purpose of this study is to evaluate whether intrinsic sympathomimetic activity (ISA) of β blocker could relate with this protective effect. Methods: Rats premedicated with celiprolol, β blocker with ISA (8 mg/kg), metprolol, β blocker without ISA (4 mg/kg) or vehicle, were restrained for 30 minutes (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) using SONOS5500 (Philips) with s12 probe (frequency: 5–12 MHz, frame rate: □†120 Hz) at the end of IMO and every 10 min for 60 minutes. Rats with celiprolol and vehicle are also measured heart rate (HR) and blood pressure (BP). Results: At 20 minutes after IMO, FAC with celiprolol was significantly higher than that with metprolol or vehicle (84±9% vs. 65±3%, 60±7%, p<0.05). Blood pressure with celiprolol during study is almost same as that with vehicle, but HR with celiprolol after IMO is higher than that with vehicle. Conclusion: Acute administration of celiprolol could prevent a sudden drop of cardiac function and heart rate after acute stress like IMO. ISA of β blocker might have a very important role to prevent stress induced cardiac dysfunction. Figure 1. No caption available.

PREVENTIVE EFFECT OF TADALAFIL ON MONOCROTALINE-INDUCED PULMONARY HYPERTENSION: STUDY OF SEXUAL DIFFERENCE: PP.13.490

Background and Purpose: We already studied that monocrotaline (MCT) easily induced pulmpnary hypertension (PH) in male rats and estrogen could have a powerful preventive effect on development of PH. But the effect of tadalafil, phosphodiesterase 5 (PDE5) inhibitor, on PH is not clear in the model without estrogen. Methods: We used 4-week-old male and ovariectomized female SD rats to induce pulmonary hypertension by 5-time subcutaneous injection of 10 mg/kg/day MCT within 2 weeks. After 5 times administration of MCT, we evaluated heart function by echocardiography. The right and left ventricular end-diastolic area (RVEDA and LVEDA) were measured from left ventricular short axis view and maximal velocity of tricuspid regurgitant flow were measured. We calculated the ratio of RVEDA to LVEDA and peak pressure gradient between right ventricle and atrium. We also observed pulmonary artery flow: the ratio of acceleration time to ejection time (AT/ET) and maximal flow velocity (Vmax), by using a pulse wave Doppler. After orally administration of tadalafil (9.5 mg/kg/day) or vehicle for 6 times every other day, we evaluated heart function again. After verification of survival rate at 8-week-old, we measured the weight of RV, LV and the lung. Result: The survival rate of males at 8-week-old with vehicle and ovariectomized females and males with tadalafil was 33.3 %, 85.7% and 58.3%, respectively (Figure). The heart functions in the tadalafil group at 8 weeks were much better than those in the vehicle group, moreover those in ovariectomized females were better than those in males (Table). Conclusion: Tadalafil could be effective in preventing deterioration of MCT induced PH in rats. There might be a sexual difference in the effect of tadalafil on PH except for estrogen. Figure 1. No caption available.