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We evaluated the effects of long-term treatment with benidipine, a long-acting calcium antagonist, on endothelial cell-type nitric oxide synthase (eNOS) activity and eNOS mRNA expression in the left ventricle (LV) and its relation to coronary flow reserve, and microvascular remodeling in renovascular hypertensive rats (RHR: 2K-1C Goldblatt). Benidipine (5 mg/kg/day) was given to RHR (B-RHR, n = 11) for 6 weeks. Vehicle-treated RHR (U-RHR, n = 11) and age-matched sham-operated rats (ShC, n = 11) served as control group. Coronary flow reserve was measured in conscious rats using colored microspheres. Fifty-micrometer slices of the LV were incubated with L-arginine to measure nitrite production using the Griess method and eNOS mRNA expression was determined by reverse transcription-polymerase chain reaction. An increased blood pressure in RHR was significantly decreased by benidipine. Nitrite production and eNOS mRNA expression in the LV of U-RHR was significantly lower than that of ShC. This suppression of nitrite production and eNOS mRNA expression was significantly reversed in B-RHR. U-RHR demonstrated a significant decrease in coronary flow reserve and capillary density, and a significant increase in wall-to-lumen ratio, perivascular fibrosis, myocardial fibrosis, and myocyte cross-sectional area. These impaired factors were improved significantly by benidipine. These findings suggest that benidipine therapy may increase nitrite production and eNOS mRNA expression not only by lessening the endothelial damage by the reduction of blood pressure levels, but also by the stimulation of NOS activity and eNOS mRNA, and this increased NOS activity and eNOS mRNA expression may play a role in the amelioration of coronary flow reserve and microvascular remodeling.

A total of 502 patients presenting in Utsunomiya city and its suburbs during a 10-year period were studied to determine the clinical features of ischemic heart disease and to identify coronary risk factors. The male/female ratio was 1.21, but the ratio decreased with increasing age. The duration of chest pain showed a continuous spectrum between angina and infarction, with a short duration of chest pain not being useful for excluding the diagnosis of myocardial infarction. Hypertension was more common than hypercholesterolemia in this study, although the prevalence of the latter increased slightly with time, along with the shift towards a modernized occupational pattern. Smoking was a more important risk factor for ischemic heart disease in younger individuals than in the elderly, and diabetes mellitus was highly associated with the development of myocardial infarction. The incidence of radiologically diagnosed cardiac hypertrophy and aortic calcification decreased over time. These changes may have resulted in part from improved blood pressure control and the development of new antihypertensive and cholesterol-lowering agents. (Jpn Circ J 1998; 62: 675 - 679)

Objective To determine whether chronic treatment with benidipine, a calcium antagonist, leads not only to regression of left ventricular hypertrophy, but also to an improvement in coronary flow reserve and microvascular remodeling. Design and methods Two-kidney, one clip Goldblatt hypertensive rats were assigned either to a benidipine-treatment group or to a group without treatment after their kidneys had been clipped for 4 weeks. Benidipine was administered to rats in the treatment group for 6 weeks. At the end of the treatment, the systemic hemodynamics and coronary blood flow were determined in conscious unrestrained rats by using nonradioactive colored microspheres injected through the left atrium. The coronary blood flow was determined in rats of both groups with the rats at rest and after near-maximal vasodilatation induced by carbochrome. For evaluation of the microvascular remodeling capillary density, the wall : lumen ratio of arterioles and perivascular fibrosis were quantified by using an image analyzer after fixation of heart tissue. Results Benidipine treatment lowered the blood pressure significantly with a decrease in total peripheral resistance, and the left ventricular mass decreased markedly compared with that of untreated hypertensive rats. The coronary flow reserve of the untreated hypertensive rats was lower than that of the controls, but benidipine treatment improved the coronary flow reserve. We found a significant decrease in capillary density, and significant increases in wall : lumen ratio and perivascular fibrosis in untreated hypertensive rats. These changes in microvasculature were improved by benidipine treatment Conclusion Taken together, these results suggest that benidipine exerts favorable effects as an antihypertensive drug by reversing cardiac hypertrophy and improving the coronary flow reserve and microvascular remodeling.

The present study examined alterations in left atrial diameter (LAD) and diastolic left ventricular diameter (LVDd) in 37 patients (72.2 +/- 9.8 years old) who received physiological pacemakers; 22 with atrioventricular (AV) block and 15 with sick sinus syndrome (SSS). After pacemaker implantation, LAD and LVDd were serially measured using echocardiography, and their diameters were expressed per body surface area (LADI and LVDdI; mm/m2). Pulmonary capillary wedge pressure (PCWP) and cardiac output (CO) were measured in ten patients with SSS and ten with AV block during both right ventricular and AV sequential pacing. After AV sequential pacing, CO increased in 19 of 20 patients (3.2 +/- 0.9 L/min to 3.9 +/- 1.0 L/min; P < 0.001). LADI decreased from 24.9 +/- 4.2 mm/m2 to 21.8 +/- 4.4 mm/m2 (P < 0.001) in 22 patients with AV block and from 24.1 +/- 3.4 mm/m2 to 20.4 +/- 3.8 mm/m2 (P < 0.001) in 15 SSS patients. However, LVDdI did not change significantly in either group of patients. The changes in LAD after the implantation of a physiological pacemaker occurred rapidly, i.e., LAD began to decrease within 1 minute after the procedure, and then reached a plateau. This plateau phase continued for at least 7 days during physiological pacing. There was a positive correlation between the changes in LADI after pacemaker implantation and those in PCWP observed during the AV sequential pacing performed prior to the implantation (r = 0.86; P < 0.001). The reduction in LAD following pacemaker implantation was rapid and seemed to be accompanied by improvement of cardiac function. Thus, it is suggested that the serial measurement of LADI is useful to predict the efficacy of physiological pacemaker implantation.

The systemic hemodynamic effects of different microsphere suspension agents were evaluated in 22 Sprague-Dawley male rats. Rats were divided into three groups, and three different solutions (distilled water; n=7, 10% dextran; n=8, and 70% glucose; n=7) were injected through the left atrium respectively. 0.2ml of each solution was injected repeatedly until significant hemodynamic changes developed. During four sequential injections, distilled water had no significant effects on cardiac output, mean arterial pressure, and heart rate. However, the 10% dextran (mol wt 70, 000) solution produced significant decreases in both cardiac output and mean arterial blood pressure during and after the third injection. The 70% glucose solution also decreased, cardiac output significantly during the third injection. Although microspheres itself must cause some hemodynamic changes, our results indicated that the hemodynamic disturbances observed during a large dose injection of microspheres might have been at least in part due to the use of high-density suspending solutions. The doses of radioactive microsphere solution in many previous rat studies were usually less than 0.6ml. However, in the case of large dose injection of microspheres, these results indicate that the suspending solutions can affect hemodynamic parameters in various ways.

We evaluated the effects of long-term treatment with amlodipine, a calcium antagonist, on nitric oxide synthase (NOS) activity and NOS messenger RNA (mRNA) expression in the left ventricle (LV) and its relation to coronary reserve, and microvascular remodeling in Nomega-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. Seventeen male Sprague-Dawley rats were given L-NAME (60 mg/kg/day) in drinking water for 6 weeks to induce hypertension, and then treated with amlodipine (L-NAME + A, 5 mg/kg/day, n = 9), or a vehicle (L-NAME + V, n = 8) for 4 weeks. Age-matched rats (C, n = 8) served as the control group. An increased blood pressure in L-NAME + V was significantly decreased in L-NAME + A. Nitrite production and endothelial cell (e) NOS mRNA in the LV were significantly decreased in L-NAME + V compared with C, and were significantly increased in L-NAME + A compared with C and L-NAME + V. L-NAME + V had a significantly decreased coronary reserve and capillary density, and a significantly increased type I collagen mRNA expression, wall-to-lumen ratio, perivascular fibrosis, myocardial fibrosis, and myocyte cross-sectional area. These parameters in the microvasculature were significantly improved by amlodipine. We concluded that NOS activity and eNOS mRNA were significantly increased by amlodipine in the LV of L-NAME-induced hypertensive rats, and that these increase NOS activity and eNOS mRNA expression may play a role in the amelioration of coronary reserve and microvascular remodeling.

The hemodynamic effects of various numbers of colored nonradioactive microspheres (CMS) and those of accumulation of CMS caused by multiple sequential injection were evaluated in 51 Sprague-Dawley male rats. CMS (15 microns) were injected into the left atrium. Regional blood flow and cardiac output were evaluated using the reference blood sample technique. Ficoll-70 was given after each blood sample withdrawal as a fluid replacement. A bolus injection of < or = 1,000,000 CMS caused no significant hemodynamic disturbances. Amounts of 500,000 CMS can be repeatedly injected up to four times (cumulative dose of 2,000,000 CMS) without producing any adverse hemodynamic effects. The values of cardiac output obtained with the CMS technique were correlated well (r = 0.971, P < 0.0001) with those obtained with electromagnetic flow probes. An excellent reproducibility of organ blood flow was observed after four sequential injections of 500,000 CMS. This study establishes the limits of CMS that can be injected into the rat without inducing hemodynamic changes and also suggests that the CMS technique can be employed to evaluate cardiac output and regional blood flow precisely and repeatedly.

The effect of captopril on steady-state pharmacokinetics of digoxin was studied in 12 patients with mild congestive heart failure (CHF; New York Heart Association functional class 1 or 2). Serum and urine digoxin concentrations were determined before and after a repeated administration of captopril in the patients on chronic digoxin therapy. The patients were taking digoxin, 0.25-0.375 mg/day, once daily, and were concurrently administered captopril, 37.5 mg/day, three times daily, for seven days. Peak serum concentration of digoxin (SCD) before and after captopril was 2.1 +/- 0.2, mean +/- SEM, and 2.0 +/- 0.1 ng/ml; the time to peak was 1.1 +/- 0.2 and 1.8 +/- 0.3 h; the terminal half-life (t1/2 alpha) was 10.9 +/- 1.0 and 8.7 +/- 0.9 h, and the area under the concentration-time curve to 24 h was 26.9 +/- 2.4 and 27.6 +/- 2.0 ng.h/ml. There was no significant difference between patients without and with captopril in SCD and its pharmacokinetic parameters. Renal digoxin clearance and creatinine clearance also showed no significant difference. After an administration of captopril, angiotensin-converting-enzyme (ACE) activity was well suppressed. These results suggest that captopril does not increase SCD in patients with CHF, and effectively suppresses ACE activity. Thus, modification in the dosage regimen of digoxin may be unnecessary in the case of coadministration with captopril.

血圧,心電図所見,血中catecholamine (CA)が周期的変動を示した発作型褐色細胞腫の1例を報告する.症例は発作型高血圧を主訴とした48才,男.発作の血圧上昇時(BP 250/150)には頭痛・悪心・胸痛を伴い,血中norepinephrine (NE) 5770pg/ml (非発作時475), epinephrine (E) 16170pg/ml (非発作時310)に上昇,血圧下降時(BP l00/50)には症状改善し,血中NE 1900pg/ml, E 5460pg/mlに低下し,血圧値と血中CAは約15分周期で平行する変動を認めた.血圧上昇時には血漿renin活性6.75ng/ml/h,血漿aldosterone 20ng/dl,血漿cortisol 19.5μg/dlで,いずれも高値であつた.血圧変動にほぼ一致して心電図上ST-T,脈拍の周期的変動を認めた.なお尿中CAも高値で,後腹膜気体造影断層法で右副腎部に直径3.0cmの腫瘤陰影を認め,右副腎静脈造影でもほぼ同大の静脈圧排像を認めた.さらに右副腎静脈血中CAも高値を示し,右褐色細胞腫と診断.手術により12gの比較的小さい腫瘍を含む右副腎を摘出した.電顕組織学的にA cell優位の褐色細胞腫であり,腫瘍内CAもNE 0.37mg/g wet tissue, E 1.35mg/g wet tissueとE濃度がより高値であつた.以上,本症例では,発作時,腫瘍からのCA分泌が周期的に変化し,血圧,心電図所見もこれに平行して周期的に変動したが,その詳細な機序は明らかでない.現在までに報告された周期的血圧変動を示したCA分泌腫瘍9例についても,文献的に考察を加えて報告した.

A fall in blood pressure (BP) and the presence of a period of unstable BP during sleep has been reported in humans. However the mechanisms responsible for these phenomena are unclear. In order to examine the role of the sympathetic nervous system in these phenomena, plasma norepinephrine (PNE) was measured in patients with essential hypertension. Blood pressure was monitored under unrestricted conditions by a canula inserted into the brachial artery. During sleep, systolic (SBP) and diastolic blood pressure (DBP) fell by 18.8/13.7 mmHg, respectively. The magnitude of the fall in SBP correlated significantly (p less than 0.05) with the level of PNE in the daytime and with the magnitude of the fall in PNE during sleep. The period of unstable BP and pulse rate was observed during sleep. During this unstable period, BP changed periodically with 20 to 120-second cycles associated with parallel changes in pulse rate. PNE during this period was higher (p less than 0.05) than that during the period of stable BP during sleep. These data suggest that the sympathetic nervous system may play an important role in the fall in BP and unstability of BP during sleep.

乳癌術後の放射線治療として縦隔に7200radsのコバルト照射を受けた女性が,その約17年後に労作時息切れを訴え,下肢浮腫・肝脾腫大・胸腹水・頚静脈怒張を認めるようになった.病歴および心膜叩打音の聴取,心臓超音波検査上左室後壁の拡張期平坦化・心膜の肥厚,心臓カテーテル検査上dip & plateau型の心室内圧曲線・M型の心房内圧曲線などより放射線照射による収縮性心膜炎と診断した.加えて,肝硬変・蛋白喪失性胃腸症の合併により著明な低蛋白血症を呈し,心膜の機械的絞扼によると思われる右室流出路漏斗部狭窄を合併していた.縦隔に放射線を受けた病歴のある患者では,長期間無症状の後に収縮性心膜炎の発症することがあり注意を要する.

Nitrendipine, a new calcium entry blocker, was administered to renovascular hypertensive rats (2K1C Goldblatt) (RHR, n = 8) and sham operated control rats (ShC, n = 8) to evaluate the effects on left ventricular hypertrophy and regional blood flow using radioactive microspheres. Nine untreated RHR and 8 untreated ShC served as control groups. After 6 weeks treatment (20 mg/kg subcutaneously, every other day), blood pressure reduced significantly in both RHR and ShC associated with a reduction in total peripheral resistance. Significant reversal of left ventricular hypertrophy was noted in RHR (1278 +/- 41 to 1024 +/- 19 mg, p less than 0.01), but not in ShC. There was a significant relationship between blood pressure and left ventricular mass in both untreated rats (r = 0.955, p less than 0.001) and treated rats (r = 0.729, p less than 0.005). Nitrendipine increased coronary blood flow in RHR (430 +/- 30 to 566 +/- 47 ml/m/100g, p less than 0.05) as well as in ShC (375 +/- 15 to 508 +/- 29 ml/ml/100g, p less than 0.05), without increasing cardiac oxygen demand. Renal blood flow was unchanged, whereas cerebral blood flow was significantly increased in both RHR (128 +/- 6 to 164 +/- 13 ml/m/100g, p less than 0.01) and ShC (124 +/- 7 to 173 +/- 5 ml/m/100g, p less than 0.01). Thus, long treatment of nitrendipine effectively regressed cardiac hypertrophy toward normal. Nitrendipine reduced total peripheral resistance; however, the effects on regional blood flow were not uniform among various organs.

The effects of cardiac hypertrophy on coronary circulation was evaluated in 4 related strains of rats: the M520/N strain (n = 7), which has genetic cardiac hypertrophy but a normal blood pressure; the La/N strain (n = 8), which has a somewhat small heart with normal blood pressure; the SHRSP/N strain (n = 8), which is hypertensive with marked left ventricular (LV) hypertrophy; and the WKY/N strain (n = 7), from which the SHR-Sp was developed. At 11 to 12 weeks of age, systemic and coronary hemodynamics were studied by 15-μ radioactive microspheres injected through the left atrium in conscious, unrestrained rats. Coronary blood flow was determined both at rest and after maximal vasodilation by carbochrome (6 mg/kg). LV weight was significantly higher in both the SHRSP/N (3.19 ± 0.10 mg/g [± standard error], p < 0.01) and the M520/N (2.82 ± 0.08 mg/g, p < 0.01) strains than in the WKY/N strain (2.30 ± 0.08 mg/g); it was significantly smaller in the LA/N strain (1.96 ± 0.04 mg/g, P < 0.01). Coronary flow at rest was similar among the 4 groups; however, carbochrome-induced “maximal” flow differed among the groups. It was almost equal among the SHRSP/N (1, 176 ± 151 ml/m/100 g), the LA/N (1, 356 ± 149 ml/m/100 g) and the WKY/N strains (1, 263 ± 143 ml/m/100 g), but it was markedly decreased in the M520/N Strain compared with the 3 other groups (632 ± 83 ml/m/100 g, p < 0.05 vs WKY/N and p < 0.01 vs SHRSP/N and LA/N). A significant correlation was found between maximal coronary flow and the ratio of arterial pressure to LV weight among all rats (r = 0.616, p < 0.001) as well as among the 3 normotensive strains (r = 0.70, p < 0.001). These results suggest that coronary flow reserve, even in genetic cardiac hypertrophy, depends on a balance between arterial pressure and LV mass.

Left ventricular (LV) coronary flow (CF) was determined by left atrial injection of microspheres in conscious rats during the development and after the reversal of LV hypertrophy in 2-kidney, 1-clip Goldblatt hypertension. Two groups of untreated renal hypertensive rats (RHR) were studied, the first (RHR1, n = 17) at 10 weeks and the second (RHR2, n = 9) at 24 weeks after clipping. Beginning 9 weeks after clipping, 2 other groups were treated either with captopril (40 to 60 mg/kg/day) in drinking water (RHR-C, n = 8) or left nephrectomy (RHR-N, n = 9) and followed for 15 weeks. Sham-operated animals followed for similar periods of time served as controls (Sham-1, n = 12, as a control for RHR1, and Sham-2, n = 11, as a control for RHR2). In all groups, LV mass increased or decreased in close correlation with changes in arterial blood pressure, and minimal total LV coronary resistance remained unchanged. The development of hypertrophy was associated with a tendency toward reduction in CF reserve (defined as maximal CF/unit mass); this flow reserve was restored with reversal of hypertrophy. The importance of the relation between pressure and LV mass as a determinant of CF reserve was investigated in a second study in which this relation was changed by altering the periods of captopril therapy; in these cases, CF reserve correlated significantly with the ratio of arterial pressure to LV mass (r = 0.76, n = 12, p less than 0.01). The results suggest that maintenance of CF reserve in LV hypertrophy depends on an appropriate balance between arterial pressure and LV mass, and might be disturbed by antihypertensive therapy that leaves LV hypertrophy unchanged.