Hiroshi Ikenouchi

Mechanisms of Adrenomedullin-Induced Vasodilation in the Rat Kidney

To explore the mechanisms of adrenomedullin-induced vasorelaxation, we tested the effects of adrenomedullin on renal function in rats in vivo and measured the release of endothelium-derived nitric oxide from isolated perfused rat kidney (using a chemiluminescence assay) and the diameters of the glomerular arterioles in the hydronephrotic kidney. Adrenomedullin decreased blood pressure in a dose-dependent manner (3 nmol/kg: -29 +/- 2% [SEM]; P < .01) and slightly increased the glomerular filtration rate and urinary sodium excretion (+108%; P < .05). These changes were associated with significant increases in urinary excretion of cyclic AMP (+54%; P < .05). Adrenomedullin decreased renal vascular resistance (10(-7) mol/L adrenomedullin: -41 +/- 2%; P < .001) and increased release of nitric oxide (+5.1 +/- 0.7 fmol/min per gram kidney weight; P < .001) in the isolated kidney. This increase in nitric oxide release was abolished by the inhibitor NG-monomethyl-L-arginine, and it also reversed the decrease in renal vascular resistance seen with adrenomedullin. Renal responses of deoxycorticosterone acetate-salt hypertensive rats to adrenomedullin were significantly smaller than those of control rats for both release of nitric oxide (10(-7) mol/L adrenomedullin: +0.8 +/- 0.2 fmol/min per gram kidney weight; P < .01 versus control) and renal vasodilation (-28 +/- 6%; P < .05). Videomicroscopic analysis revealed that adrenomedullin increased the diameters of both afferent and efferent arterioles (3 nmol/kg: +11%; P < .05). Thus, adrenomedullin-induced renal vasodilation is partially endothelium dependent and is attenuated in deoxycorticosterone acetate-salt hypertension, probably due to endothelial damage.

Negative Inotropic Effect of Adrenomedullin in Isolated Adult Rabbit Cardiac Ventricular Myocytes

BACKGROUND Adrenomedullin (AM) is a potent vasodilator peptide. AM-induced vasodilatation is mediated by an increase of NO as well as cAMP. Both AM and binding sites for this peptide have been found in cardiac tissue, indicating the possible existence of an autocrine or paracrine system of AM in the heart. METHODS AND RESULTS Myocytes were isolated by use of retrograde coronary perfusion with physiological solution containing collagenase and hyaluronidase from adult rabbit ventricles. Contraction of cardiac myocytes was traced with a video motion detector, and [Ca2+]i was measured with indo 1 at 37 degrees C. The Ica was measured with a whole-cell patch clamp at 23 degrees C. AM and calcitonin gene-related peptide (CGRP), another member of the same peptide family, showed a concentration-dependent negative inotropic effect (10(-7) mol/L AM: contraction amplitude, 64 +/- 7% of control; [Ca2+]i, 52 +/- 5% of control; n = 10; 10(-6) mol/L CGRP: contraction amplitude, 64 +/- 25%; [Ca2+]i, 70 +/- 3%; n = 5; mean +/- SD). Ica was decreased to 60 +/- 39% by superfusion with AM after the cessation of NG-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor. Pretreatment with L-NMMA (10 mumol/L) abolished the negative inotropic effect of AM, whereas switching from AM+L-NMMA to AM+L-arginine (1 mmol/L) restored it. Superfusion with 8-bromo-cGMP also showed a negative inotropic effect. AM significantly increased the intracellular content of cGMP, a second messenger of NO, but not that of cAMP. AM (10 nmol/L) blunted the effect of 1 mumol/L forskolin. CONCLUSIONS AM has a negative inotropic effect and decreased both [Ca2+]i and Ica, with these effects being at least party mediated via the L-arginine-NO pathway in adult rabbit ventricular myocytes.

Doppler echocardiographic-determined changes in left ventricular diastolic filling flow velocity during the lower body positive and negative pressure method

Changes in parameters of left ventricular (LV) diastolic filling flow obtained with Doppler echocardiography during the lower body positive and negative pressure method were analyzed in 15 patients (12 with coronary artery disease and 3 with dilated cardiomyopathy). Lower body pressure was altered at 5 steps (+20, +10, 0, -20 and -40 mm Hg vs atmospheric pressure). Pulmonary capillary wedge pressure measured with a balloon-tipped catheter was changed proportionally with lower body pressure during the procedures (p less than 0.01). Mean systemic arterial pressure was changed slightly during lower body positive pressure and negative pressure of -40 mm Hg. Heart rate was almost unchanged except at lower body pressure of -40 mm Hg. The peak velocity of LV early diastolic filling flow was changed with pulmonary capillary wedge pressure in an almost parallel fashion during the procedures (p less than 0.01). The peak velocity of LV late diastolic filling flow showed smaller changes than that of early diastolic filling flow. Changes in pulmonary capillary wedge pressure correlated positively with changes in the peak velocity of LV early diastolic filling flow (r = 0.759, p less than 0.01), but not with changes in the peak velocity of LV late diastolic filling flow (r = 0.039, not significant) during lower body negative pressure of -20 mm Hg. These data suggest that left atrial pressure is one of the important determinants of LV early diastolic filling flow in this acute clinical setting and that LV late diastolic filling flow is less sensitive to changes in left atrial pressure than LV early diastolic filling flow.

Ca2+-growth coupling in angiotensin II-induced hypertrophy in cultured rat cardiac cells

OBJECTIVES There remain some controversies about the effect of angiotensin II on intracellular Ca2+ concentration ([Ca2+]i) in cardiac myocytes. The aim of this study was to investigate different roles of intracellular Ca2+ in the responses to angiotensin II between cardiac myocytes and nonmyocytes. METHODS Primary cultures of neonatal rat cardiac myocytes and nonmyocytes were prepared. [Ca2+]i was measured with indo-1. Cellular growth was assayed by [3H]thymidine uptake, RNA content, [3H]phenylalanine incorporation and protein content. Induction of immediate-early gene was examined by Northern blot analysis. RESULTS In myocytes, angiotensin II decreased [Ca2+]i transients, induced c-fos mRNA, and accelerated hypertrophy. These effects were completely suppressed by AT1 receptor blockade or protein kinase C inhibition. After chelation of extracellular Ca2+, angiotensin II caused no change in [Ca2+]i or no induction of c-fos in myocytes. Phorbol 12-myristate 13-acetate also decreased [Ca2+]i transients, caused c-fos induction, and provoked hypertrophy in myocytes. In nonmyocytes, angiotensin II increased [Ca2+]i transiently, induced c-fos mRNA and hypertrophy. These effects of angiotensin II were not fully abolished by protein kinase C inhibition. Extracellular Ca2+ chelation did not completely inhibit the effects of angiotensin II on [Ca2+]i or c-fos induction in nonmyocytes. Phorbol 12-myristate 13-acetate did not affect [Ca2+]i or cellular growth in nonmyocytes but did cause c-fos induction. CONCLUSIONS These results suggest that angiotensin II induces cellular hypertrophy and immediate-early genes through the activation of protein kinase C in myocytes, although angiotensin II decreases [Ca2+]i transients via this signaling pathway. Induction by angiotensin II of hypertrophy and immediate-early genes in nonmyocytes may be in part mediated by a transient increase in [Ca2+]i which acts synergistically with protein kinase C activation.

Silent Double Aortic Arch Found in an Elderly Man

A 73-year-old male was hospitalized for cerebral bleeding in his thalamus and complained of chest pain during his hospitalization. During the heart attack, the ECG showed an ST-segment depression in leads II, III, and aVF. A thulium cardiac scintigram showed an inferior redistribution, indicating the presence of coronary heart disease. The patient had a history of hypertension and hypercholesterolemia, but no history of bronchial asthma or esophageal problems. Three months later, the patient was transferred to the cardiology department and a cardiac catheterization was scheduled. A plain chest roentgenogram showed a bilateral …

Acute hemodynamic effects of nilvadipine, a new calcium channel blocker, in patients with congestive heart failure.

The acute hemodynamic effects of nilvadipine, a newly synthesized calcium channel blocker, were studied in 12 patients with congestive heart failure. Hemodynamic measurements were made before and 15, 30, and 60 min after oral administration of 6 mg nilvadipine. Substantial reductions in systemic vascular resistance (–28.8 ± 6.3%, p < 0.01) and forearm vascular resistance ( −52.0 ± 6.2%, p < 0.01) after nilvadipine administration were associated with increases in cardiac index (31.1 ± 8.3%, p < 0.01) and forearm blood flow (105.2 ± 27.4%, p < 0.01). Mean arterial and pulmonary arterial pressures were decreased by 12.2 ± 3.0% (p < 0.01) and 14.7 ± 5.0% (p < 0.05), respectively, after nilvadipine administration; however, heart rate remained unchanged. Decreases in mean arterial pressure correlated with the baseline arterial pressure (y = 0.58x – 41.6, r = 0.75, p < 0.01). Pulmonary capillary wedge pressure decreased by 33.1 ± 9.1% (p < 0.01) after nilvadipine administration. However, right atrial pressure and the venous stiffness constant remained unchanged, and the venous pressure-volume curve was not shifted significantly. There-fore, the decrease in pulmonary capillary wedge pressure was attributed primarily to afterload reduction. Nilvadipine holds promise as a vasodilator for the therapy of congestive heart failure.

Combined factor VII and protein C deficiency found in a patient with peripheral pulmonary artery stenosis accompanied by progressive pulmonary hypertension and hemoptysis

A congenital deficiency of factor VII and protein C was found in a 21-year-old female suffering from recurrent and progressive attacks of dyspnea and hemoptysis over the last four years. She has been followed in our Department since the age of 17 under a diagnosis of peripheral pulmonary artery stenosis and pulmonary hypertension as confirmed by cardiac catheterization and angiography. Prolonged prothrombin time repeatedly examined during this time period prompted us to perform detailed coagulation studies. We found that factor VII and protein C were both half normal in activity as well as in antigen. Three other members of her immediate family were also found to be affected with this combined deficiency. Since the genes encoding factor VII and protein C are located in different chromosomes, the 13th and the second chromosomes, respectively, expression of the combined hereditary deficiency is a random and very rare association on the basis of frequencies of 1:50,000 for factor VII and 1:16,000 for protein C deficiencies.

Pulmonary Embolism Due to Popliteal Venous Aneurysm

A 33-year-old man was admitted to our hospital for shortness of breath on exertion. His symptoms started suddenly a week before admission when he was driving a car and worsened daily. He was amateur football player and had no history of hypertension, dyslipidemia, diabetes mellitus, smoking, or leg injury. On admission, an arterial pulse oxygen saturation monitor showed that his arterial blood oxygen saturation was 94% with room air. His blood pressure was 114/82 mm Hg and his pulse rate was 92/min with regular rhythm. His height was 162 cm and body weight was 62 kg. No other outstanding physical abnormalities were observed. Laboratory data showed slightly an elevated C-reactive protein level of 0.87 mg/dL with a normal white blood cell count of 6100 cells/mL. Arterial blood sampling revealed a normal CO2 level of 41 mm Hg and pH of 7.42 with low oxygen tension (52 mm Hg). An ECG showed a small S wave in lead I and a small Q wave and inverted T wave in …

Diastolic Abnormalities in Low-Flow and Pacing Tachycardia-Induced Ischemia in Isolated Rat Hearts—Modification by Calcium Antagonists

An increase in left ventricular diastolic pressure relative to volume during spontaneous attacks of angina pectoris [1] and angina attacks provoked by exercise [2] or pacing tachycardia [3–5] has been reported by many investigators in patients with coronary artery disease. This decreased left ventricular diastolic distensibility is usually accompanied by a decrease in the rate of left ventricular relaxation. Similar changes in diastolic properties have been observed in open- chest dogs with severe coronary stenoses and super-imposed pacing tachycardia [6,7]. Several possible mechanisms producing such changes have been proposed [8], and one of the most likely of these is an alteration in intrinsic myocardial properties due to ischemia-induced calcium overload and/or decreased availability of ATP. However, investigations using open-chest dogs could not completely exclude other mechanisms, such as extrinsic diastolic compression by the right ventricle, or dyssynchrony between the ischemic and normal myocardium.

Distribution of cardiac troponin I in the Japanese general population and factors influencing its concentrations

The 99th percentile of cardiac troponin I level in the general population is accepted as the cut‐off for the diagnosis of acute myocardial infarction (AMI). However, it is not clear whether the cut‐offs derived in racially and geographically different populations are applicable in Japan.