Twenty patients in whom intracardiac thrombi were detected by indium-111 platelet scintigraphy (the first platelet scintigraphy) were prospectively studied to examine the effect of warfarin therapy under full dose on the intracardiac thrombogenecity. Eleven patients (group I) who received 2-6 mg/day of warfarin and 9 patients (group II) who did not receive warfarin had the second platelet scintigraphies 14-71 days after the first platelet scintigraphies. In group I, 10 platelet scintigraphies became negative and one remained positive for intracardiac thrombi after administration of warfarin, while in group II 8 platelet scintigraphies remained positive and only one changed to negative. The incidence of negative image at the second platelet scintigraphy was significantly lower in group II than that in group I. In group I, the degree of accumulation of platelets onto the surface of the thrombus (%IE), showed significant reduction (0.69 ± 0.48 to 0.11 ± 0.21) after warfarin therapy, while in group II %IE at the second scintigraphy (1.07 1.03) were not significantly different from those at the first scintigraphy (1.13 0.79). These results indicated that warfarin therapy under full dose inhibited the deposition of platelets on the intracardiac thrombi and thrombogenecity in the patients with intracardiac thrombi which were detected by indium-111 platelet scintigraphy.

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The internal mammary artery (IMA) grafting for myocardial revascularization was performed in 100 Japanese patients during a three-year period. These were 86 males and 14 females with the mean age of 58 ± 9 (37∼ 75 years-old). Unilateral IMA was used in 88 patients and bilateral IMA was used in 12 patients. Sequential IMA grafting was performed in 5 patients. The sites of IMA grafting were 91 left anterior descending arteries (LAD), 16 diagonal branches, 8 circumflex arteries and 2 right coronary arteries. Saphenous vein or gastroepiploic artery was concomitantly used to bypass the other coronary arteries in 90 patients. The number of distal anastomosis ranged from 1 to 6 and the mean was 2.8 per patient. Two patients died within 30 days and one patient died at 3 months after surgery. Perioperative myocardial infarction was noted in 3 patients. Symptomatic relief was obtained in 94 (97%) of 97 survivors. The patency of the IMA graft at mean 2.2 postoperative months was 97% (58/60) in LAD, 100% (14/14) in the diagonal branch, 100% (5/5) in the circumflex artery, 100% (1/1) in the right coronary artery, and 98% (78/80) in over-all grafted coronary arteries. Pre- and postoperative exercise thallium scintigraphy in 13 patients, who received the IMA graft to severely stenosed LAD, showed significant improvement of the washout ratio (from 33.1 16.9% to 47.4 14.8%) which was nearly equivalent to that of the saphenous vein graft to LAD (from 24.8 6.2% to 48.1 6.6%, n = 7). Considering these favorable results, we conclude that the IMA grafting can be performed safely and effectively in Japanese ischemic heart patients, and its aggressive utilization is warranted.

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To study myocardial contractility in hypertensive hearts with normal wall motion, we examined left ventricular end-systolic wall stress-dimension relationships (ESWDR) during a baseline period (CS: control stage) and in the eighth week after induction of systemic hypertension by Page's method (HS: hypertensive stage) in unanesthetized dogs. The mean aortic blood pressure increased from 94 ± 11 to 142 ± 26 mmHg (p<0.01). The end-diastolic left ventricular posterior wall thickness increased significantly during the HS (9.4 ± 1.3 vs 7.3 ± 1.3 mm; HS vs CS), and its dimension was significantly (p<0.05) smaller than it was during the CS (37.0 ± 4.2 vs 39.9 ± 4.6 mm; HS vs CS). There were no significant differences between the 2 stages in left ventricular fractional shortening (31.9 ±5.0 vs 32.6 ± 2.8; HS vs CS), in end-systolic meridional left ventricular wall stress (75.3 ± 10.8 vs 68.3 ± 15.6 10³ dynes/cm²; HS vs CS), or in he ESWDR slopes (98.6 ± 17.7 vs 94.0 ±19.7; HS vs CS). The ESWDR dimension intercepts significantly decreased from 2.0 0.3 to 1.8 0.3 cm during the HS; that is, the relationship shifted to the left with no significant change in the slope. At autopsy, the ratio of left with no significant change in the slope. At autopsy, the ratio of left ventricular weight to body weight of the hypertensive dogs was significantly (p<0.01) grater than that of sham-operated control dogs (6.0 0.9 vs 4.3 0.5 g/kg). These findings indicated that myocardial contractility was normal in concentric hypertrophied hearts induced by systemic hypertension, although the cause of the decreased ESWDR dimension intercept remains unknown.

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The characteristics of the senescence accelerated mouse (SAM), a new murine model of accelerated senescence, are early senescence and a high incidence of senile amyloidosis. This study was performed to clarify histopathologically the details of senile cardiac amyloidosis in SAM, and the incidence of amyloidosis in the heart of SAM (-P) was 46.0% (1+: 22.0; 2+: 16.0; 3+: 8.0%). Amyloid infiltrated the ventricular walls, interventricular septum, atrial walls and interatrial septum. Amyloid deposition was prominent around the myocardial fibers and in the vascular walls. Amyloid involvement was greater in the veins than in the arteries. Senile cardiac amyloidosis of SAM was mild or moderate and not severe, in general. The age dependency of amyloidosis incidence of the heart was confirmed. The heart/body weight ratio tended to parallel the grade of cardiac amyloidosis. SAM often had complication such as abscess, lymphoma, skin ulcer, etc. The incidence of amyloidosis was higher in SAM with these complications than in SAM without them. The complications seemed to promote the progress of cardiac amyloidosis and to superimpose secondary amyloidosis. In SAM senile cardiac amyloidosis is less frequent than renal amyloidosis (64.4%) or hepatic amyloidosis (63.3%).

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A conscious rat system has been developed to investigate the ability of alpha- and beta-adrenoceptor blocking agents to modify the severity of ischemia- and reperfusion-induced arrhythmias. Ischemia-induced arrhythmias. Ischemia-induced arrhythmias were studied during a 30 min period of occlusion animals (n-24) exhibited ventricular tachycardia and 63% ventricular fibrillation. Beta-adrenoceptor blockade with atenolol (1 mg/kg body weight) significantly reduced the incidence of ventricular fibrillation to 17% (p < 0.05). In contrast, alpha-adrenoceptor blockade with prazosin (0.01, 0.1 or 1 mg/kg body weight) failed to reduce the incidence of arrhythmias and actually increased mortality. This higher mortality with prazosin was associated with bradyarrhythmias. Administration of atenolol (1 mg/kg body weight) also reduced the incidence of reperfusion-induced ventricular fibrillation after a 5 min period of ischemia from 100% to 58% (p < 0.05). Prazosin could not be tested due to the high mortality during coronary occlusion. Autopsy studies of hearts from the control, atenolol and prazosin groups indicated that all groups had similar occluded zone volumes. In conclusion, in conscious rats beta-blockade with atenolol reduced the incidence of both ischemia- and reperfusion-induced arrhythmias, whereas alpha-blockade with prazosin at the 3 doses studied failed to exert a protective effect and actually increased mortality.

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We measured mean circulatory pressure (MCP) in anesthetized, Open-chest dogs before and after intravenous administration of Ca⁺⁺-antagonists to estimate the effects on systemic capacitance vessels and on venous return (VR) curves both with and without continuous intravenous infusion of norepinephrine (NE). Diltiazem (300μg/kg) decreased total peripheral resistance (TPR) and MCP significantly. Nifedipine (5μg/kg), nicardipine (30μg/kg) and verapamil (200μg/kg) decreased TPR significantly without any change in MCP in the absence of NE, but with the exception of verapamil, they decreased MCP in the presence of NE. This indicated that diltiazem relaxed the systemic capacitance vessels, and nifedipine and nicardipine significantly decreased the tone of the systemic capacitance vessels that had been previously elevated by NE, but this action was very slight with verapamil. These Ca⁺⁺-antagonists rotated VR curves clockwise, decreased resistance to VR (RVR) and increased VR both in the presence and absence of NE. It was suggested that the decrease in the RVR would be at least partially responsible for the increase in the VR.

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A 42-year-old woman presented with orthostatic hypertension. Increased plasma renin activity was noted and blood pressure rose gradually with standing. Selective renal arteriography indicated narrowing of the distal portion of the right renal artery and poststenotic dilatation and signs of arterial stenosis due to fibromuscular dysplasia. Greater arterial narrowing resulted from tortion due to nephroptosis brought about by excessive renin secretion. Thus, both renal arterial stenosis and nephroptosis were considered responsible for the present orthostatic hypertension. Percutaneous transluminal renal angioplasty was found very effective for normalizing standing blood pressure and renal blood flow.

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A female patient with severe aortic stenosis had suffered from repeated syncope. Transaortic valve pressure gradient at cardiac catheterization was 117 mmHg. Continuous electrocardiographic monitoring was done after admission. During syncope, the electrocardiogram showed bradycardia with the lowest heart rate 44 beats per minute, while arterial pulses were not palpable. Rather than arrhythmia, other mechanisms, such as an inhibitory reflex from left ventricular receptors, should be postulated as the cause of syncope in patients with severe aortic stenosis.

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To define transmembrane and intracellular mechanisms of production and release of atrial natriuretic polypeptide (ANP) in the absence of mechanical atrial stretch, we studied the direct effects of physiological stimuli on isolated adult rat atrial myocytes maintained under tissue culture. Although stimulation of beta-adrenergic receptors on the surface of atrial myocytes by isoproterenol did not affect ANP release, adrenergic alpha-1 receptor stimulation by methoxamine enhanced ANP release with reciprocal intracellular ANP reduction. When muscarinic receptors were stimulated by acetylcholine, ANP release was accelerated and intracellular ANP reduced. The activation of the phosphatidylinositol system, which is a common pathway for muscarinic and alpha-1 adrenergic receptor stimulation, was thus considered to regulate ANP release, but not ANP production.

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We have examined physiological factors in atrial natriuretic polypeptide (ANP) release and whether or not the cardiac nerves control release of ANP. Two possible factors were tested, an increase in plasma sodium level (PNa) and an increase in atrial pressure. Injection of 1.0 or 2.0 mEq/kg of sodium ions elevated PNa by 5.3±0.3 or 7.3±0.4 mEq/L, respectively, but plasma ANP level (PANP) did not change. Infusion of 18 ml/kg of 3% Dextran-40 over 5 min increased mean left atrial pressure (MLAP) by 7.6±0.9 mmHg. PANP increased from 206±17 pg/ml to 260±25 pg/ml, which was not significant. PANP, corrected for hemodilution, significantly increased to 348±34 pg/ml. These results suggest that PNa increase does not promote ANP release, but that an atrial pressure increase does. This transient volume load did not induce full response of the ANP releasing system. A prolonged volume load for 45 min increased corrected PANP to 435±73 pg/ml. A close linear correlation was found between the increases in MLAP and PANP. These facts indicate that prolonged volume expansion is necessary to induce full response of the ANP releasing system. Complete cardiac denervation did not affect the tonic level of plasma ANP, volume expansion-induced increase in PANP, or the sensitivity of the ANP releasing system. Thus we conclude that the cardiac nerves do not control ANP release caused by volume expansion.

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The mechanism by which atrial natriuretic peptide (ANP) acts on cells remains obscure. Using cultured vascular smooth muscle cells (VSMC) from rat aorta, we studied the structure-activity relationship of α-human(h) ANP and attempted to clarify its cellular mechanism of action .Binding studies using a variety of synthetic α-hANP^7-28 analogs with deletion and substitution of amino-acid residue(s) within the ring structure and deamino-dicarba analogs with replacement of the disulfide bond with an ethylene linkage, suggested that the original cyclic structure is a minimum requirement for biological activity and the disulfide bond is not essential for receptor binding. The present study using VSMC loaded with a fluorescent Ca²⁺ indicator quin-2 revealed that α-rat(r) ANP has no effect on increases in cytosolic free Ca²⁺ concentration stimulated by angiotensin (A) II or arginine-vasopression (AVP). While both vasoconstrictive hormones rapidly stimulated phosphatidylinositol (PI) response in VSMC, pretreatment with rANP did not affect AII-or AVP-induced PI response. However, AII-stimulated phosphorylation level of 20 K-dalton (Da) myosin light chain (MLC), a regulatory contractile protein of VSMC, was attenuated by pretreatment with rANP. These data suggest that ANP may not act at site of either agonist-induced membrane PI hydrolysis or intracellular Ca²-signal system, but may partly be involved in phosphorylation/dephosphorylation of 20 K-Da MLC in cultured rat VSMC.

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The pharmacological activities of synthetic atrial natriuretic factor (ANF) on cat coronary artery were studied in vitro. In the preparation of isolated cat coronary artery perfused at a constant flow, ANF (3-300 nM) decreased perfusion pressure in a concentration dependent manner, indicating coronary vasodilating activity .ANF also relaxed feline coronary strips when contracted by U-46, 619, CTA₂, angiotensin II, serotonin, leukotriene C₄ and D₄. This relaxant effect was independent in the presence of endothelial cells and occurred in the presence of guanylate cyclase inhibitor, methylene blue. ANF had no direct effect on electrically driven isolated cat papillary muscles signifying a lack of direct inotropic activity. It can be concluded that ANF may potentiate coronary vasodilation and therefore contribute to coronary regulation, without directly altering myocardial performance.

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VARIOUS aspects of atrial natriuretic peptides (ANP) have been studied since its reports by de Bold. Although ANP is known to play an important role in the volume regulation of body fluid by displaying natriuresis probably due to vasodilating mechanism, its significance in renal failure has not been clarified. The present study was carried out in order to clarify the renal physiological and systemic hemodynamic effect of exogenous ANP in animal models with deteriorated renal function. In addition, the site of action of ANP was also evaluated in the kidney.

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To assess the pathophysiological role of atrial natriuretic factors in mineralocorticoid hypertension, we studied the effects of chronic infusion of synthetic atrial natriuretic factor on blood pressure and sodium-water excretion in rats with aldosterone salt-induced hypertension. Administration of synthetic atrial natriuretic factor (150 μg/kg/day) to rats made hypertensive by 7-day infusion of aldosterone (100 μg/kg/day) and sodium loading with 1% NaCl as drinking water returned the blood pressure to control levels, and the anti-hypertensive effect was not associated with any changes in urine volume and urinary sodium excretion. These results indicate that atrial natriuretic factors may be involved in the regulation of blood pressure in mineralocorticoid hypertension, independent of the renal effects of these substances.

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To explore factors that modulate the magnitude of vasorelaxation and natriuretic/diuretic responses to exogenous ANP, clearance studies were performed in unilateral hydronephrotic rats with renal vasocontraction complications. An increase in renal plasma flow associated with a decrease in calculated renal vascular resistance in response to ANP (2 μg·min^-1·kg^-1, i.v.) was obtained only in the hydronephrotic kidney. In contrast, the control kidney of the unilateral hydronephrotic rat had a decrease in glomerular filtration rate and an abolished natriuretic response following ANP administration. A prior renal denervation in the control kidney restored the natriuretic effect of ANP and obolished the lowering of glomerular filtration rate. These data suggest that the vasodilatory effect of ANP may depend on the vascular tone itself, and that renal responses to ANP are significantly modified by renal nerve activity.

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To clarify the production mechanism of atrial natriuretic peptide (ANP) in right (RA) and left atria (LA) in mitral valve disease, histopathological and immunohistocytochemical analyses were performed and ANP levels were investigated by radioimmunoassay (RIA) in 28 patients. Atrial tissues were obtained during mitral valve replacement. ANP-like immunoreactivity of the myocytes applied by the avidin-biotin peroxidase complex method was observed around the nuclei of the atrial myocytes. Electronmicroscopically, immunoreactivity was observed in atrial specific granules. Light-microscopically determined intensity of the immunoreactivity was classified into 4 grades and the intensity in 100 myocytes was expressed by adding the scores of each myocyte. Mean right atrial pressure was positively correlated with the activity score in RA (r=0.80). Pulmonary capillary wedge pressure was not correlated with the score in LA. The score in RA was significantly higher than that in LA. The ANP level in RA investigated by RIA was also higher than that in LA. Histopathological findings such as myocyte hypertrophy, degeneration and interstitial fibrosis were more severe in LA than in RA. In conclusion, longstanding atrial overloading, especially in LA, caused severe pathological damage, resulting in a smaller production of ANP. Much more ANP may be produced from RA in long-standing mitral valve disease.

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To study the role of α-human atrial natriuretic polypeptide (α-hANP) in body fluid regulation, we measured the plasma concentration of α-hANP and renal function in 9 patients with congestive heart failure (CHF), 10 with chronic renal failure (CRF) and 8 normotensives (NT) before and during α-hANP infusion at 0.025 μg/kg·min. The plasma concentration of α-hANP was significantly higher in the CHFs and CRFs than in the NTs (319, 168 and 72 pg/ml, respectively). Alpha-hANP infusion decreased mean blood pressure in a similar manner in the 3 groups (-5%, p<0.01 each). Increases in urinary sodium excretion and glomerular filtration rate during α-hANP infusion, however, were greater in the CHFs and CRFs than in the NTs. Furthermore, the higher the preinfusion level of renal vascular resistance (RVR), the greater was the reduction in RVR by α-hANP (r=-0.80, p<0.001). The metabolic clearance rate (MCR) of α-hANP was significantly smaller in the CHFs and CRFs than in the NTs (38, 35 and 67 ml/min·kg, respectively). These results suggest that the renal vasodilatory actions of -hANP seem to be enhanced in patients with increased RVR and that the elevation of the basal plasma concentration of -hANP in CHFs and CRFs may be in part due to the low MCR.

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To investigate the significance of atrial natriuretic peptides (ANP) in essential hypertension, plasma ANP concentrations in 43 essential hypertensives, 16 borderline hypertensives and 17 normotensive controls were measured. Furthermore, effects of high-sodium and low-sodium intakes on plasma ANP concentration were examined in "salt-sensitive" [SS] and "nonsalt-sensitive" [NSS] patients with essential hypertension. Plasma ANP concentration was significantly higher in hypertensives than in borderline hypertensives and in normotensive controls. No significant difference in plasma ANP concentration was observed between borderline hypertensives and normotensive controls. Plasma ANP concentration increased with the high-sodium diet in both the SS and NSS patients, but the mean increment was significantly greater in the SS than the NSS patients. Urinary excretion of sodium was lower in the SS patients taking the high-sodium diet than the coresponding value in the NSS patients. These findings suggest that an increased level of circulating ANP in hypertensive patients represents a compensatory mechanism to offset further elevation of blood pressure and sodium retention.

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