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In hypertension, endothelium-dependent relaxation is attenuated and this attenuation contributes to the increased peripheral resistance. However, the role of endothelium-derived hyperpolarizing factor (EDHF) in the arteries of hypertensive rats remains unclear. Therefore, the aim of this study was to evaluate the role of EDHF in the femoral resistance arteries of hypertensive rats. The femoral resistance arteries were isolated from 5-, 15- and 25-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). Changes in internal diameter were examined with videomicroscopy. EDHF-mediated dilatation was determined by differences between the degree of acetylcholine (ACh)-induced dilatation in the presence of NG-monomethy-L-arginine (L-NMMA) plus a prostaglandin I2 inhibitor (indomethacin) and the degree of such dilatation in the presence of L-NMMA, indomethacin and KCl. Charybdotoxin (CTx) and apamin (a Ca2+-activated K+ channel [KCa] inhibitor)-sensitive EDHF dilatation was also compared between in 5-, 15- and 25-week-old SHR and WKY. ACh-induced vasodilatation was not different between 5-week-old SHR and WKY. There was no difference between NO- and EDHF-mediated vasodilatation in 5-week-old rats. ACh-induced vasodilatation was weaker in 15-week-old SHR than in WKY. NO-mediated vasodilatation did not differ between the two groups. EDHF-mediated dilatation was attenuated in SHR but not in WKY. ACh-induced dilatation was weaker in 25-week-old SHR than in WKY. NO- and EDHF-mediated vasodilatation were attenuated in SHR but not WKY. EDHF-mediated vasodilatation was attenuated before the loss of NO-mediated vasodilatation in the femoral resistance arteries of SHR. The attenuation of this vasodilatation was mediated by the CTx plus apamin-sensitive EDHF.

A 22-year-old man was hospitalized after 3 months of persistent fever and malaise. He had undergone abdominal surgery 24 months before admission. Echocardiography demonstrated two mobile pedunculated masses in the right ventricle. Multiple blood cultures were positive for Candida parapsilosis. After 4 weeks of miconazole treatment, the two masses were excised via a right atriotomy incision and the transtricuspid value approach. Histological examination revealed that they were fungal vegetation. Antifungal agents were continued for 1 year after surgery. The patient has remained well with no further symptoms for 3 years. This case suggests the necessity for careful evaluation of past history to avoid diagnostic delay in fungal endocarditis.

Heart and aorta possess biologic clocks, but their involvement in genetic hypertension has been unknown. Plasminogen activator inhibitor-1 (PAI-1) expression is directly regulated by clock genes, while angiotensin II modulates both PAI-1 and clock gene expression. We therefore examined circadian expression of PAI-1 and clock genes, and effects of angiotensin type 1 (AT1) receptor antagonism, in heart and aorta of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats.We examined cardiac and aortic mRNA expression for PAI-1 and clock genes (Per2, Bmal1, Clock, and Dbp) every 4 h throughout the day by quantitative reverse transcription-polymerase chain reaction, and intervention with the AT1 receptor antagonist candesartan and equihypotensive hydralazine.Cardiac PAI-1 expression was high in the dark, while aortic PAI-1 expression was high in the light. Both cardiac and aortic PAI-1 expression were greater in SHR than in WKY rats. Candesartan treatment decreased cardiac PAI-1 expression only in the dark in WKY rats but throughout the day in SHR. Candesartan but not hydralazine strongly attenuated circadian fluctuation of aortic PAI-1 mRNA in SHR and WKY rats. Clock genes oscillated synchronously in heart and aorta of SHR and WKY rats. Clock gene expression was increased in heart but not aorta of SHR. Candesartan did not affect clock gene expression.Enhanced expression of clock genes may increase PAI-1 expression in concert with activated renin-angiotensin system in SHR heart. Rather than clock genes, the renin-angiotensin system induces daily fluctuation and increased expression of aortic PAI-1 mRNA in SHR.

Administration of short-acting antihypertensive agents to patients with ischemic heart disease results in increased sympathetic nervous activity and is associated with worsened outcomes. Cilnidipine is an agent which blocks not only L-type calcium channels at the smooth muscle in the artery, but also N-type calcium channels at the presynaptic terminal. The goal of the present study was to determine the effect of cilnidipine on sympathetic nervous activity as on agent which blocks both L-type and N-type calcium channels at the presynaptic terminal, on sympathetic nervous activity in an experimental rat model using iodine-123 metaiodobenzylguanidine (MIBG) myocardial imaging.Fourteen-week-old Wistar-Kyoto rats were divided into 3 separate groups: CTR group (control: distilled water administered), Nif group (nifedipine administered), or Cil group (cilnidipine administered). Agents were administered via a stomach tube, followed by injection of MIBG via the femoral vein. Systolic blood pressure (SBP) and heart rate (HR) were measured by tail-cuff plethysmography just prior to administration of antihypertensive drugs and 150 minutes later. Initial imaging (Ce) and delayed imaging (Cd) were defined as the sum of density counts in the region of interest created by adjusting to myocardial edge, and were corrected for both physical decay and weight. The myocardial washout rate (WR) was defined as the percent change in the count density from the initial to delayed images.Significant decreases in SBP were seen in the Nif group (from 132 +/- 3 mmHg to 85 +/- 5 mmHg, p0.0001) and the Cil group (from 128 +/- 4 mmHg to 92 +/- 7 mmHg, p = 0.0008), whereas no significant change in SBP was noted in the CTR group (from 123 +/- 5 mmHg to 127 +/- 3 mmHg). HR significantly increased in the Nif group (from 290 +/- 12/min to 378 +/- 14/min, p0.0001) but not in the CTR (from 278 +/- 3/min to 300 +/- 6/min) or Cil (from 291 +/- 6/min to 303 +/- 5/min) groups. WR was significantly greater in the Nif group (64.7 +/- 0.5%) when compared to the CTR (56.4 +/- 1.2%, p = 0.0031) or the Cil (55.4 +/- 2.2%, p = 0.0016) groups.In contrast to nifedipine, administration of cilnidipine did not result in increased myocardial sympathetic nervous activation.

Triglyceride-rich lipoproteins have been suggested to promote atherosclerosis. Plasminogen activator inhibitor type 1 (PAI-1) plays an important role in the events of cardiovascular pathophysiology. The renin-angiotensin system influences various vascular functions, including PAI-1 production. We examined whether or not chylomicron remnants increased PAI-1 mRNA and protein production in endothelial cells and whether or not an inhibition of the renin-angiotensin system interfered with this effect. Chylomicron remnants were isolated from functionally hepatectomized rats injected with chylomicrons. Human umbilical vein endothelial cell cultures (HUVECs) were incubated with chylomicron remnants with or without an angiotensin-converting enzyme inhibitor (temocaprilat), an angiotensin II receptor type 1 antagonist (RNH-6270), or an angiotensin II receptor type 2 antagonist (PD123319). Chylomicron remnants increased PAI-1 secretion in HUVECs (0.5 microg/ml; 128.3 +/- 6.1%, the mean +/- SEM) as well as angiotensin II (10 nmol/l; 130.7 +/- 9.5%) in 18 h, as compared with the controls, as well as stimulated PAI-1 mRNA expression to a maximum level at 4 h. Temocaprilat and RNH-6270, but not PD123319, attenuated all of these effects. Chylomicron remnants enhanced nuclear extract binding to a very low-density lipoprotein response element in the PAI-1 promoter region and activated nuclear factor-kappaB. Extracellular signal-regulated kinase (ERK 1/2) was phosphorylated in response to chylomicron remnants. These effects were inhibited by temocaprilat or RNH-6270. In conclusion, chylomicron remnants increased protein secretion and mRNA expression of PAI-1 in HUVECs. Inhibition of the renin-angiotensin system reduced this stimulation.

In recent years, it has been suggested that many factors are involved in the development of hypertension accompanying insulin resistance. Because changes in vascular reactivity could be one of these factors, we here investigated chronological changes of α-adrenoceptor (AR)-mediated peripheral arteriolar vasoconstriction in a rat model of type II diabetes. Otsuka-Long-Evans-Tokushima fatty (OLETF) rats that naturally develop insulin resistance at the age of 16 weeks and type II diabetes at the age of 30 weeks (DM group) and control rats (N group) were used. Arterioles with a diameter of approximately 100μm were removed from the cremaster muscle of 8-, 16- and 40-week-old rats and their diameters were measured in a tissue bath. The concentration-response curve (CRC) was determined for phenylephrine and UK14, 304 both with and without NG-monomethyl-L-arginine (LNMMA). Although there were no significant differences in the CRC for phenylephrine between the 8-week-old DM group and N group, a leftward shift was seen for the 16- and 40-week-old DM groups. There were no significant differences in the CRC for UK14, 304 between the two groups at any age, but in the presence of LNMMA, a leftward shift was seen in the 8- and 16-week-old but not in the 40-week-old DM groups. One possible explanation for these results is that impaired endothelium-dependent dilatation may have offset the reduction in arteriolar smooth muscle contraction. In conclusion, in the OLETF rats, the sensitivity of α1-AR-mediated arteriolar vasoconstriction increased after the onset of insulin resistance. The sensitivity of α2-AR-mediated arteriolar smooth muscle contraction and endothelium-dependent vascular relaxation were both presumed to be impaired after the onset of type II diabetes. (Hypertens Res 2003; 26: 559-567)

lodine-123 metaiodobenzylguanidine (MIBG) uptake was reported to be reduced compared to Tl-201 (Tl) in acute myocardial infarction (AMI). Within such an area, degrees of both sympathetic neural function and ischemic myocardial cell damage are considered to be greatly dispersed. These kinds of damage were reported to effect reporalization time in myocardial cells, and we evaluated our hypothesis that extension of the discordant MIBG uptake area correlates with recovery time (RT) dispersion and relate ventricular arrhythmias in AMI. MIBG and Tl images were obtained in AMI patients. Regional Tl or MIBG uptake was estimated in 9 segments of SPECT by using four-point scoring. The total score was the sum of scores in 9 SPECT segments. ATI-MIBG was calculated by subtracting the total MIBG score from the total Tl score. Corrected RT (RTc) was measured as a signal-averaged ECG. RTc dispersion was defined as the difference between maximal and minimal RTc. The patients were assigned to two groups (group A;or = Lown 4a, group B;or = Lown 4b) according to the results of 24-hour Holter monitoring. A positive correlation between RTc dispersion and ATI-MIBG was found. ATI-MIBG and RTc dispersion in group B were greater than those in group A. These results suggested that ATI-MIBG could be used to predict the development of malignant ventricular arrhythmias.

Background Activation of Na + /H + exchanger (NHE) is known to be related to elevated blood pressure in hyperinsulinemia. To test whether there is the change in NHE activity in insulin resistance, we measured NHE activity of platelets in fructose-induced hyperinsulinemia in Wistar-Kyoto rats (WKY), in borderline hypertensive rats (BHR), and in spontaneously hypertensive rats (SHR). Materials and methods All rats were fed a 60% fructose diet for 4 weeks to induce hyperinsulinemia and hypertriglyceridemia. Intracellular pH (pHi) was measured with a pH-sensitive fluorescent dye 2'7'-bis (2-carboxyethyl)-5-carboxyfluorescein acetoxymethyl ester. NHE activity was evaluated by the recovery of pHi following addition of sodium propionate (Vmax). Measurement of intracellular calcium ([Ca 2+ ]i) was performed using fura2/acetoxymethylester. Results Systolic blood pressure in fructose diet BHR elevated significantly greater than that in control diet BHR with the increase of both [Ca 2+ ]i and Vmax. In WKY, there was no significant increase in systolic blood pressure and [Ca 2+ ]i except Vmax in a fructose diet. Vmax in control diet SHR was greater than in control diet WKY and BHR, and we found no additional increase in Vmax with a fructose diet in SHR. In BHR, a high salt diet increased systolic blood pressure and Vmax to a similar degree as a fructose diet or a high salt combined with a fructose diet. Plasma insulin concentration correlated positively with Vmax in WKY and BHR, but not SHR. Conclusion A fructose diet induces hyperinsulinemia and elevates blood pressure in BHR. Hyperinsulinemia appears to activate NHE in a different manner in SHR, and might be associated with an elevation in blood pressure in BHR.

It is likely that a close association exists between findings obtained by two methods: dobutamine stress echocardiography and 123I-MIBG scintigraphy. Both of these methods are associated with beta-adrenergic receptor mechanisms. This study was conducted to demonstrate the relation between myocardial response to dobutamine stress and sympathetic nerve release of norepinephrine in the failing heart. In 12 patients with heart failure due to idiopathic dilated cardiomyopathy, the myocardial effects of dobutamine stress were evaluated by low-dose dobutamine stress echocardiography: and sympathetic nerve function was evaluated by scintigraphic imaging with iodine-123 [123I] meta-iodobenzylguanidine (MIBG), an analogue of norepinephrine. Echocardiography provided quantitative assessment of wall motion and left ventricular dilation; radiotracer studies with 123I-MIBG provided quantitative assessment of the heart-to-mediastinum (H/M) uptake ratio and washout rate. Results showed that H/M correlated with baseline wall motion (r = 0.682, p = 0.0146), wall motion after dobutamine stress (r = 0.758, p = 0.0043), the change in wall motion (r = 0.667, p = 0.0178), and with left ventricular diastolic diameter (r = 0.837, p = 0.0007). In addition, the 123I-MIBG washout rate correlated with baseline wall motion (r = 0.608, p = 0.0360), wall motion after dobutamine stress (r = 0.703, p = 0.0107), and with the change in wall motion (r = 0.664, p = 0.0185). Wall motion, especially in the myocardial response to dobutamine stress, is related to sympathetic nerve activity in heart failure.

Background: Brain (B-type) natriuretic peptide (BNP) is known to be secreted predominantly from the myocardium. Brain natriuretic peptide plasma concentrations have been shown to be markedly increased in patients with acute myocardial infarction; however, plasma BNP response during episodes of myocardial ischemia has not been established. Hypothesis: This study was designed to examine plasma BNP in patients with transient myocardial ischemia induced by inflation of a percutaneous transluminal coronary angioplasty (PTCA) balloon. Methods: Thirty consecutive patients (26 men and 4 women; mean age 61 years) who underwent PTCA, and another 49 patients (39 men and 10 women; mean age 63 years) who underwent diagnostic coronary angiography were enrolled in this study. Serum BNP concentrations were assayed in all patients. Results: Plasma BNP was increased significantly with a peak concentration of 66.1 ± 65.2 pg/ml 24 h after PTCA. Coronary angiography did not cause plasma BNP increase (immediately before 30.4 ± 29.0 pg/ml, 24 h after 33.7 ± 30.6 pg/ml). No significant differences were present in hemodynamic parameters measured immediately before and 24 h after PTCA. Conclusion: Plasma BNP is increased by transient myocardial ischemia induced by PTCA.

This article reviews simple, noninvasive ways to assess physical activity in patients with chronic heart failure. Six- or 9-minute walk tests appear to be useful not only for selecting patients with relatively advanced heart failure but also as prognostic screening tests. The Master-Borg test (Master's two-step testing and 10-point Borg scale) is useful for assessing symptoms during exercise. Weekly pedometer counts show that the level of activity in patients with heart failure is dramatically less than in healthy controls. Physical activity can be determined directly by an ambulatory calorie counter that measures step scores and energy expenditure using specific accelerometers. Careful clinical interviewing regarding symptoms, together with submaximal exercise testing and use of motion sensors, are recommended as useful, simple, noninvasive alternatives for assessing physical activity in this patient population. (c)2000 by CHF, Inc.

It has been reported that the increased function of the voltage-dependent calcium channels (VDCC) in the artery is involved in the increase of peripheral resistance in hypertension, and that the sarcoplasmic reticulum (SR) in the artery plays an important role in preventing the development of hypertension via a buffering effect. However, no reports have described the role of VDCC and SR in resistance arterioles in the development or maintenance of hypertension. We investigated the function of VDCC and of SR in the cremaster arterioles of spontaneous hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). The changes in diameter and the intracellular calcium ion concentration ([Ca2+]i) in the microdissected arterioles, using fluorescent dyes, were measured with videomicroscopy. The KCl concentration-response curves were analyzed in 4- to 5- and 7- to 8-week-old SHR and WKY. The changes in the vascular diameter and [Ca2+]i in response to ryanodine, an alpha-1 adrenoceptor, and angiotensin-II stimulation were compared between the 7- to 8-week-old SHR and WKY. We found an increase in the Ca2+ influx by VDCC in the early hypertensive stage, but not in prehypertensive SHR. However, after the onset of hypertension, there were no significant differences from WKY in the SR function mediated by Ca2+-induced Ca2+ release or inositol 1,4,5-trisphosphate-induced Ca2+ release. In conclusion, an increased influx of Ca2+ in the cell membrane, without a buffering effect of SR, was associated with progression of hypertension in the cremaster arterioles of SHR.

The role of the stimulatory guanine nucleotide-binding protein (Gs) in heart failure is unclear. We therefore determined the amount of protein and mRNA of Gs in the failing myocardium using two animal models: the BIO 53.58 hamster, a model of genetic cardiomyopathy, and adriamycin-treated rats (ADR rats), a model of secondary cardiomyopathy. The maximal number of myocardial β-adrenoceptors in the BIO 53.58 hamsters as well as in the ADR rats was significantly lower than that in the respective controls, indicating that the β-adrenoceptors were down-regulated in heart failure. Analysis by Western blot and Northern blot revealed a significant decrease in Gs protein and mRNA in the BIO 53.58 hamsters relative to the control. There were no differences in the level of Gs protein or mRNA in the ADR rats vs the controls. The functional activity of Gs was investigated by measuring adenylate cyclase activity. The activity of adenylate cyclase in response to stimulation by sodium fluoride or forskolin was decreased in the BIO 53.58 hamsters relative to control animals, whereas no differences were observed in the ADR rats vs the controls. Thus, alterations in Gs in the failing heart appear to differ according to its cause.

In this study, we evaluated the relationship between the endothelium-dependent vasodilation and salt sensitivity in patients with essential hypertension. Fifteen untreated hypertensive male patients (age, 29 to 54 years) were sodium restricted (5 g/day) for 1 week, and placed on a high salt diet (20 g/day) the second week. At the end of each period, measurements of forearm vascular responses to drugs (acetylcholine, 3 to 24 microg/min; sodium nitroprusside, 0.15 to 1.2 microg/min; norepinephrine, 0.15 to 1.2 microg/min; and N(G)-monomethyl-L-arginine [L-NMMA], 1 to 8 micromol/min) were obtained by using strain-gauge venous plethysmography. Subjects were divided into two groups according to the blood pressure response to sodium loading: salt-sensitive hypertensive group (24-h mean increase of arterial pressure > or = 10%; n = 6) and salt-resistant group (< 10%; n = 9). The two groups showed no significant difference in clinical data or mean arterial pressure during low salt intake. The dose-dependent vasodilation induced by acetylcholine was significantly reduced (P < .05) in the salt-sensitive hypertensive patients v the salt-resistant patients regardless of sodium loading. There were no differences between the two groups in response to sodium nitroprusside, norepinephrine, or L-NMMA. These results indicate that vasodilation to acetylcholine is reduced in salt-sensitive hypertensive patients even on restricted sodium diets. This may contribute to blood pressure elevation when sodium intake is increased.

We explored the relationship between body surface recovery time (RT), the interval between the QRS onset and the time of maximum derivative in the T-wave on a 16 precordial lead system electrocardiogram (ECG), and monophasic action potential (MAP) duration of the left ventricular endocardium in 9 patients in whom electrophysiologic testing was indicated. The usefulness of RT measurement on body surface ECG for the detection of coronary artery disease was evaluated in 98 patients who had chest pain. The RT located in the right clavicular or upper sternal area showed a very high positive correlation (r= 0.91, p < 0.001) with MAP duration from the left ventricular endocardium and showed specific shortening in patients with one-vessel disease of the left anterior descending coronary artery. With a criterion of the RT located in the right clavicular or upper sternal area corrected by Bazett's formula < 380 msec 1/2 , a sensitivity of 81% and a specificity of 80% were achieved for detection of one-vessel disease of the left anterior descending coronary artery.

We investigated whether impaired endothelium-dependent vasodilatory response recovers as heart failure improves. The femoral blood flow responses to intra-arterial administration of nitroglycerin (NTG) and acetylcholine (ACh) were examined in dogs with 2-week pacing-induced chronic congestive heart failure (congestive heart failure group; CHF, n=12). Thereafter, pacing was stopped and hemodynamic changes and femoral blood flow responses were re-examined either 1 week (recover 1 week group; Re 1W, n=6) or 4 weeks (recover 4 weeks group; Re 4W, n=6) after the cessation of pacing. Another group in which a pacemaker was implanted without pacing served as the control group (n=8) . In CHF, heart rate and pulmonary artery pressure increased, and echocardiography revealed increased left ventricular diastolic dimension and reduced percent fractional shortening compared with those in the control group. In Re 1W, all hemodynamic parameters returned to the basal levels and did not differ from those in the control group. Although there was no significant difference in the blood flow responses to NTG among the 4 groups, the responses to ACh in CHF were significantly reduced compared with those in the control group. Despite the recovered hemodynamics, femoral blood flow responses to ACh were still reduced in Re 1W, but they returned to the levels of the control group in Re 4W. Thus, vascular endothelial dysfunction recovers along with improvement in CHF, however, the recovery of endothelial function is delayed in comparison with improvement in cardiac function. (Jpn Circ J 1997; 61: 936 - 942)

Left ventricular hypertrophy is an adaptive response to long standing hypertension. However, the influence of left ventricular hypertrophy with hypertension on extent of infarct expansion has not been studied. We compared the effects of left ventricular hypertrophy with hypertension on infarct expansion in spontaneously hypertensive rats (SHR, n = 76), Wistar-Kyoto rats (WKY ; n = 46) and spontaneously hypertensive rats treated with delapril, an angiotensin converting enzyme (ACE) inhibitor (SHRD ; n = 39). The survival rates at 7 days after myocardial infarction were 41%, 24%, and 46% for WKY, SHR, and SHRD. The survival rate of SHR was significantly lower than those of both SHRD and WKY (P

To clarify the role of the guanine nucleotide binding proteins (G-proteins) in the pathogenesis of myocardial hypertrophy, we investigated the alterations in myocardial G proteins in 20-week-old F1b hamsters with pressure overload induced for 3 days (3-day AS), 7 days (7-day AS) and 14 days (14-day AS) by the stenosis of the abdominal aorta, and in 4- and 20 week-old BIO 14.6 Syrian hamsters (4-wk and 20-wk BIO) with genetic myocardial hypertrophy. The hearts of 7-day AS, 14-day AS and 20-wk BIO with left ventricular hypertrophy exhibited a decrease in the mRNA levels detected by Northern blot analysis and protein levels of G protein detected by Western blot analysis as compared with sham-operated and age-matched F1b hearts. The function of Gs or Gi showed a concomitant reduction in both models of myocardial hypertrophy. The hearts of 3-day AS and 4-wk BIO without myocardial hypertrophy showed no changes in G proteins as compared with sham-operated and age-matched F1b hearts. These results suggest that a decrease in G proteins is not involved in the pathogenesis of myocardial hypertrophy, but that myocardial hypertrophy reduced the G proteins.

Guanine nucleotide-binding regulatory proteins (G proteins) play a major role in the regulation of a number of physiological processes, such as stimulation or Inhibition of adenylate cyclase activity or gaiting of ionic channels. Myocardial ischemia could induce the changes in receptor-G protein signal transduction system in the heart. Therefore, this article will focus on the role and alterations of G proteins (especially, Gs and Gi) in myocardial ischemia. The Gi protein rapidly loses functional activity during very early myocardial ischemia. In contrast to Gi protein, the function of Gs protein during this phase has not been evaluated. Moreover, the changes in Gs protein after 30 min of ischemia are contradictory. However, the sensitization of the adenylate cyclase activity in the very early phase of acute ischemia is gradually replaced by a decrease in adenylate cyclase activity with prolonged ischemia. The decrease in the function and amount of Gs protein may be one of the factors that induce these changes. The function of Gs protein was also decreased in the canine hearts with ischemia and reperfusion. In contrast to ischemia and reperfusion, there are no significant alterations in G proteins and modulation of adenylate cyclase in the stunned myocardium. It has become increasingly evident that Gi protein may play an important role in the cardioprotective effects of preconditioning. When β-adrenoceptor densities are reduced in chronic myocardial ischemia, decreased in the amount and function of Gi protein and increased amount of Gs protein may play the role in preservation of the adenylate cyclase activity. These alterations in G proteins may play the important role in the myocardial function during myocardial ischemia. (Mol Cell Biochem 160/161:153–158, 1996)

Sensitivity of blood pressure to dietary salt is a common feature in subjects with hypertension. These features are exemplified by the mendelian disorder, Liddle's syndrome, previously shown to arise from constitutive activation of the renal epithelial sodium channel due to mutation in the beta subunit of this channel. We now demonstrate that this disease can also result from a mutation truncating the carboxy terminus of the gamma subunit of this channel; this truncated subunit also activates channel activity. These findings demonstrate genetic heterogeneity of Liddle's syndrome, indicate independent roles of beta and gamma subunits in the negative regulation of channel activity, and identify a new gene in which mutation causes a salt-sensitive form of human hypertension.

We investigated whether right ventricular infarct size is increased in the hypertrophied right ventricle. In dogs, we produced chronic pressure overload-induced right ventricular hypertrophy (RVH) and acute pulmonary stenosis (APS) with a similar right ventricular systolic pressure to RVH. Then, in an open-chest model, right coronary artery occlusion for 4 h followed by 1 h of reperfusion was performed in animals with RVH or APS or in controls. Regional myocardial blood flow was measured with nonradioactive colored microspheres. Compared with the control group, regional myocardial oxygen consumption in the right ventricle was increased in the APS but not in the RVH group. The risk area and collateral blood flow were comparable in the three groups. However, the infarct size relative to risk area was increased in the APS group (42.3 +/- 4.9%), but that in the RVH group (21.1 +/- 4.4%) was not different from controls (26.1 +/- 4.2%). Thus right ventricular infarction in the heart with RVH was not increased compared with the normal heart.

The localization of protein kinase C (PKC) α, β and γ subspecies in sensory axon terminals of muscle spindles in the plantar lumbrical muscles of rat was investigated by light and electron microscopic immunocytochemistry using monoclonal and polyclonal antibodies. Immunoreactivity for these subspecies was detected specifically in sensory axon terminals which wound spirally around the intrafusal muscle fibres of the muscle spindle. Immunostaining was found to be stronger with polyclonal than with monoclonal antibodies. By electron microscopy, immunoreactivity for α, β and γ subspecies was almost diffusely distributed in the cytoplasm of the axon terminal, and the overall pattern of distribution of immunoreactivity was similar for all three subspecies. In the cases of a and β subspecies, some intensely immunostained regions were found in the cytoplasm, but no definite subcellular structures corresponding to such regions could be identified. Considering that PKC plays a crucial role in the regulation of ion channels, it is suggested that PKC might be involved in the control of mechanoelectric transduction in sensory axon terminals.

The vasodilatory response is known to be diminished in chronic heart failure. In the present study, we used dogs with chronic heart failure to investigate whether endothelium-dependent vasodilation in the resistance vessels in the hindlimb is decreased in chronic heart failure, and if so, to determine if endothelium-derived relaxing factor (EDRF) is involved in the mechanism. We induced heart failure in dogs by continuous rapid ventricular pacing. Under anesthesia, an internal carotid artery-femoral artery bypass system was established and perfusion pressure to the femoral artery was kept constant. Changes in hindlimb blood flow in response to various concentrations of acetylcholine (ACh), adenosine 5'-diphosphate disodium salt (ADP) and nitroglycerin (NTG) were examined in dogs with and without heart failure. The vasoconstrictive responses to L-NG-monomethyl L-arginine monoacetate (L-NMMA) were also studied. In dogs with heart failure, vasodilatory responses to both of the endothelium-dependent vasodilators, ACh and ADP, were decreased, while there were no differences in the responses to the endothelium-independent vasodilator NTG. The vasoconstrictive response to L-NMMA was diminished in heart failure. Thus, endothelium-dependent vasodilation in hindlimb resistance vessels is impaired in dogs with congestive heart failure. This impairment may be related to diminished EDRF/NO production or release in these vessels.

The effects of alpha-hANP (0.3 micrograms/kg body weight/min) on the baroreflex system were studied in anesthetized dogs according to three different protocols. In the first protocol, the effects of alpha-hANP on an open-loop gain (G(AP)) of the overall baroreflex system and a gain (GHR) of the baroreflex heart rate control system during quick mild hemorrhage and blood infusion were studied. G(AP) was decreased from 7.6 +/- 0.6 to 2.8 +/- 0.5 by alpha-hANP with hemorrhage. G(AP) decreased 7.4 +/- 0.8 to 2.9 +/- 0.4 by alpha-hANP with blood infusion. G(AP) was restored nearly to the control levels one hour after alpha-hANP administration. GHR did not change by alpha-hANP administration. In the second and third protocol, a site of action of alpha-hANP was analysed. alpha-hANP inhibited the responses of systemic vascular resistance to quick mild hemorrhage and blood infusion, but did not affect the responses of cardiac output to quick mild hemorrhage and blood infusion in the second protocol. After carotid sinus denervation and vagotomy, alpha-hANP inhibited an arterial pressure responses to phenylephrine and nitroglycerin bolus injection in the third protocol. These findings suggest that alpha-hANP has mainly an effect on the peripheral vascular system to decrease its responsiveness, resulting in a decrease in G(AP).

The myocardial uptake and redistribution in thallium scintigraphy and the regional wall motion by echocardiography were evaluated by a semi-quantitative method in 42 patients who previously had myocardial infarction (50 target vessels) and underwent coronary revascularization. The aim of this study was to elucidate the significance of the initial image, delayed image and redistribution on thallium-201 scintigraphy for clinical diagnosis of the myocardial viability. As a semi-quantitative analysis, we used a bull's-eye display for thallium image and centerline method for echocardiographic wall motion, and compared the results before and after revascularization. As a result, the thallium grade improved postoperatively in all 17 areas which preoperative had showed redistribution, and also in 11 of the 32 areas without preoperative redistribution. The sensitivity, specificity and accuracy of preoperative thallium redistribution for predicting myocardial viability were 61%, 100% and 78%, respectively, when the postoperative improvement in the thallium grade was used as the standard. The postoperative probability of improvement in the thallium grade increased in proportion to the preoperative thallium grade (delayed image) (p less than 0.01). There was no correlation between the preoperative thallium delayed image and postoperative improvement in wall motion. Postoperative improvement in thallium image and wall motion could not be predicted from the preoperative wall motion. Thus, postoperative improvement in thallium images can be anticipated if redistribution is present on the preoperative thallium image, and the preoperative thallium delayed image is useful for predicting myocardial viability. Improvement in wall motion could not be predicted preoperatively by these methods.

ホルター心電図記録を用いた加算平均心電図 (SAE) の信頼性について, Late Potential (LP) に関連したパラメーターを中心にリアルタイム記録法と比較検討した.対象は45例, 記録法は3チャンネルポルター心電図計にてX, Y, Z誘導を記録, simsonらの方法に準じてQRS vector magnitudeを求め, リアルタイム記録も同様に行い, 各々RMS40, QRSD, LAS40を測定した.結果: (1) 三つのパラメーターすべてでホルター記録とリアルタイム記録間での相関を認めた. (2) リアルタイム記録でのLP (+) 群においては, 両記録間でRMS40に有意な相関を得た. (3) VT (+) 群においても, 両記録間で, RMS40に有意な相関を認めた. (4) RMS40のVTに対するnegative predictive valueは両記録ともに高値であった.以上よりホルター記録を用いたSAEは信頼性があり, LPの検出を中心に今後臨床的有用性が高いと考えられた.

Studies were made on the effects of Li+ on ADP ribosylation of inhibitory GTP-binding (Gi) protein by islet-activating protein (IAP), pertussis toxin. The ADP ribosylation of 40-41 kDa proteins of the membranes of rat cardiac ventricular cells by IAP was reduced by the addition of a nonhydrolyzable analog of guanine nucleotide, GTP gamma S, indicating that these proteins included Gi protein. The addition of LiCl (0.5-10 mM) to the membrane fractions of the cells attenuated the ADP ribosylation of the Gi protein of the cell membranes by IAP dose-dependently. The effects of LiCl were reversible. Of the monovalent ions tested, Li+ inhibited the ADP ribosylation of the protein by IAP most strongly. The effects of LiCl (2 mM) were observed even in the presence of 150 mM KCl. Moreover, LiCl decreased the ADP ribosylation of purified Gi protein by IAP. These results support that Gi proteins are one of the targets for the therapeutic effects of lithium.

The patient, a 51-year-old man, was receiving immunosuppressants for 2 yr after renal allotransplantation. He had heart failure with aortic regurgitation, fever, anemia and a history of odontectomy on admission. He was resistant to medical treatments and died from cerebral emboli. On autopsy, vegetation of the aortic valve was identified. Progression of atherosclerosis, which may have been due to steroids and chronic rejection, was prominent. This report is the first case of infective endocarditis following organ transplantation in Japan. Such complications as infective endocarditis and atherosclerosis will be on the rise with the increase of numbers or organ transplantations.

Addition of lithium ion to the inhibitory GTP-binding (Gi) protein resulted in a decrease of its ADP-ribosylation by islet-activating protein (pertussis toxin, IAP). The possibility that this decrease was due to dissociation of the Gi protein trimer was examined. Results showed that lithium ions had no appreciable effect on either the Gi protein trimer or its dissociation into its three subunits induced by Mg2+ and GTP gamma S. Next, the effect of lithium ions on Gi protein-mediated adenylate cyclase inhibition and alpha 2-adrenoceptor in human platelet membranes was examined. Lithium ion was found to impair adenylate cyclase inhibition of alpha 2-adrenoceptor stimulation of forskolin-stimulated enzyme activities. The monovalent ion also abolished guanine nucleotide modulation (GTP shift) of agonist binding, while it had no remarkable effects on antagonist binding in alpha 2-adrenoceptor of human platelet membranes. These results suggested that lithium ion caused functional change of the Gi protein without remarkable change of its dissociation, causing modulation in a coupling between alpha 2-adrenoceptor and Gi protein.

A 42-year-old man with limb-girdle muscular dystrophy who showed prominent cardiac involvement is described. He was treated for and diagnosed with dilated cardiomyopathy before admission. Initially, no overt feature of muscular dystrophy was evidenced, but serum enzymes were elevated. During the 2-year follow-up period, distinct features of muscular dystrophy appeared, and muscle biopsy confirmed the diagnosis. He was regarded as experiencing a sporadic occurrence. Because some patients diagnosed with and treated for dilated cardiomyopathy may have similar results, this form of muscular dystrophy should be recognized as occasionally associated with cardiac muscle disease.

Thallium-201 exercise myocardial scintigraphy and quantitative analysis using a bull's-eye display were performed in 40 cardiac patients ― 22 bypass and 18 percutaneous transluminal coronary angioplasty (PTCA) cases ― to determine the indications for coronary artery bypass surgery and PTCA and to evaluate the degree of postoperative improvement. The results were as follows: 1) The preoperative mean WR of the improved areas (33 vessels) was 20±15%, while that of the unimproved areas (17 vessels) was 33±8%. We judged that an area was suitable for revascularization when the preoperative WR was less than 25% which was the lower limit of the normal range. In this way 21 vessels were judged to be suitable for surgery, and a postoperative improvement was obtained in 18 areas. We concluded that a myocardial region was suitable for revascularization when the preoperative WR and percent uptake were below the normal range. Since the scintigraphic evaluation accorded with the improvement in exercise tolerance and with patency on coronary angiography, the method seems useful for the postoperative follow-up

Viral vector systems are efficient for transfection of foreign genes into many tissues. Especially, retrovirus based vectors integrate the transgene into the genome of the target cells, which can sustain long term expression. However, it has been demonstrated that the transduction efficiency using retrovirus is relatively lower than those of other viruses. Ultrasound was recently reported to increase gene expression using plasmid DNA, with or without, a delivery vehicle. However, there are no reports, which show an ultrasound effect to retrovirus-mediated gene transfer efficiency. Retrovirus-mediated gene transfer systems were used for transfection of 293T cells, bovine aortic endothelial cells (BAECs), rat aortic smooth muscle cells (RASMCs), and rat skeletal muscle myoblasts (L6 cells) with beta-galactosidase (beta-Gal) genes. Transduction efficiency and cell viability assay were performed on 293T cells that were exposed to varying durations (5 to 30 seconds) and power levels (1.0 watts/cm(2) to 4.0 watts/cm(2)) of ultrasound after being transduced by a retrovirus. Effects of ultrasound to the retrovirus itself was evaluated by transduction efficiency of 293T cells. After exposure to varying power levels of ultrasound to a retrovirus for 5 seconds, 293T cells were transduced by a retrovirus, and transduction efficiency was evaluated. Below 1.0 watts/cm(2) and 5 seconds exposure, ultrasound showed increased transduction efficiency and no cytotoxicity to 293T cells transduced by a retrovirus. Also, ultrasound showed no toxicity to the virus itself at the same condition. Exposure of 5 seconds at the power of 1.0 watts/cm(2) of an ultrasound resulted in significant increases in retrovirus-mediated gene expression in all four cell types tested in this experiment. Transduction efficiencies by ultrasound were enhanced 6.6-fold, 4.8-fold, 2.3-fold, and 3.2-fold in 293T cells, BAECs, RASMCs, and L6 cells, respectively. Furthermore, beta-Gal activities were also increased by the retrovirus with ultrasound exposure in these cells. Adjunctive ultrasound exposure was associated with enhanced retrovirus-mediated transgene expression in vitro. Ultrasound associated local gene therapy has potential for not only plasmid-DNA-, but also retrovirus-mediated gene transfer.

1. Previous studies have suggested that the production of nitric oxide (NO) is reduced in coronary vessels of animals with congestive heart failure (CHF). However, the response to endothelium-derived hyperpolarizing factor (EDHF) in small coronary resistance arteries from CHF rats has not been investigated. The aim of the present study was to determine whether flow-induced dilation (FID) is altered in small coronary arteries from CHF rats and to characterize the role of EDHF in this process. 2. Small coronary arteries (97 +/- 6 microm) were isolated from control rats and from rats in which CHF was induced by left coronary artery ligation. The arteries were cannulated at 60 mmHg with flow. Changes in internal diameter were examined using videomicroscopy. 3. There was no significant difference in FID in small coronary arteries between control and CHF rats (68 +/- 6 vs 61 +/- 4% (expressed as a percentage of maximal dilation induced by nitroprusside (%MaxD(NP))), respectively). Flow-induced dilation in control rat vessels showed greater attenuation by N(G)-monomethyl-L-arginine (L-NMMA) than vessels from CHF rats (%NO-mediated FID 32 +/- 5 vs 16 +/- 3% (%MaxD(NP)), respectively). Pretreatment with indomethacin had no significant effect on FID in vessels from either rat group. Flow-induced dilation was attenuated by KCl (40 mmol/L) to a greater degree in vessels from CHF rats in the presence of L-NMMA and indomethacin compared with vessels from control rats (%EDHF-mediated FID: 36 +/- 4 vs 25 +/- 5% (%MaxD(NP)), respectively). Flow-induced dilation was abolished by removal of the endothelium and was significantly decreased in vessels from CHF rats in response to charybdotoxin plus apamin or tetrabutylammonium compared with control rat vessels. 17-Octadecynoic acid had no significant effect on FID in vessels from either control or CHF rats. 4. In conclusion, the FID of small coronary arteries is mediated by K+ channels, including the K(Ca) channels. Endothelium-derived hyperpolarizing factor-mediated dilation may compensate for the loss of NO-mediated dilation in CHF.

We compared the ischemic diagnosis ability and adverse events of 201Tl myocardial perfusion imaging with SUNY4001 (adenosine) stress to that with exercise (ergometer) stress both on random crossover trial. Thirty one known or suspected chronic stable angina patients who are able to exercise and 10 healthy volunteers were enrolled for the trial. The early and delayed images were obtained by SPECT imaging. The concordance of diagnoses [ischemia vs. no ischemia] between the two types of stresses was 97.3% (36/37) [Kappa: 0.9068]. The sensitivity and specificity based on the exercise test were 100% (6/6) and 96.8% (30/31) respectively. The incidence of adverse events caused by SUNY4001 and the exercise were 44.7% (17/38) and 52.6% (20/38), respectively. Major adverse events caused by SUNY4001 were BP decrease, flushing and headache. And those by exercise were ST decrease, dyspnea and chest pain. None of the adverse events required the intervention or caused life-threatening complication in the trial. The trial showed that the ischemic diagnosis ability and safety of 201Tl scintigraphy with SUNY4001 stress are almost equal to those of the exercise stress that is considered as the standard stress method. We concluded that 201Tl imaging with SUNY4001 is safe and useful for detecting ischemic heart disease, especially for patients unable to exercise adequately.

The evaluation of myocardial damage by [123I] 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) imaging, which represents free fatty acid metabolism, has not been reported in patients with Duchenne-type muscular dystrophy (DMD). To date, the relationship between clinical stage, prognosis and myocardial damage has not been evaluated by radionuclear cardiac imaging. The main goal of this study was to elucidate the relationship of quantitative indices of myocardial damage obtained by radionuclear cardiac imaging ([201T1] and [123I] BMIPP) to clinical stage and incidence of severe cardiac events in patients with Duchenne-type muscular dystrophy (DMD).Methods: The study population consisted of 28 male patients with DMD. The average age at the beginning of observation was 19.1 ± 7.4 yrs. Nuclear tomographic imaging was performed using [201T1] and [123I] BMIPP. The mid-ventricular short axial slices were classified into four anatomical regions, and the normalized count data in these areas (TL, BM) were obtained. The endpoint was the occurrence of heart failure during the follow up period.Results: Thirteen cases of heart failure occurred during the 5-year follow-up period, including three cases with cardiac death due to congestive heart failure. Clinical staging correlated directly with TL (p = 0.0118) and BM (p = 0.0401) in the whole left ventricle. In regional TL analysis, an association was observed only in the septum (p = 0.0151), and in the anterior (p = 0.0361) region. The only discrepancy between the tracer parameters (TL — BM) in the septum was observed with the radionuclear cardiac values, which exhibited a relationship with cardiac events (p = 0.0124). This discordance, TL < BM, was contrary to that usually observed in patients with ischemic heart disease.Conclusion: The septum is the critical area of significance for cardiac events and outcome in patients with DMD. The uptake of [201T1] in this area was representative of the clinical stage, and TL-BM correlated well with the prognosis.

We used Wavelet transform (WT) to investigate whether variation in autonomic tone was associated with spontaneous coronary spasm in patients with variant angina by analysis of heart rate variability (HRV). Twenty-one episodes preceding ST-segment elevation were selected under Holter monitoring in 12 men and 3 women with variant angina. HRV indices were calculated at 10 second intervals with the continuous WT, and analyzed within 30 minutes preceding ST-segment elevation. High frequency (HF; 0.15 approximately 2.00 Hz) increased significantly during the 4 minutes prior to ST-segment elevation, low frequency (LF; 0.04 approximately 0.15 Hz) decreased significantly during the period from 10 to 5 minutes and increased significantly during the 2 minutes prior to ST-segment elevation, the LF/HF ratio decreased significantly during the period from 10 to 3 minutes and increased significantly during the 2 minutes prior to ST-segment elevation. The RR interval decreased significantly during the 2 minutes prior to ST-segment elevation. These results suggest that the acute variation in autonomic tone was associated with spontaneous coronary spasm in patients with variant angina. A reduction in sympathetic activity, then enhancement of vagal activity may play a key role in triggering the spontaneous coronary spasm, and the secondary activation of sympathetic activity may worsen the coronary spasm resulting in the attack.

Activation of the Na+/H+ exchanger (NHE) is known to be related to elevated blood pressure in hyperinsulinemia. We previously demonstrated that a fructose-enriched diet induced hyperinsulinemia and hypertriglyceridemia, elevated NHE activity, increased intracellular calcium concentrations ([Ca2+]i), and increased blood pressure in borderline hypertensive rats (BHR). This study examines whether pharmacologically reducing plasma triglyceride or insulin concentrations lowers blood pressure and reduces NHE activity in fructose-fed BHR. Eicosapentaenoic acid (EPA), bezafibrate (BEZ), and troglitazone (TRO) were administered to treat hypertriglyceridemia and/or hyperinsulinemia. Rats were fed a 60% fructose diet or a control diet for 4 weeks, followed by a diet with either vehicle, EPA, BEZ, or TRO for 4 weeks. Intracellular pH (pHi) was measured in platelets by fluorescent dye. Platelet NHE activity was evaluated by the recovery of pHi following addition of sodium propionate (Vmax). [Ca2+]i in platelets were measured fluorometrically. In fructose-fed rats, EPA prevented further increase in blood pressure, and reduced triglyceride concentration and [Ca2+]i without affecting Vmax or plasma insulin concentrations. BEZ reduced triglyceride concentrations without affecting blood pressure, Vmax, [Ca2+]i, or insulin concentrations. TRO prevented an increase in blood pressure, and reduced Vmax, [Ca2+]i, and insulin, but not triglycerides. Plasma insulin and Vmax were positively correlated. In conclusion, improvement of hyperinsulinemia can decrease NHE activity and blood pressure in fructose-fed BHR. (Hypertens Res 2003; 26: 111-116)

Left ventricular (LV) dysfunction after myocardial infarction is associated with higher risk of serious ventricular arrhythmias and sudden death. We suspected that heterogeneity in ventricular repolarization contributes to these arrhythmias. To quantify this heterogeneity, we measured the recovery time (the interval between QRS onset and the time of maximum dV/dt in the ST-T segment) using an 87-lead body surface mapping electrocardiogram and estimated recovery time dispersion (the difference between maximum recovery time and minimum recovery time) in each lead. Differences between 110 patients with previous myocardial infarction and 31 healthy controls were compared. Recovery time dispersion [medians (25th, 75th percentiles)] was greatest in patients with a dilated LV [169 ms (154, 201) vs. 155 ms (137, 172), P.005], impaired ejection fraction [173 ms (155, 202) vs. 152 ms (138, 165), P.0005] and LV dyskinesis [175 ms (159, 201) vs. 155 ms (137, 161), P.0005]. This study suggests that LV dysfunction associated with myocardial infarction leads to heterogeneous ventricular repolarization and may provide the electrical substrate for ventricular arrhythmias.

There are several controversies concerning the enhanced gene expression of cardiac renin-angiotensin system components in spontaneously hypertensive rats (SHR) compared with their normotensive control Wistar-Kyoto (WKY) rats. We hypothesized that these discrepancies arise from circadian fluctuations in gene expression. We examined the circadian mRNA expression of renin, angiotensinogen, ACE, and angiotensin type 1a (AT1a) and type 2 (AT2) receptors in the hearts of SHR and WKY rats by real-time quantitative reverse transcription–polymerase chain reaction. The cardiac mRNA expression of the renin-angiotensin system components showed circadian oscillations in both SHR and WKY rats. The amplitudes of these circadian fluctuations were greater in the SHR than in the WKY rats. The mRNA levels of the renin-angiotensin system components were also increased in the SHR compared with the WKY rats at many time points (especially during the dark phase). However, the levels of ACE, AT1a receptor, and AT2 receptor mRNA in the SHR and WKY rats were almost the same during the late light phase. In contrast to mRNA expression, ACE activity was similar both at the time of maximum and minimum mRNA expression. The AT1 receptor antagonist candesartan upregulated AT1a receptor mRNA and downregulated ACE mRNA at specific time points only in the SHR group. Our findings of differential diurnal expression of cardiac renin-angiotensin system genes in SHR and WKY rats appear to explain the discrepancies between prior studies. However, the physiological relevance of the differential circadian mRNA expression of the renin-angiotensin system components remains to be elucidated.

We investigated the concentration of stimulatory GTP-binding protein (Gs protein) in the peripheral resistance arteries of spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and renovascular hypertensive rats (RHR). Changes in the function of Gs protein in SHR and WKY were also investigated by microcannulation techniques. The localization and abundance of Gs protein were determined immunohistochemically in 4-, 10- and 20-week-old SHR and age-matched WKY (control), as well as in RHR. Sections of the cremaster artery were stained with polyclonal antibodies to Gs protein. The concentration of Gs protein-like immunoreactivity in the cremaster artery was significantly lower in SHR at 4, 10, and 20 weeks of age, relative to that in age-matched WKY. In contrast, no significant differences were detected in the abundance of Gs between RHR and control rats. The dilatory response by isoproterenol in the presence of β1-adrenoceptor blocker was lower in 4- and 10-week-old SHR than in age-matched WKY. The dilatory response by cholera toxin was also lower in SHR than in WKY for these two age groups. These results indicated that the amount and function of Gs protein in the peripheral resistance vessels in SHR was reduced. Since this change occurred before the onset of hypertension and no changes were seen in the secondary hypertensive rats, this change was not a secondary change due to hypertension. The impaired receptor-Gs protein-mediated signal transduction in the peripheral resistance arteries may be one of the possible mechanisms responsible for the pathogenesis of hypertension in SHR. (Hypertens Res 2002; 25: 743-749)

Background Epidemiologic investigations suggest that fish oil, which contains eicosapentaenoic acid (EPA), has favorable cardiovascular effects. Fish oil improves endothelial function in subjects with hypercholesterolemia or diabetes. However, controversy persists regarding relationships between primary hypertriglyceridemia and endothelial dysfunction. Moreover, lipoproteins are more susceptible to oxidation in vitro after incorporation of fish oil. Methods We determined the effects of EPA on serum lipids, susceptibility of low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) to oxidation, and endothelial function in hypertriglyceridemic (HTG) subjects. In 8 men with untreated primary hypertriglyceridemia (plasma triglyceride between 150 and 500 mg/dL) and 7 control subjects (triglyceride below 150 mg/dL), forearm blood flow (FBF) responses were tested. In HTG subjects, this was repeated 3 months after initiation of EPA (1800 mg / day). Cu 2+ -induced oxidation of VLDL and LDL was determined by serial measurement of conjugated dienes. We used lag time, which corresponded to the period when the lipoproteins were resistant to oxidation, as a parameter of oxidizability. FBF responses to acetylcholine and sodium nitroprusside were determined by strain-gauge plethysmography. Results Plasma triglyceride in HTG subjects fell 31% with EPA supplementation. Before EPA, VLDL and LDL lag times in HTG subjects were shorter than in control subjects. EPA further reduced lag time for VLDL but not LDL. The FBF response to acetylcholine (but not to nitroprusside) was significantly less in HTG subjects before EPA than in control subjects. EPA normalized the FBF response to acetylcholine. Conclusions EPA improves endothelial function in HTG subjects despite increasing in VLDL oxidizability.

Background Hepatocyte growth factor (HGF), a member of the endothelial-specific growth factors with the greatest mitogenic activity, may play a role in the protection and/or repair of vascular endothelial cells injured by atherosclerosis. As a result, plasma HGF concentration may increase in response to endothelial cell damage. To test this hypothesis, we measured plasma concentrations of HGF in patients with or without aorto-iliac artery atherosclerotic disease. Methods One hundred ten consecutive patients who underwent coronary angiography were enrolled in this study. Abdominal aortography was performed after coronary arteriography to determine whether aorto-iliac artery atherosclerotic disease was present. Peripheral venous blood samples were obtained to measure the plasma HGF concentration. Results Aortography revealed aorto-iliac atherosclerotic disease in 35 patients (32%). The plasma HGF concentration was significantly higher in patients with arteriosclerotic lesions (0.35 ± 0.11 ng/mL) than in patients without atherosclerotic lesions (0.27 ± 0.09 ng/mL, P =.0002). On the basis of multiple logistic regression analysis of the relationships between coronary risk factors, age, sex, severity of coronary artery disease, plasma HGF concentration, and the presence of arteriosclerotic lesions, plasma HGF concentration ( P =.0005) and age ( P =.035) were found to predict independently the presence of aorto-iliac arteriosclerosis. Conclusion Plasma HGF concentration can be used to predict the presence of arteriosclerotic lesions in the region from the abdominal aorta to the femoral arteries. (Am Heart J 2002;143:272-6.)