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This study aimed to find how ribavirin increases viral disappearance in patients with hepatitis C virus (HCV) of genotype 1 and high baseline viral loads (>5.0 x 10(5) copies/mL) when given with interferon (IFN). Using the real-time quantitative polymerase chain reaction, we measured serum HCV in 20 patients during the first 12 weeks of therapy with IFN-alpha 2b and ribavirin. Controls were 10 similar patients given IFN-alpha 2b alone. IFN-alpha 2b was given at 6 MU daily for 2 weeks, and then three times weekly. Ribavirin was given at 600 or 800 mg daily. Serum HCV RNA decreased rapidly in the first phase, during the first 24 h of therapy (day 0), and more slowly in the early second phase (days 1-14). The median decrease was by 1.41 and 0.078 log 10/day in these two phases in the combination therapy group, and 0.90 and 0.081 log 10/day in the monotherapy group. The difference between groups in the first phase was not significant (P = 0.24), nor was that in the next phase (P = 0.68). Later in the second phase, between days 14 and 84, the median decrease was larger in the combination therapy group (0.030 log 10/day) than in the monotherapy group (0.015 log 10/day, P = 0.035). In patients with HCV genotype 1 and high viral loads, the effects of ribavirin with IFN-alpha appeared slowly, after the earliest days of treatment. A long-term favourable outcome of combination therapy may be associated with a rapid viral decline in this later phase of therapy.

Abstract The study evaluates whether the Watanabe heritable hyperlipidemic (WHHL) rabbit is an adequate model to study mechanisms that underlie differences in tissue response after postangioplasty injury. Postangioplasty studies of human coronary arteries have revealed that healing and restenotic processes differ depending on whether the laceration is limited to the atherosclerotic plaque or whether injury extends into the media. Forty-five homozygous WHHL rabbits underwent percutaneous transluminal angioplasty of the left subclavian artery. The inflated arterial segment was studied histologically at 3, 7, 14, 28, and 56 days, using conventional and immunohistochemical techniques to identify macrophages, smooth muscle cell (SMC) phenotypes, and cell proliferation. Electron microscopy was done to study reendothelialization. There were marked differences in response between those segments with medial injury and those with injury limited to the atherosclerotic plaque tissues. The latter category shows a distinct retardation in redifferentiation of SMCs, confirming previous observations in human coronary arteries. In these segments, moreover, cell proliferation occurred mainly in macrophages and spindle cells. Medial injury showed a more florid fibrocellular response, as in human coronary arteries, with cell proliferation initially confined to areas with dedifferentiated SMCs in the preexistent media and, once neointimal tissue was formed, among spindle cells also. The similarities with the repair processes encountered in postangioplasty human coronary arteries suggest that the WHHL rabbit is an adequate model to study differences in the response related to different types of angioplasty injury.

Patients with chronic active hepatitis C and cirrhosis often develop hepatocellular carcinoma. Interferon (IFN) seems to be effective in some patients but whether it prevents carcinogenesis is unknown. In a prospective randomised controlled trial, we evaluated the effects of IFN-alpha in cirrhotic patients with HCV infection because of their high risk of hepatocellular carcinoma. 90 patients with compensated chronic active hepatitis C with cirrhosis were randomly allocated to receive IFN-alpha (6 MU three times weekly for 12-24 weeks) (45 patients) or symptomatic treatment (45 controls), and were followed up for 2-7 years. In nine controls, alanine aminotransferase (ALT) decreased to less than 80 IU/L but did not stay in the normal range. In 19 patients given IFN-alpha, ALT decreased to less than 80 IU/L (in seven patients, it became and stayed normal; p = 0.011, Wilcoxon rank-sum test). However, the mean change in ALT was not significantly different between the two groups. The mean change in peak alpha-fetoprotein values was smaller in patients given IFN-alpha than in controls (p = 0.021). The mean change in the serum albumin level was higher in the IFN-alpha group (p < 0.001). The histological activity index in the 12 IFN-alpha patients undergoing a second biopsy after therapy was improved (p = 0.031). Hepatitis C viral RNA disappeared in seven (16%) of the 45 IFN-alpha patients (95% CI, 7-29%) and in none of the 45 controls (0-8%; p = 0.018). Hepatocellular carcinoma was detected in two (4%, 1-15%) IFN-alpha patients and 17 (38%, 24-54%) controls (p = 0.002, Wilcoxon signed-rank test). The risk ratio of IFN-alpha treatment versus symptomatic treatment was 0.067 (0.009-0.530; p = 0.010 Cox's proportional hazards). IFN-alpha improved liver function in chronic active hepatitis C with cirrhosis, and its use was associated with a decreased incidence of hepatocellular carcinoma.

Abstract Vascular endothelial cell migration is proposed to be an important process in the initiation and progression of atherosclerosis. We designed the present study to examine the effects of atrial and brain natriuretic peptides on fetal calf serum–stimulated migration of cultured rat aortic endothelial cells using Boyden’s chamber method. Fetal calf serum clearly stimulated migration in a concentration- and time-dependent manner. Rat atrial natriuretic peptide-(1-28) and rat brain natriuretic peptide-45, which are the major circulating forms of atrial and brain natriuretic peptides in rats, inhibited fetal calf serum–stimulated migration in a concentration-dependent manner between 10 −10 and 10 −6 mol/L. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. The addition of a cGMP analogue 8-bromo-cGMP, significantly inhibited fetal calf serum–stimulated migration in a concentration-dependent manner between 10 −7 and 10 −3 mol/L. Rat atrial natriuretic peptide-(5-25) was much less effective than atrial natriuretic peptide-(1-28) or rat brain natriuretic peptide-45 with respect to inhibiting migration and increasing cGMP levels. These results indicate that atrial and brain natriuretic peptides inhibit fetal calf serum–stimulated vascular endothelial cell migration, probably through a cGMP-dependent process.

SUMMARY 1. We examined preproendothelin-1, ETA and ETb receptor mRNA levels in aortic endothelial and smooth muscle cells from cyclosporine (CyA)-induced hypertensive rats using the reverse transcription polymerase chain reaction method. 2. Aortic endothelial preproendothelin-1 mRNA expression was about 1.5-fold higher, while that of ETB receptor mRNA was markedly decreased in CyA-treated rats compared with those in controls. 3. The expression of ETA receptor mRNA in smooth muscle cells from CyA-induced hypertensive rats was increased about two-fold over that in cells from control animals. 4. Thus, increased endothelial preproendothelin-1, and ETa receptor mRNA levels in smooth muscle cells, which are concomitant with the decrease in ETB receptor mRNA levels in endothelium, may contribute to CyA-induced hypertension in rats.

Angiotensin II (Ang II) regulates a variety of physiological functions, including contraction of smooth muscle. Peptide leukotrienes (LTs) have recently been reported to be potent bronchoconstrictors and may play a role in the pathogenesis of airway inflammation. However, the possibility that Ang II and peptide LTs interact in the control of airway function has not been studied. In this study, we showed that Ang II receptors are present on guinea pig airway, and that they are of the AT1 subtype. We showed the possibility that Ang II induced the release of peptide LTs from guinea pig airway by activation of the AT1 receptor pathway. Our findings thus suggest that interaction between Ang II and peptide LTs might increase airway inflammation in the guinea pig.

Purpose Secretion of brain natriuretic peptide (BNP), a cardiac hormone, is accelerated via hypertrophied ventricles in experimental hypertension. The present study examined whether regression of left ventricular (LV) hypertrophy by long-term treatment with an angiotensin-converting enzyme inhibitor (ACEI) affects plasma BNP concentration in patients with essential hypertension. Patients and methods Thirty-one hypertensive patients with LV hypertrophy were treated with ACEI (16 with enalapril; 15 with lisinopril) for 1 year. Serial changes were recorded in LV mass index, LV systolic function, and plasma concentrations of BNP and atrial natriuretic peptide (ANP). Results ACEI therapy significantly reduced LV mass index at 6 months, and more so at 1 year. Septal and posterior wall thicknesses were also reduced. Plasma BNP and ANP were markedly elevated at study entry, but only BNP levels correlated with LV mass index. Both peptide levels declined after 6 months, and this decline was enhanced at 1 year. There was a close relation between BNP decline and LV mass index reduction overall and with enalapril and lisinopril separately. Changes in ANP and in LV mass index were not related. Conclusion Long-term ACEI therapy can reduce elevated plasma BNP. In this study, changes in BNP reflected the magnitude of regression of LVH. Plasma BNP may be a useful marker for LVH during antihypertensive therapy in patients with essential hypertension and LVH.

To clarify the role of PDGF A-chain in hypertensive vascular hypertrophy of spontaneously hypertensive rats (SHRs), we studied levels of PDGF A-chain gene expression and transcription factors related to the gene in vascular smooth muscle cells (VSMCs) of SHRs in vivo. RNase protection assay and in situ hybridization showed that PDGF A-chain mRNA levels in VSMCs of SHRs were twofold higher than in those of normotensive Wistar-Kyoto rats. Gel retardation assays showed that levels of Sp1 and AP-2 in VSMCs of SHRs were twofold more abundant than in those of Wistar-Kyoto rats. Treatment with four pharmacologically different species of antihypertensive drugs for 2 wk decreased the levels of both PDGF A-chain mRNA and Sp1, but not AP-2 level in VSMCs of SHRs with regression of aortic hypertrophy, indicating that increases in levels of both PDGF A-chain mRNA and Sp1 in VSMCs of SHRs were associated with high blood pressure. These results suggest that high blood pressure is a stimulus which upregulates PDGF A-chain gene expression in VSMCs of SHRs, resulting in an autocrine enhancement in hypertensive vascular hypertrophy, and that the activation of the gene may be mediated through increases in Sp1 in these cells.

The late troponin T (TnT) peak concentration, which is known to be independent of reperfusion of the infarcted zone in acute myocardial infarction (MI), has been suggested to be correlated with clinical estimates of cardiac function and myocardial infarct size. To refine the clinical application of the late TnT peak in infarct sizing, and to examine differences in this estimation in different infarct sites, we measured the serum concentrations of TnT and myosin light chain 1 (MLC1), and compared these values with left ventricular ejection fraction (LVEF) obtained from left ventriculography, and extent score (ES) and severity score (SS) obtained from 201Tl scintigraphy in patients with anterior and inferior myocardial infarction. The late TnT peak concentration was strongly correlated with the MLC1 peak value in patients with anterior MI (r = 0.67, p0.05) and in those with inferior MI (r = 0.92, p0.0005). Furthermore, there were strong linear correlations between the late TnT peak values and all of the clinical data (LVEF; r = -0.79, p0.01, ES; r = 0.75, p0.05, SS; r = 0.75, p0.05, respectively) in patients with anterior MI. However, these correlations were weak in patients with inferior MI. Similar correlations were observed between MLC1 and the clinical data. Thus, TnT and MLC1 have similar kinetics in the serum at the late phase and can be used to estimate the size of anterior infarct.

To examine the regulation of angiotensin receptors in vascular smooth muscle cells, we studied the effects of antihypertensive drugs on angiotensin type 1A (AT1A) receptor gene expression in aortic smooth muscle cells (ASMCs) from spontaneously hypertensive rats (SHRs) using both ribonuclease protection assay and reverse-transcription polymerase chain reaction. An increase in AT1A receptor gene expression in ASMCs of SHRs was induced by treatment with an angiotensin converting enzyme inhibitor (enalapril) for 2 weeks and 4 weeks, but not by other types of antihypertensive drugs such as alpha-blocker (doxazosin), alpha, beta-blocker (arotinolol), Ca antagonist (nicardipine) or vascular smooth muscle relaxant (hydralazine). Since all antihypertensive drugs lowered the blood pressure of the rats almost equally, our results suggest that AT1A receptor gene expression in ASMCs of SHRs may be regulated by the vascular renin-angiotensin system.

To investigate the contribution of the cardiac renin-angiotensin system to ventricular dilatation after myocardial infarction, we examined the effects of 3-week treatments with an angiotensin converting enzyme inhibitor, delapril, and a selective angiotensin II type 1 (AT1) receptor antagonist, TCV-116, on haemodynamics and ventricular angiotensin II contents in myocardial-infarcted rats. TCV-116 reduced mean aortic pressure, and prevented the increase of right and left ventricular weight, left ventricular end-diastolic pressure and volume of myocardial-infarcted rats, to a similar extent to delapril. Thus, AT1 receptor-mediated action of angiotensin II plays a central role in the development of ventricular dilatation. Angiotensin II contents in the right and non-infarcted left ventricles (6.0 +/- 1.0 and 5.9 +/- 0.7 pg/g tissue, respectively, mean +/- S.E.M.) of myocardial-infarcted rats were not different from those of sham-operated rats. However, angiotensin II contents in the infarcted scar (21.7 +/- 3.5 pg/g) of myocardial-infarcted rats were 4.2-fold higher than those in the left ventricle of sham-operated rats. Delapril reduced angiotensin II contents in the right and non-infarcted left ventricles, and the scar by 48, 81 and 60%, respectively, but did not reduce plasma angiotensin II in myocardial-infarcted rats. TCV-116 also decreased angiotensin II in the right and non-infarcted left ventricles by 57 and 56%, respectively, while increased plasma angiotensin II by 4.3-fold. Thus, the prevention of ventricular dilatation by these two agents was associated with the decrease in ventricular angiotensin II contents. These observations suggest that the cardiac renin-angiotensin system rather than the circulating system may play an important role in ventricular dilatation after myocardial infarction.

To examine the role of brain natriuretic peptide (BNP) in acute myocardial infarction (AMI), we measured the plasma concentration of immunoreactive (ir) BNP together with that of atrial natriuretic peptide (ANP) over the 4-week course of AMI in 16 patients treated with early coronary angioplasty. Both the plasma ir-ANP and ir-BNP levels were increased on the first day of the infarction compared with the values in normal subjects. During the clinical course of the infarction, the plasma ir-ANP concentration soon decreased, while the plasma ir-BNP level remained elevated at 2 weeks after the infarction, also exhibiting a high level at 4 weeks. Plasma ir-BNP levels on day 1 or days 14 and 28 were inversely correlated with left ventricular ejection fraction obtained by left ventriculography at the acute or chronic phase, respectively. Plasma ir-BNP concentrations on days 14 and 28 were positively correlated with the maximal myosin light chain I level, an indicator of infarct size. These observations suggest that the plasma ir-BNP level increased to compensate for the ventricular dysfunction associated with the size of the infarct in AMI. BNP may act as a cardiac hormone in AMI, differing somewhat from ANP in its synthetic, secretory, or clearance behavior.

Peptide leukotrienes (LT) have been postulated to play a major role in the etiology of bronchial asthma. The present study investigated the effect of a new peptide LT receptor antagonist, ONO-1078, on isolated human bronchial smooth muscle in vitro. Helical strips of bronchi were suspended in the organ baths filled with 37°C Krebs solution and mechanical responses were recorded isometrically. ONO-1078 produced dose-dependent relaxations, which suggested that the spontaneous basal tone was in part mediated by LT. ONO-1078 caused dose-dependent relaxations of the tissues which were precontracted with LTC 4 or LTD 4 (3 × 10 −8 M). Pretreatment of bronchi with ONO-1078 (10 −8 M, 10 −7 M) significantly inhibited dose-dependent contractions induced by LTC 4 and LTD 4 . ONO-1078 (10 −6 M) also significantly reduced the antigen-induced contractions in bronchi passively sensitized with atopic serum from mite-allergic patients. Moreover the combination of an H 1 -receptor antagonist, diphenhydramine (10 −5 M), and ONO-1078 (10 −6 M) completely abolished the antigen-induced contractions. The present findings demonstrate that ONO-1078 is a potent antagonist of exogenous and endogenous LT in the human airway. The selective LT antagonist such as ONO-1078 may be valuable in the therapy of allergic asthma.

Endothelin-1 (ET-1) represents one of the most potent constrictors of guinea pig bronchial smooth muscle. In our study, various doses of aerosolized ET-1 increased airway resistance. But a very low concentration of ET-1 (10(-12) M) could not change airway resistance. We examined low doses of ET-1 enhanced the sensitivity of bronchial contractions to histamine. ET-1 may play one of the most important roles in contributing directly or indirectly to the pathogenesis of bronchial asthma.

Objective: The excessive release of adenosine has been reported to cause hyperaemia and to attenuate ischaemic injury in microembolised hearts. The direct effects of exogenous adenosine on cardiac performance were investigated in microembolised guinea pig hearts with the simultaneous measurement of phosphate compounds. Methods: 21 male guinea pig hearts were perfused according to the Langendorff technique and microembolism was induced by injecting microspheres. Hearts were then treated as follows: group A, adenosine 20 μM and theophylline 60 μM; group B, theophylline 60 μM; group C, saline (control). Cardiac performance was monitored and phosphate compunds were measured by 31P magnetic resonance spectroscopy. Results: Group A showed a significant increase in the left ventricular developed pressure and coronary flow, and a modest restoration of ATP content. Pi/(Pi+Pcr) remained virtually constant. There were no significant changes in left ventricular developed pressure or coronary flow in groups B and C. There was a gradual decrease in tissue ATP content and slight increase in Pi/(Pi+Pcr). Conclusions: Adenosine improved cardiac performance without adverse effect on energy metabolism in microembolised hearts. Adenosine also restored the ATP stores in microembolised hearts. (Pi=inorganic phosphate; Pcr=phosphocreatine.) Cardiovascular Research 1992; 26 :851–856

1. Na+ influx into cultured vascular smooth muscle cells (VSMC) obtained from spontaneously hypertensive rats (SHR) and from Wistar-Kyoto rats (WKY) was measured. Na+ influx via the Na+/H+ exchange system was measured as the rate of 22Na+ influx into cultured VSMC sensitive to ethylisopropylamiloride (EIPA), a specific inhibitor of the exchange system. 2. The total 22Na+ influx rate in SHR was significantly higher than in WKY (6.08 +/- 0.16 vs 4.13 +/- 0.09 nmol/min per mg protein; P less than 0.001; n = 14). The EIPA (1 X 10(-4) mol/L)-sensitive 22Na+ influx rate in SHR was significantly higher than that in WKY (4.32 +/- 0.27 vs 2.17 +/- 0.14 nmol/min per mg protein; P less than 0.001; n = 14). There was no difference in EIPA-insensitive 22Na+ influx between SHR and WKY. The EIPA-sensitive 22Na+ influx rate into VSMC was significantly decreased in SHR but not in WKY by the addition of 1 X 10(-4) mol/L 1-(5-isoquinoline-sulfonyl)-methylpiperazine (H-7), an inhibitor of protein kinase C (PK-C). 3. These results suggest that the increase in Na+ influx in SHR may be due to elevation of the Na+/H+ exchange activity, and possible involvement of PK-C in the increased Na+/H+ exchange activity in VSMC from SHR.

Plasma levels of platelet-derived growth factor (PDGF) were measured in 24 normal control subjects, 31 patients with stable angina pectoris, 25 patients with unstable angina pectoris, and 31 patients with acute myocardial infarction (AMI) by a sensitive direct radioimmunoassay. The plasma PDGF level in normal control subjects was 273 +/- 25 pg/ml; there was no significant correlation between the plasma PDGF level and age. Plasma PDGF levels in patients with unstable angina pectoris and acute myocardial infarction were significantly lower than those in normal control subjects and patients with stable angina pectoris (p less than 0.05). In patients with acute myocardial infarction the plasma PDGF level in the chronic phase was significantly higher than that in the acute phase (p less than 0.05). These observations raise the possibility that PDGF is involved in the pathophysiology of ischemic heart disease.

We described a 37-year-old man with a subaortic "fibrous sac", admitted for congestive heart failure. On 2-dimensional echocardiography a saccular structure was seen to extend from the left coronary cusp of the aortic valve to the outflow tract of the left ventricle. By color Doppler imaging, a grade 3 aortic regurgitation was recognized. Aortic regurgitant flow was recorded from the left coronary cusp to the saccular lesion. When congestive heart failure became exacerbated, the repeat examination showed the regurgitant flow passing through the perforated bottom of this lesion and reaching the left ventricular cavity. On microscopic examination of the excised valve, capillary proliferation and inflammatory changes were recognized near the annular region of the left coronary cusp. The edge of the valve leaflet and the other 2 cusps were intact. It is likely that our patient had a mycotic aneurysm near the aortic ring. We speculate that aortic regurgitation followed inflammation. It dilated the left ventricular cavity and contributed to congestive heart failure. Inflammation also weakened the tissue near the annulus, causing it to protrude into the subaortic region thus forming a small aneurysm. It may have grown to become a large saccular structure under high aortic pressure. That is, it became a "giant" endocardial pocket with inflammatory process. Finally, the rupture of this sac caused a massive aortic regurgitation, exacerbating congestive heart failure.

Endothelin plays a role in the regulation of vascular tonus. Therefore, it has been hypothesized that increased production or release of endothelin or both may contribute to the pathogenesis of hypertension. To assess any changes in the plasma endothelin concentration in essential hypertension, plasma immunoreactive endothelin concentrations were measured in patients with essential hypertension.We measured plasma immunoreactive endothelin concentrations in 42 subjects with essential hypertension, 12 subjects with borderline hypertension, and 25 normotensive control subjects.The concentrations were higher in hypertensive patients than in borderline hypertensive patients and normotensive subjects (both p less than 0.05), although values in normotensives and hypertensives overlapped. Reverse-phase high-performance liquid chromatography (HPLC) and radioimmuno-assay showed two components of plasma endothelin, one corresponding to synthetic endothelin-1 (1-21) and the other corresponding to synthetic big endothelin (human, 1-38). The HPLC profile of plasma endothelin of hypertensive patients was the same as that of normotensive subjects. Hypertensives with reduced glomerular filtration rates or increased serum creatinine levels had higher plasma endothelin concentrations than hypertensive patients as a whole (p less than 0.05). Mean blood pressure and serum creatinine levels were correlated to plasma endothelin in the hypertensives. Correlation was negative between glomerular filtration rate and the endothelin level in the hypertensives.Plasma endothelin was elevated in many hypertensive patients with severe hypertension or renal involvement. Its major components were endothelin-1 and big endothelin.

The present study was designed to examine the effect of antihypertensive therapy on plasma and atrial concentration of atrial natriuretic peptides (ANP) in spontaneously hypertensive rats (SHR) by using alpha-methyldopa and hydralazine. Methyldopa and hydralazine treatment reduced blood pressure (P less than .05, P less than .05, respectively); however, ventricular weight was reduced by methyldopa (P less than .05) but not by hydralazine. Plasma ANP concentration in untreated SHR was higher than that observed in Wistar-Kyoto rats (WKY). Methyldopa treatment decreased plasma ANP concentration, but hydralazine treatment did not. Moreover, plasma ANP concentration and ventricular weight were positively correlated in untreated and treated SHR. The left atrial ANP concentration in untreated SHR was lower than that observed in WKY. Methyldopa treatment increased left atrial ANP concentration, but hydralazine treatment did not. These results suggest that the ANP release from the left atrium is chronically stimulated in adult SHR, and that a decrease in plasma ANP concentration by methyldopa treatment is, in part, associated with the decline of ANP release from the heart due to the reductions of blood pressure and cardiac hypertrophy.

The mechanism and prognostic implications of Q wave regression following transmural acute myocardial infarction (AMI) were assessed in 54 patients. Of these subjects, 14 lost their Q waves. Exercise myocardial thallium-201 (201Tl) scintigraphy and two-dimensional echocardiography were performed before the patients were discharged from hospital. Two-dimensional echocardiography and electrocardiography were simultaneously repeated about 18 months after AMI. Both the relative 201Tl activity in the infarcted area and the improvement of echocardiographic wall motion index were higher in patients who had lost their Q waves than in those with retained Q waves (70 +/- 14% vs 58 +/- 13%, p less than 0.01; 5.2 +/- 3.0 vs 2.0 +/- 3.4, p less than 0.01, respectively). The prevalence of post-infarction angina pectoris was significantly higher in the former (29% vs 0%, p less than 0.01). We concluded that remnants of viable myocardial muscle might be responsible for Q wave regression following transmural acute myocardial infarction, and the prevalence of post-infarction angina pectoris was high among these patients.

The acute effects of endothelin, a potent vasoconstrictor peptide, were investigated on renal hemodynamics, blood pressure and heart rate in conscious and unrestrained DOCA-salt hypertensive rats to compare with those in normotensive, sham-operated rats. The plasma concentration of immunoreactive endothelin was measured following the administration of endothelin, 0.4 nmole IV. After a dose of 1 nmole/kg IV, the blood pressure fell transiently and then rose gradually, while the renal blood flow remained decreased throughout the observation period. Both the blood pressure elevation and the renal blood flow decline in DOCA-salt hypertensive rats exceeded that in controls. In both experimental groups the arterial plasma endothelin concentration decreased rapidly after the peak was achieved. The disappearance of endothelin from plasma was significantly delayed in the DOCA-salt hypertensive rats. These findings suggest that the marked increase in blood pressure and the altered renal hemodynamics induced by endothelin in DOCA-salt hypertensive rats are due in part to a decrease in endothelin clearance.

Background: Interferon (IFN) improves hepatic inflammation/fibrosis and reduces the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CH-C). However, HCC develops in some patients who have a sustained virological response (SVR) to IFN therapy. We designed this study to establish a follow-up protocol for patients with CH-C who have SVR to IFN therapy. Methods: We retrospectively studied 1124 patients with CH-C who received IFN. Results: HCC developed in 3.5% of patients with SVR to IFN. As compared with SVR patients without HCC, SVR patients with HCC were predominantly male (P=0.003), older at the initiation of IFN therapy (P=0.002), and at a more advanced histologic stage of disease (P

Brain natriuretic peptide (BNP) is secreted through the coronary sinus of the human heart. The purpose of this study was to determine whether BNP secretion from the heart is stimulated by exercise and to examine the relationship between pulmonary arterial BNP concentrations and hemodynamic measurements, especially cardiopulmonary hemodynamics, during exercise in patients with essential hypertension. The exercise protocol consisted of three fixed workloads (25, 50, 75 W) on a bicycle ergometer in the supine position. The mean pulmonary arterial BNP level at rest was 14.8 +/- 4.1 pg/mL, and BNP values gradually increased with higher stages of exercise. At the maximum exercise stage, the BNP value increased to 40.9 +/- 6.5 pg/mL. Close correlations of pulmonary arterial pressure (PAP) and pulmonary arterial wedge pressure (PAWP) with pulmonary arterial BNP level were observed at four points at rest and during each stage of exercise. In contrast, heart rate, mean blood pressure, cardiac index (CI), and stroke index (SI) were not correlated with BNP values. Results suggest that cardiac secretion of BNP was increased during exercise in essential hypertensive subjects, and the observed increase of BNP may be related to elevated PAP and PAWP. The enhancement of BNP secretion during exercise in these patients may reflect increased redistribution of blood to the cardiopulmonary compartment.

The present study was designed to examine the possible influence of hypoxia on plasma immunoreactive (ir) endothelin-1 concentrations in anesthetized rats. Plasma ir-endothelin-1 concentration, blood pressure, heart rate, and arterial gas levels were measured 1 and 2 hours after exposure to normoxic (20% O2), mildly hypoxic (16% O2), and severely hypoxic (12% O2) gas. Mean blood pressure and heart rate were significantly decreased and the plasma ir-endothelin-1 concentration was significantly increased in severely hypoxic rats after both 1 and 2 hours. In mildly hypoxic rats, the plasma ir-endothelin-1 concentration was also increased, but this value was not statistically significant. The plasma ir-endothelin-1 concentration was inversely correlated with arterial blood PO2 in the three study groups (normoxic, mildly hypoxic, and severely hypoxic rats) after 1 hour (n = 18, r = -.74, P less than .01), and after 2 hours (n = 18, r = .71, P less than .01). Our results indicate that severe hypoxia increased the plasma ir-endothelin-1 level in anesthetized rats. The observed increase in plasma ir-endothelin-1 level may represent a compensatory mechanism against the blood pressure reduction associated with severe hypoxia.

The present study was designed to examine the effect of synthetic rat endothelin, a novel potent vasoconstrictor isolated from endothelial cells, on the release of immunoreactive atrial natriuretic factor (ir-ANF) in anesthetized rats. Systemic blood pressure and plasma ir-ANF concentration were measured at 1, 3, 5, 15, 30, and 60 minutes after rat endothelin administration (0.01, 0.10, 1.00 nmol/kg body weight [BW]). Administration of rat endothelin caused a long-lasting increase in mean blood pressure and produced a dose-dependent increase in plasma ir-ANF that peaked 5 minutes after the injection and remained higher than the basal value 60 minutes after the injection. These data suggest that administration of pharmacological doses of rat endothelin produces a profound release of ir-ANF into the circulation, which may cause vasodilation and diuresis to antagonize the effect of endothelin.

BACKGROUND: H1 antihistamines have been shown to have an antitussive effect in patients with asthma, postnasal drip, and allergic rhinitis. No study has been performed to determine whether orally administered H1 antihistamines can reduce the number of coughs induced by stimulation of cough receptors in non-asthmatic patients with chronic dry cough. METHODS: The effect of loratadine (10 mg) on the number of coughs induced by ultrasonically nebulised distilled water (UNDW) was examined in 10 patients with nasal disease and in seven patients with unexplained chronic cough using a randomised, double blind crossover method. Eleven normal volunteers were also studied. Each subject inhaled UNDW for one minute, and the numbers of coughs during the one minute inhalation and the 30 seconds following it were counted. RESULTS: There was no difference in the results of pulmonary function tests performed before and one minute after UNDW inhalation for either patients or normal subjects. There was also no significant difference between the results of pulmonary function tests before or after oral administration of loratadine. Loratadine significantly reduced the number of coughs in patients with nasal disease and in those with unexplained chronic cough, but not in normal subjects. CONCLUSIONS: The H1 antihistamine loratadine reduces cough induced by UNDW. The release of histamine may contribute to the chronic cough in patients with unexplained chronic cough or nasal disease.

Interleukin-8 (IL-8) belongs to the family of chemotactic cytokines and has been shown to activate neutrophils in vitro and in vivo. In this study, we measured IL-8 concentration in the serum of patients with pulmonary emphysema or bronchial asthma. IL-8 concentration in serum of emphysema patients was significantly higher than in asthmatics; in emphysema patients it was significantly correlated with the smoking index and the annual decrease of FEV1.0. In asthmatics IL-8 concentration was below the level of detection, but was markedly increased during exacerbation of asthma. Our findings suggest that IL-8 may be one of the causal factors in these diseases.

We investigated the effect of chronic administration of an angiotensin II type-1 receptor antagonist in the development of heart failure due to volume overload in rats.Aortocaval fistula (AVF), a model of volume overloaded heart failure, was induced in rats by our newly developed technique using a simple and rapid 18-gauge needle multipuncture. After 3 weeks of oral administration of an angiotensin II receptor antagonist TCV-116, 1 mg/kg per day, we evaluated the hemodynamics, heart weight, and degree of left ventricular dilatation. We also compared the effect of TCV-116 with that of an angiotensin-converting enzyme inhibitor delapril, 1 g/L in drinking water.AVF heart failure produced by our technique exhibited significant increases in the left ventricular end-diastolic pressure (LVEDP) (12 = 1 vs 4 +/- 1 mmHg, p0.05), right atrial pressure (RAP) (5.0 +/- 0.6 vs 1.0 +/- 0.4 mmHg, p0.05), right ventricular systolic pressure (RVSP) (58 +/- 6 vs 33 +/- 1 mmHg, p0.05), left ventricular weight (LVW) (3.00 +/- 0.13 vs 2.09 +/- 0.04 g/kg BW, p0.05), right ventricular weight (RVW) (0.93 +/- 0.05 vs 0.59 +/- 0.01 g/kg BW, p0.05), and left ventricular end-diastolic volume index (LVEDVI) (2.55 +/- 0.14 vs 0.80 +/- 0.12 ml/kg BW, p0.05) as compared with these values in sham-operated rats. There were no differences in shunt ratio between untreated and TCV-116- and delapril-treated AVF groups. TCV-116 improved these hemodynamics, as did delapril (TCV-116 vs delapril: LVEDP 8 +/- 1 vs 8 +/- 1, RAP: 3.8 +/- 0.6 vs 2.3 +/- 1.4, RASP: 50 +/- 2 vs 46 +/- 3, LVW: 2.53 +/- 0.11 vs 2.52 +/- 0.15, RVW: 0.80 +/- 0.04 vs 0.77 +/- 0.06, LVEDVI: 1.67 +/- 0.15 vs 1.70 +/- 0.17).These results suggest that AVF rats with volume overload produced by a new multipuncture method exhibit both right- and left-side heart failure. Angiotensin II type-1 receptor antagonist as well as angiotensin converting enzyme inhibitor attenuate the development of this type of heart failure in rats.

The purpose of this study was to examine the cardiac phenotype and remodeling after myocardial infarction and the effect of the angiotensin II type 1 (AT1) receptor antagonist (TCV-116) on the gene expression. Myocardial infarction in rats was produced by ligation of the coronary artery. TCV-116 (10 mg/kg/day) was administered orally to rats from 1 day after myocardial infarction. At 1, 2 and 3 weeks after myocardial infarction, blood pressure and heart rate were measured, and the heart was removed. The left ventricle was measured for infarct size and weight, and then the total RNA from the non-ischemic left ventricle was extracted. mRNAs in the non-ischemic left ventricle were measured by Northern blot analysis. The weight of the non-ischemic left ventricle was significantly increased 3 weeks after infarction. This was completely prevented by TCV-116 treatment. mRNA levels for beta-myosin heavy chain (beta-MHC), atrial natriuretic polypeptide (ANP), collagen types I and III and transforming growth factor-beta 1 (TGF-beta 1) in the non-ischemic left ventricle were increased by a factor of 3.0, 6.7, 7.9, 4.0 and 1.4 (P0.01), respectively, 1 week after infarction. There was no increase in alpha-skeletal actin mRNA at 1 and 2 weeks, but it was increased by a factor of 2.9 (P0.05) at 3 weeks. On the other hand, there was no change in alpha-MHC mRNA during the 3 weeks. TCV-116 significantly suppressed the increased gene expression of beta-MHC and alpha-skeletal actin in the non-ischemic myocardium at all time points, and also suppressed the expression of ANP at 2 and 3 weeks. However, TCV-116 failed to inhibit the expression of collagen I and III mRNAs at 1 and 3 weeks. These results show that myocardial infarction causes a rapid shift of myocytes to fetal phenotype and a rapid activation of collagen genes in the non-ischemic myocardium. AT1 receptor may be responsible for the phenotypic modulation of myocytes following myocardial infarction.

Objective: The aims were (1) to investigate the effect of hypertension on left ventricular dilatation and haemodynamic alterations following acute myocardial infarction in spontaneously hypertensive rats (SHR) and normotensive rats (WKY); (2) to compare haemodynamic indices between the two groups; (3) to assess whether the angiotensin II type 1 receptor antagonist (AIIA), TCV-116, prevented left ventricular dilatation after myocardial infarction; and (4) to compare the effect of AHA with that of the angiotensin converting enzyme (ACE) inhibitor, delapril. Methods: Myocardial infarction was produced in SHR and WKY by coronary artery ligation. Haemodynamic measurements were obtained three weeks later in rats that had been treated from the next day after the operation for three weeks with TCV-116 (1 mg·kg−1·d−1) or delapril (1 g·litre−1 in drinking water), and in untreated controls. Results: After myocardial infarction, left ventricular systolic pressure, mean arterial pressure, left ventricular end diastolic volume index (LVEDVI), right ventricular weight, and left ventricular weight were greater in SHR than in normotensive rats. Right ventricular weight, left ventricular end diastolic pressure, and LVEDVI correlated positively with infarct size in both SHR and WKY and these slopes were steeper in SHR than in WKY (P < 0.05). TCV-116 and delapril each significantly attenuated the increases in left ventricular end diastolic pressure, left ventricular weight, right ventricular weight, and LVEDVI following myocardial infarction in both in WKY and SHR, and shifted pressure-volume curve significantly to the left. Conclusions: Hypertension accelerates left ventricular dilatation and haemodynamic alterations following myocardial infarction in rats. These effects are attenuated by an angiotensin II type 1 receptor antagonist as well as by an ACE inhibitor.

Angiotensin II (Ang II) and nitric oxide (NO) regulate a variety of physiological functions. In this study, we suggest that inhaled Ang II produces an initial bronchodilation apparently by stimulating NO production via AT 1 receptors. Also, we demonstrate that following the initial bronchodilation, Ang II causes bronchoconstriet ion in the guinea pig, also via AT 1 receptors. Both of the findings are important for our understanding of airway functions induced by Ang II.

Thrombomodulin (TM) is a membrane protein present in the vascular endothelium. It has also been found in human plasma, within which, however, its pathological functions have not been clearly described. In this study, the plasma TM concentrations in 19 asthmatic patients were determined by sandwich enzyme immunoassay using two monoclonal antibodies for human TM. The concentration of plasma TM in exercise-induced asthma (EIA)-positive asthmatic patients was significantly increased by exercise challenge. In addition, for these patients a positive correlation was found between the severity of EIA and the degree of change in plasma TM induced by exercise challenge. These findings suggest that the increase in influx of TM into the plasma in EIA-positive asthmatics may be due to generalized pulmonary endothelial damage following exercise challenge.

It is widely accepted that perfusion defects in 3 to 4-h delayed images in exercise thallium-201 (201Tl) myocardial scintigraphy underestimate the viability of myocardium in the infarct region. In the present study, to examine the contribution of the condition of myocardium which demonstrates reverse redistribution in resting scintigraphy to the insufficiency of redistribution in the 4-h delayed image in exercise scintigraphy, we performed exercise and resting 201Tl myocardial single-photon emission computed tomography in 58 patients with acute myocardial infarction and a single diseased coronary artery. Twenty eight patients demonstrated reverse redistribution (group RR) and 28 showed a fixed defect (group FD) in resting scintigraphy. Redistribution in the 4-h delayed image in exercise scintigraphy was significantly more insufficient in group RR than in group FD (p < 0.01), and the degree of the insufficiency of redistribution in exercise scintigraphy closely correlated with the degree of reverse redistribution in resting scintigraphy (r = 0.79, p < 0.001). We conclude that in patients with acute myocardial infarction, the condition of myocardium which demonstrates reverse redistribution in resting myocardial scintigraphy is related to the insufficiency of redistribution in the delayed image in exercise scintigraphy.

Beta-adrenergic receptor blockade reduces the mortality rate after acute myocardial infarction (AMI) in humans. However, the effects of beta blockade on left ventricular remodeling remain unknown. Therefore, in the present study we investigated the effect of prolonged beta-adrenergic receptor blockade with atenolol on left ventricular remodeling following AMI in rats. Myocardial infarction (MI) was produced in Wistar-Kyoto rats by ligating the coronary artery. Four groups of rats were studied: sham-operated (n = 10); atenolol (1 g/l in drinking water) treated sham-operated (n = 8); untreated MI (n = 11); atenolol treated MI (n = 10). Hemodynamic measurements were made about 3 weeks after the operation. Infarct size was similar in treated and untreated MI rats (31.2 +/- 2.5% cf. 33.5 +/- 2.0%). MI rats were characterized by increases in left ventricular end-diastolic pressure (LVEDP), right atrial pressure (RAP), right ventricular systolic pressure (RVSP), and left ventricular end-diastolic volume index (LVEDVI), as compared with sham-operated rats. In sham-operated rats, prolonged beta-adrenergic receptor blockade produced only a reduced HR. Atenolol-treated MI rats had a significantly higher LVEDP, RAP and LVEDVI than did rats with untreated MI. Prolonged beta-adrenergic receptor blockade with atenolol appeared to promote left ventricular remodeling after AMI. Thus, the treatment of AMI with beta-adrenergic receptor blockade in the clinical setting should be evaluated with respect to ventricular remodeling during prolonged therapy.

We investigated the effects of a macrolide antibacterial, roxithromycin, on the generation of free radicals by peripheral polymorphonuclear leukocytes (PMNs) and on the severity of bronchial hyperresponsiveness. Ten asthmatic patients were treated for 3 months with roxithromycin, 150 mg orally once daily; such treatment significantly reduced the production of superoxide anion by PMNs (p = 0.0029) and reduced the bronchial hyperreactivity (p = 0.0016), as compared with results in healthy controls. Most of the patients required at least 2 months of treatment with roxithromycin for clinical improvement. We conclude that long-term, low-dose administration of roxithromycin may be useful in treatment of patients with bronchial asthma.

Objective: The aim was to investigate changes in cardiac transforming growth factor β1, (TGF-β1), fibronectin, and collagen types I and III mRNA levels in isoprenaline induced cardiac hypertrophy, and the effects of delapril, an angiotensin converting enzyme inhibitor, and TCV-116, an angiotensin II type 1 receptor antagonist, on this hypertrophy. Methods: Rats were continuously infused with saline and low or high dose of isoprenaline (0.5 or 3 mg·kg−1·d−1) by an osmotic minipump for 24 h, 48 h or 7 d. Treatment with delapril (100 mg·kg−1·d−1) or TCV-116 (10 mg·kg−1·d−1) was started from 1 d before the implantation of minipump to the end of experiments. After the experimental periods, left ventricular weight was measured and the mRNA was extracted and measured by northern blot hybridisation. Results: Both low and high doses of isoprenaline infusion resulted in increased left ventricular weight. With low dose infusion, cardiac TGF-β1, mRNA was not stimulated throughout the infusion, while fibronectin mRNA and collagen types I and III mRNAs began to increase at 24 h and 48 h, respectively, after the infusion. In high dose isoprenaline infusion, not only was extracellular matrix mRNA but also TGF-β1, mRNA in the ventricle significantly increased. TCV-116 prevented isoprenaline induced left ventricular hypertrophy as much as delapril. However, with delapril or TCV-116, the time course of TGF-β1 and ECM mRNA expression was almost similar to isoprenaline infusion only. Conclusions: The extracellular matrix mRNA expressions are enhanced in myocardial hypertrophy by a low dose of isoprenaline, which is probably not mediated by TGF-β1. The preventive effects of TCV-116 on this hypertrophy indicate that the inhibitory effects of angiotensin converting enzyme inhibitor on cardiac hypertrophy are due to the inhibition of angiotensin II and that angiotensin II type I receptor plays an important role in isoprenaline induced left ventricular hypertrophy. However, the renin-angiotensin system may play a minor role in isoprenaline induced cardiac fibrosis. Cardiovascular Research 1994; 28 :1835-1842

A multicenter, open-label trial in Japan examined the efficacy, safety, and optimal dose of monatepil (AJ-2615) as monotherapy and in combination therapy with angiotensin-converting enzyme (ACE) inhibitors or beta-blockers. Patients with essential hypertension who had never been treated or had been refractory to conventional antihypertensive agents were enrolled in the trial. During a 4-week control period patients assigned to monotherapy received placebo and those assigned to combination therapy received an ACE inhibitor or beta-blocker and placebo. Patients with systolic blood pressure (BP)or = 160 mm Hg and diastolic BPor = 95 mm Hg at the end of the control period were enrolled in the study. The initial dose of monatepil was 30 mg/day in monotherapy and 15 mg/day in combination therapy; the daily dose was titrated to 60 mg/day according to the antihypertensive response. The treatment period was 8 to 12 weeks. Blood pressure decreased from 168 +/- 8/100 +/- 6 to 142 +/- 9/85 +/- 7 mm Hg (SD) with monatepil monotherapy, from 171 +/- 11/102 +/- 6 to 141 +/- 9/84 +/- 6 mm Hg in combination with ACE inhibitors, and from 175 +/- 13/102 +/- 7 to 153 +/- 21/91 +/- 9 mm Hg in combination with beta-blockers (P.001). When patients in whom mean BP decreased byor = 13 mm Hg were defined as responders, the response rate was 80.4%, 78.1%, and 51.6% in the respective groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Restoration of the ATP level after brief ischemia is limited by slow de novo ATP synthesis and substrate loss in a salvage pathways for ATP synthesis, and complete recovery requires several days in the stunned heart. Adenosine is a substrate for myocardial ATP synthesis. We measured myocardial ATP in both ex vivo and in vivo experiments by 31P magnetic resonance spectroscopy (31P-MRS) and investigated the time course of ATP content recovery after application of adenosine. Guinea-pig perfused hearts were subjected to 30 min of global ischemia and reperfused for 3 h with 50 microM adenosine. The ATP level increased from 54 +/- 5% to 117 +/- 4% of the pre-ischemic value (p < 0.01). In dogs, we occluded the left anterior descending coronary artery for 40 min to produce regional ischemia. Afterwards, we administered 100 mumol/h adenosine into the left ventricle for 2 h. ATP levels increased from 63 +/- 4% to 77 +/- 5% of the pre-ischemic value with adenosine (p < 0.05). However, ATP levels did not increase for a few hours after reperfusion both ex vivo and in vivo. Our 31P-MRS studies demonstrated that brief ischemia depressed ATP levels and that administration of adenosine accelerated ATP formation in post-ischemic hearts.

We investigated the protective effect of angiotensin II (Ang II) type 1 receptor antagonist on myocardial ischemia-reperfusion injury and the role of exogenous Ang II to this injury in perfused hearts. We orally administered TCV-116 (Ang II type 1 receptor antagonist) and delapril (angiotesin converting enzyme inhibitor) to Wistar rats for 1 week and measured the immunoreactive cardiac Ang II. Immunoreactive cardiac Ang II (pg/gm tissue) was 14.3 ± 2.0 in control group, 11.8 ± 0.8 in TCV-116-treated group, and 7.3 ± 0.6 in delapril-treated group (p < 0.05) compared to TCV-116-treated group; p < 0.01 compared to control group). The 15 hearts (five rats in each group) were perfused by a Langendorff method and global ischemia was maintained for 30 min. Both TCV-116 and delapril were found to improve postischemic cardiac function and decrease reperfusion creatine kinase (CK) release. Ang II injection before ischemia worsened postischemic cardiac function and increased reperfusion CK release. Only TCV-116 prevented this injury. These data indicated that TCV-116 Ang II type 1 receptor antagonist was effective against myocardial ischemia-reperfusion injury, and exogenous Ang II accerelated this injury through Ang II type 1 receptor.

We compared the effects of 2 inotropic agents, dobutamine and isoproterenol on regional coronary blood flow, contractile function, hemodynamics and levels of phosphate compounds in the acutely ischemic canine heart. Dogs were instrumented to determine regional coronary blood flow (non-radioactive microsphere method), contractile function (sonomicrometry), and hemodynamics. Myocardial phosphate compounds were measured simultaneously by the phosphate-31 (31P) magnetic resonance spectroscopic technique. Both drugs augmented the global performance of the heart, but produced no significant improvement in regional contractile function in the ischemic region. Isoproterenol significantly increased the ratio of inorganic phosphate to phosphocreatine in the ischemic region, as compared to dobutamine. However, no significant differences were seen in myocardial lactate consumption with inotropic stimulation between the 2 groups. 31P magnetic resonance spectroscopy could be used to differentiate between the effects of dobutamine and isoproterenol on energy metabolism in ischemic myocardium despite the lack of significant differences in regional function and myocardial lactate consumption. The significant tachycardia without an augmentation of systemic blood pressure induced by isoproterenol may account for this unfavorable effect on myocardial energy metabolism.

Angiotensin II is well known to have a cardiotoxic effects. However, it is still unclear whether exogenous angiotensin I or angiotensin II has a deleterious effect on myocardial ischemia-reperfusion injury. To examine this deleterious effect, we administered angiotensin I and angiotensin II to perfused hearts before ischemia, and measured creatine kinase (CK) release and cardiac function during subsequent reperfusion. Wistar Kyoto rats were used and the hearts were perfused by the Langendorff technique at a constant flow (10 ml/min). Seven hearts were perfused for 20 min and then subjected to 15 min of global ischemia (Control). In the experimental groups, during the 5 min before ischemia, we administered 100 ng /ml angiotensin I (Ang I; n=9), 1 μg/ml enalaprilat (ACEI; n=5), both agents (ACEI+Ang I) (n=6), or 10 ng/ml angiotensin II (Ang II; n = 6) . The perfusates were then sampled to measure angiotensin II. After 15 min of ischemia, the hearts were reperfused with control perfusate. Throughout the 20 min of reperfusion, the effluent was collected to measure cumulative CK release. Angiotensin I increased coronary perfusion pressure (CPP) by 32±4 mmHg, however, the angiotension converting enzyme inhibitor inhibited the increase of CPP by angiotension I (11±1 mmHg) (p

The blood pressure was decreased after chronic treatment with enalapril, MK-954, and hydralazine in deoxycorticosterone acetate (DOCA)-salt-induced malignant hypertension of spontaneously hypertensive rats (SHR); however, ventricular weight and plasma brain natriuretic peptide (BNP) concentration were decreased after enalapril and MK-954 but not after hydralazine. The BNP secretory rates from the ventricle in enalapril- and MK-954-treated DOCA-salt SHR were decreased to approximately 50% of those in untreated DOCA-salt SHR. The BNP secretory rate from the ventricle was positively correlated with ventricular weight in untreated and treated DOCA-salt SHR. In contrast, acute administration of captopril or MK-954 did not decrease the BNP secretory rate from the heart. Results suggest that the decrease in plasma BNP after enalapril and MK-954 is attributed to a decline in the secretion from the ventricle but not from the atrium. The reduction in ventricular mass appeared to be related to this decline.

The role of nitric oxide in the coronary vasodilation caused by acetylcholine or bradykinin in perfused guinea-pig hearts was investigated by using 1 mM L-NG-nitro arginine (L-NNA), a specific inhibitor of the formation of nitric oxide from L-arginine. L-NNA increased coronary perfusion pressure and inhibited the vasodilator responses to acetylcholine and bradykinin. The extent of vasodilation was evaluated in terms of the reduction of perfusion pressure from the initial baseline that had been induced by U-46619. L-NNA markedly attenuated coronary vasodilation caused by 5 x 10(-11) mol of acetylcholine from 15 +/- 1 to 4 +/- 1 mmHg (p < 0.01), and that caused by 1 x 10(-11) mol bradykinin from 21 +/- 2 to 8 +2- 1 mmHg (p < 0.01). On the other hand, L-NNA only weakly inhibited coronary vasodilation caused by 5 x 10(-7) mol of acetylcholine from 40 +/- 3 to 27 +/- 4 mmHg (p < 0.01), and that caused by 1 x 10(-9) mol of bradykinin (from 39 +/- 2 to 32 +/- 2 mmHg (p < 0.01). L-NNA had no effect on the vasodilation induced by 1 x 10(-8) mol of bradykinin. Ibuprofen, cyclooxygenase inhibitor, did not affect these vasodilatory responses. These results suggest that the formation of nitric oxide from L-arginine in coronary resistance vessels helps to regulate vascular tone, and that prostaglandins are not related to the vasodilatory responses to acetylcholine or bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined the gene expression of angiotensin AT1A receptors in aortic endothelial cells of cyclosporine induced hypertensive rats using reverse transcribed polymerase chain reaction method. The gene expression of angiotensin AT1A receptors in aortic endothelial cells of cyclosporine induced hypertensive rats showed a two-fold increase when compared with that in normotensive control rats. These results raise a possibility that the up-regulation of endothelial angiotensin AT1A receptors participates in the pathogenesis of cyclosporine induced hypertension.

To estimate the size of myocardial infarction, serum troponin T concentration was measured in 34 patients with acute myocardial infarction. Left ventriculography, 2-dimensional echocardiography and resting 201thallium myocardial single photon emission computed tomography (SPECT) were performed about 4 weeks after the onset of myocardial infarction and used for correlation with the late serum troponin T peak concentration which occurred on the 3rd to 5th day after onset. Both left ventricular ejection fraction (LVEF) obtained from left ventriculography and wall motion index (WMI) obtained from 2-dimensional echocardiography were inversely related to late troponin T peak value (LVEF: r = 0.68, p < 0.001, WMI: r = 0.70, p < 0.001). Extent score (ES) and severity score (SS), which were estimated from the initial resting 201thallium SPECT image, showed excellent linear correlations with late troponin T peak concentrations (ES: r = 0.77, p < 0.001, SS: r = 0.66, p < 0.001). This correlation was present both in patients with an early troponin T peak on day 1 (group A-16 patients) and in those without an early peak (group B-10 patients). Thus, late troponin T peak concentration can be used to predict infarct size regardless of the kinetics of its appearance in serum.

Objective: The aim was to evaluate regional coronary blood flow, contractile function, and concentration of phosphate compounds with inotropic stimulation in moderately ischaemic canine hearts. Methods: Dogs were prepared with instrumentation for the determination of regional coronary blood flow (non-radioactive microsphere method), contractile function (sonomicrometry), and haemodynamics. Myocardial phosphate compounds were measured simultaneously by the phosphorus-31 magnetic resonance spectroscopic technique. Results: In the non-ischaemic condition, dobutamine increased regional coronary blood flow and enhanced contractile function with no significant changes in myocardial phosphate compounds. After constricting the left anterior descending coronary artery, dogs were divided into two groups according to their heart beat response to dobutamine, classified as no pronounced tachycardia with dobutamine (group NT), and pronounced tachycardia (group T). In group NT, dobutamine increased regional coronary blood flow and improved regional contractile function with no significant effect on myocardial phosphate compounds. In group T, dobutamine failed to increase regional coronary blood flow or to improve contractile function, but there was a significant increase in the inorganic phopshate to creatinine phosphate ratio. Conclusions: Dobutamine increased coronary blood flow and augmented contractile function without significant changes in phosphate compounds in the moderately ischaemic heart, when pronounced tachycardia was not induced. The augmentation of contractile function occurred without prominent improvement in energy metabolism. Cardiovascular Research 1993; 27 :1435-1443

Background: Neuropeptide Y (NPY) and neutral endopeptidase have been shown to regulate the response of airway smooth muscle. However, their interactions have not been studied. Methods: To determine the role of NPY and endogenous neutral endopeptidase in regulating the effects of NPY, we investigated the effects of NPY and a neutral endopeptidase inhibitor, phosphoramidon, on the contractile response of isolated human bronchial segments to electrical field stimulation (EFS). Results: Concentrations of up to 10 −6 mol/L of NPY did not change resting tension. NPY inhibited the cholinergic contractions induced by EFS at 5 Hz dose-dependently. Phosphoramidon (10 −5 mol/L) enhanced the inhibitory effect of NPY on EFS-induced contractions at 5 Hz. NPY (3 × 10 −7 mol/L) shifted the frequency-response curve for EFS (1 to 50 Hz) to the right and significantly increased the mean logarithm of frequency that produced 50% of maximal contraction (control: 0.54 ± 0.07 versus NPY: 0.79 ± 0.09, p −5 mol/L) did not affect the frequency response to EFS, but enhanced the inhibitory effect of NPY (3 × 10 −7 mol/L) on frequency response to EFS, resulting in a significant increase in the mean logarithm of frequency that produced 50% of maximal contraction (NPY: 0.79 ± 0.09 versus NPY plus phosphoramidon: 1.18 ± 0.15, p −7 mol/L) did not affect the response of tissues to exogenously applied acetylcholine. Conclusions: These observations suggest that NPY inhibits the output of acetylcholine from nerve endings and that endogenous neutral endopeptidase modulates the effect of NPY in the human airway by inactivating this peptide.