Activation of adenosine receptors before ischemia enhances tolerance against myocardial stunning in the rabbit heart.

OBJECTIVES: This study examined whether stimulation of adenosine receptors before ischemia enhances myocardial resistance to stunning in vivo. BACKGROUND: We previously demonstrated the attenuation of myocardial stunning by ischemic preconditioning through adenosine receptor activation in rabbits. METHODS: 1) To confirm the efficacy of an intravenous infusion of adenosine to stimulate adenosine receptors in the heart, we assessed the effect of an adenosine infusion on the inotropic response to an isoproterenol challenge. 2) Myocardial stunning was induced by 10 min of coronary occlusion and reperfusion. The regional thickening fraction was monitored by an epicardial Doppler sensor. Rabbits were pretreated with either no drug (control group), adenosine, 8-phenyltheophylline or a combination of 8-phenyltheophylline plus adenosine. RESULTS: An intravenous infusion of adenosine at 0.15 mg/kg body weight per min attenuated by 50% the elevation of left ventricular dP/dtmax by isoproterenol (0.075 microgram/kg per min). The same dose of adenosine infused for 15 min before ischemia significantly improved the postischemic recovery of the thickening fraction, and the thickening fraction at 30 min reperfusion was 76.8 +/- 3.3% (mean +/- SE) of the baseline value, which was significantly higher than the control value (42.9 +/- 4.5%). The relation between thickening fraction and systolic left ventricular pressure after reperfusion was shifted toward higher thickening fraction by adenosine. This beneficial effect of adenosine was not detected in rabbits given 8-phenyltheophylline before adenosine, and 8-phenyltheophylline-treated rabbits showed a time course of thickening fraction similar to that in the control group. CONCLUSIONS: An intravenous infusion of adenosine is capable of protecting rabbit hearts against stunning through adenosine receptor activation.

Captopril potentiates the myocardial infarct size-limiting effect of ischemic preconditioning through bradykinin B2 receptor activation.

OBJECTIVES: To investigate the role of kinin in preconditioning against infarction, the present study assessed the effect of captopril, a kininase II inhibitor, on preconditioning and arterial plasma kinin levels. BACKGROUND: Recent studies suggest a possible contribution of kinin to preconditioning against infarction. However, its role and the site of kinin production remain uncharacterized. METHODS: Six groups of rabbits (n = 6 to 13) underwent 30-min coronary occlusion and 3-h reperfusion. The infarct size and area at risk were determined by tetrazolium staining and fluorescent particles, respectively. Arterial blood was sampled under baseline conditions, before the 30-min ischemia and after reperfusion for radioimmunoassay of the kinin level. RESULTS: Infarct size expressed as a percentage of area at risk (%IS/AR) was 42.9 +/- 2.9% (mean +/- SEM) in the control group, 34.5 +/- 3.3% in the group preconditioned with 2 min of ischemia/5 min of reperfusion and 41.7 +/- 5.1% in the group given captopril (1 mg/kg body weight) alone before the 30-min ischemia. These %IS/AR values were not significantly different between the three groups. However, a combination of captopril and subsequent preconditioning with 2 min of ischemia markedly limited %IS/AR to 21.2 +/- 2.4%. This potentiation of 2 min of preconditioning by captopril was not observed when 2 micrograms/kg body weight of Hoe 140, a specific bradykinin B2 receptor antagonist, was administered before preconditioning (%IS/AR = 41.2 +/- 5.7%), whereas Hoe 140 alone did not modify infarct size (%IS/AR = 38.5 +/- 5.1%). Arterial plasma kinin levels were comparable between the control rabbits, the group given captopril alone and the group that received captopril plus 2 min of preconditioning at baseline (3.8 +/- 1.0, 6.3 +/- 1.9 and 5.2 +/- 1.7 pg/ml, respectively), and there was no significant change in kinin levels after the captopril injection or the combination of captopril plus 2 min of preconditioning. CONCLUSIONS: The present results indicate that captopril is capable of potentiating preconditioning without increasing the arterial kinin level and that the beneficial effect of captopril can be inhibited by Hoe 140. These findings support the hypothesis that kinin produced locally in the heart during preconditioning may contribute to the cardioprotective mechanism through bradykinin receptor activation.

Limitation of myocardial infarct size by adenosine A1 receptor activation is abolished by protein kinase C inhibitors in the rabbit.

OBJECTIVE: The aim was to test whether infarct size limitation by adenosine A1 receptor activation is mediated by protein kinase C. METHOD: In the first series of experiments, myocardial infarction was induced in rabbits under pentobarbitone anaesthesia by 30 min coronary artery occlusion and 3 h reperfusion. Rabbits were pretreated with no drugs (control). 1 mg.kg-1 of R(-)N6-2-phenylisopropyl adenosine (PIA), 50 micrograms.kg-1 of staurosporine (Stauro), 2.5 mg.kg-1 of polymyxin B (PolyB), and a combination of PIA and either Stauro or PolyB. Infarct size and the area at risk were determined by tetrazolium staining and fluorescent particles, respectively. In the second series of experiments, the inotropic response to 4 beta-phorbol 12-myristate 13-acetate (PMA) was assessed in rabbits with and without pretreatment using the same doses of Stauro and PolyB as those in the first series of experiments. RESULTS: Infarct size expressed as percent of area at risk (%IS/AR) was significantly smaller in the PIA treated group than in the control: %IS/AR = 19.0(SEM 2.4)% v 37.7(4.0)%, P < 0.05. However, %IS/AR in the groups given Stauro [35.0(4.2)%], PolyB [37.9(3.2)%], PIA plus Stauro [34.9(3.9)%], and PIA plus PolyB [36.3(3.3)%] did not differ from the control value. PMA at the dose of 0.02 and 0.05 micrograms.kg-1 caused a dose dependent increase of the left ventricular dP/dtmax in the untreated rabbits. Such a positive inotropic response to PMA was not detected in rabbits pretreated with Stauro or PolyB, suggesting that the doses of the protein kinase C inhibitors were appropriate to block protein kinase C in the heart. CONCLUSIONS: Infarct size limitation by A1 receptor stimulation is mediated by activation of protein kinase C in pentobarbitone anaesthetised rabbits.

Role of adenosine receptor activation in myocardial infarct size limitation by ischaemic preconditioning.

OBJECTIVE: The aims were to examine the role of adenosine receptors in the mechanism of preconditioning in a chronic rabbit model of myocardial infarction; to assess whether the preconditioning effect is blocked by an adenosine receptor antagonist, 8-phenyltheophylline; and to determine whether an adenosine A1 receptor agonist, R(-)N6-2-phenylisopropyl adenosine (R-PIA), mimics infarct size limitation by preconditioning. METHODS: Myocardial infarction was induced in male rabbits by occlusion of the left coronary artery for 30 min, which was followed by 72 h reperfusion. Before the 30 min ischaemia, rabbits were subjected to one of the following six protocols: (1) untreated control; (2) intravenous injection of 8-phenyltheophylline; (3) preconditioning with 5 min ischaemia; (4) pretreatment with 8-phenyltheophylline plus preconditioning; (5) intravenous injection of R-PIA; or (6) R-PIA plus atrial pacing (240.min-1). Infarct size and area at risk were determined by histology and fluorescent particles, respectively. RESULTS: Preconditioning significantly limited infarct size, normalised as a percent of area at risk (%IS/AR), to 19.2 (SEM 2.3)% v control value of 46.5(2.8)%. 8-Phenyltheophylline alone did not modify the %IS/AR, but its injection before preconditioning attenuated the preconditioning effect such that IS/AR = 34.4(2.5)%. While R-PIA did not achieve statistically significant myocardial salvage, R-PIA plus atrial pacing limited infarct size to 33.7(3.0)% (p<0.05 v control). The R-PIA group had severe hypotension and their infarct sizes were inversely correlated with diastolic blood pressure at reperfusion. There was no such correlation in the R-PIA plus pacing group in which bradycardia and hypotension induced by R-PIA were attenuated by atrial pacing. CONCLUSIONS: The infarct size limiting effect of preconditioning was attenuated by 8-phenyltheophylline, and pretreatment with R-PIA was able to limit myocardial infarct size when severe hypotension was avoided by atrial pacing. These findings suggest that adenosine receptor activation plays a crucial role in the mechanism of preconditioning.

Preconditioning enhances myocardial resistance to postischaemic myocardial stunning via adenosine receptor activation.

OBJECTIVE: The aim was to test a hypothesis that ischaemic preconditioning attenuates myocardial stunning via adenosine receptor activation. METHODS: Myocardial stunning was induced in male rabbits by a transient 5 or 10 min coronary artery occlusion, and alteration of regional systolic thickening fraction (TF) was measured by using an epicardial Doppler sensor before and after the regional ischaemia. Rabbits were either untreated, preconditioned with 1 min ischaemia, given 8-phenyltheophylline (8-PT, 10 mg.kg-1 intravenously), or given 8-PT plus 1 min ischaemic preconditioning. Preconditioning and 8-PT were given 5 min and 20 min before stunning the heart, respectively. RESULTS: Postischaemic recovery of the thickening fraction was significantly improved by preconditioning with 1 min ischaemia. TF (% baseline) after 10 min ischaemia/30 min reperfusion was 84.3(SEM 5.0)% in the preconditioned group, which was significantly higher than the value of 51.3(8.1)% in the control rabbits. Treatment with 8-PT alone did not significantly alter the recovery of TF from 10 min ischaemia [TF = 45.0(7.4)%,], but 8-PT treatment completely abolished the effect of 1 min preconditioning [TF = 51.3(6.4)%]. Attenuation of myocardial stunning by 1 min preconditioning was also observed when the stunning was induced by 5 min ischaemia [92.2(1.3)% in preconditioned group v 75.9(3.2)% in controls]. CONCLUSIONS: These findings suggest that preconditioning protects the myocardium against stunning through activation of the adenosine receptors.

Adenosine infusion during early reperfusion failed to limit myocardial infarct size in a collateral deficient species.

STUDY OBJECTIVE: Intracoronary or intravenous adenosine during reperfusion in combination with lignocaine may attenuate "reperfusion injury" and limit myocardial infarct size in the canine heart. The aim of this study was to test whether intravenous adenosine also protects myocardium in the rabbit heart, which lacks xanthine oxidase and significant coronary collaterals in contrast to the canine heart. DESIGN: Five groups of rabbits underwent a 30 min occlusion of the circumflex coronary artery, followed by reperfusion. In adenosine treated groups, either a high dose of adenosine (0.37 mg.kg-1.min-1) with lignocaine treatment (5 mg intravenously 1 min before coronary occlusion and before reperfusion) or a low dose (0.15 mg.kg-1.min-1) of adenosine with or without lignocaine was infused for 60 min starting 5 min before the onset of reperfusion. Group 1 was untreated, while group 2 received a high dose of adenosine with lignocaine. These groups were reperfused for 3 h. Group 3 was untreated, group 4 received a low dose of adenosine, and group 5 a low dose of adenosine and lignocaine. These groups were reperfused for 72 h. EXPERIMENTAL MATERIAL: 60 anaesthetised open chest rabbits were used. Groups 1 and 2 were killed after 3 h coronary reperfusion. Groups 3, 4, and 5 recovered from surgery for 72 h and were then killed for further study. MEASUREMENTS AND MAIN RESULTS: The high dose of adenosine reduced mean blood pressure to 44% of baseline value and diminished reactive hyperaemia in the area at risk by "coronary steal". The low dose of adenosine did not significantly alter systemic blood pressure or heart rate. Infarct size did not differ between groups 1 and 2, at 39.7(SD 20.1)% of area at risk v 33.2(15.9)% (by tetrazolium staining), nor between groups 3, 4, and 5: 50.3(12.6)% v 52.7(15.6)% v 47.8(9.3)% (by histology). CONCLUSION: Neither a high dose nor a low dose of adenosine limited myocardial infarct size in the rabbit heart even when adenosine was combined with lignocaine treatment.

Insulin sensitivity and the effects of insulin on renal sodium handling and pressor systems in essential hypertensive patients.

Insulin resistance and hyperinsulinemia are linked with essential hypertension. To clarify insulin sensitivity in Japanese essential hypertensive patients and the role of insulin resistance in these patients, a euglycemic hyperinsulinemic glucose clamp was applied in 17 essential hypertensive patients and 12 normotensive subjects. The mean glucose infusion rate was used as an indicator of insulin sensitivity (M value). This study revealed a significantly lower M value in essential hypertensive patients than in normotensive subjects. Increased plasma norepinephrine, renin activity, and aldosterone levels were observed after hyperinsulinemia for 120 minutes after glucose clamp in normotensive subjects and essential hypertensive patients. Urinary sodium excretion and fractional excretion of sodium were decreased in essential hypertensive patients as well as normotensive subjects during glucose clamp compared with the period before glucose clamp. No difference in the percent change was observed between essential hypertensive patients and normotensive subjects. These results indicate that selective insulin resistance with respect to glucose metabolism exists in essential hypertensive patients and that insulin action on renal sodium handling and pressor systems was maintained in these patients.

A case of adrenal tumor producing renin, aldosterone, and sex steroid hormones.

A 27-year-old woman with an adrenal tumor that produced renin and aldosterone, associated with hypertension and adrenogenital syndrome, is described. Severe hypertension, cardiomegaly, a low serum potassium level, clinical symptoms of adrenogenital syndrome, and a left upper abdominal tumor also were found. Endocrinological studies showed that plasma and urinary levels of sex steroid hormones such as dehydroepiandrosterone, androsterone, and testosterone were markedly increased. Plasma renin activity, plasma angiotensin II, and plasma aldosterone levels also were increased markedly, although deoxycorticosterone levels remained within the normal range. The possibility of renovascular hypertension was excluded by angiography of the renal artery and by venous sampling of plasma renin activity. Abnormal elevations in plasma aldosterone levels persisted despite normalization of plasma angiotensin II by converting enzyme inhibitor administration. It was suspected that this patient had an adrenal tumor producing renin as well as sex steroids and aldosterone. Microscopy of the resected tumor revealed that the tumor was composed mostly of cells with large nuclei and light cytoplasm. The tumor contained dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, aldosterone, and renin. Immunohistochemical study showed that some of the tumor cells produced renin. Biopsy of the left renal tissue showed evident atrophy of the juxtaglomerular cells and pronounced arteriosclerosis. After resection of the tumor, all blood and urinary levels of the abnormally increased hormones returned to a normal range and an apparent fall of blood pressure was noted. To our knowledge, this is the first report of a renin and aldosterone-producing adrenal tumor associated with hypertension and adrenogenital syndrome.

Mechanisms of suppression of renal kallikrein activity in low renin essential hypertension and renoparenchymal hypertension.

The mechanism of suppression of renal kallikrein activity in low renin essential hypertensive and renoparenchymal hypertensive patients was investigated in this study. From Sephadex G-200 column chromatography studies, a single kallikrein peak was observed in both kallikrein radioimmunoassay and kininogenase activity in all samples from normal subjects, low renin essential hypertensive and renoparenchymal hypertensive patients, and in purified kallikrein solution. The enzyme-specific activity around the kallikrein peak in all urine samples from each group was significantly lower than that in purified kallikrein, and a significantly lower specific activity was found in both patient groups than was found in normal subjects. Moreover, it was also recognized that the specific activity of kallikrein decreased in all cases with the increase of the molecular weight of kallikrein, and this tendency was observed more obviously in the low renin essential hypertensive and renoparenchymal hypertensive patients than in the normal subjects. These results suggest the presence of a kallikrein-specific inhibitor with a low molecular weight in human urine, although the possibility of a variant form of kallikrein cannot be excluded.

Changes in osteoprotegerin and markers of bone metabolism during glucocorticoid treatment in patients with chronic glomerulonephritis.

It is well known that long-term glucocorticoid treatment causes osteoporosis, but the precise mechanism remains unclear. Recently, osteoprotegerin (OPG) has been identified as a cytokine that inhibits osteoclast differentiation. We have previously demonstrated that serum OPG is suppressed by glucocorticoids. Therefore, the present study was carried out to clarify the interrelationships between OPG and other markers of bone metabolism during glucocorticoid treatment. Thirteen patients (7 men, 6 women; 44.1 +/- 5.9 years old) with chronic glomerulonephritis who were to be treated with glucocorticoids for the first time were chosen for this study. Markers of bone metabolism, including serum OPG, osteocalcin (OC), bone-specific alkaline phosphatase activity (bAP), parathyroid hormone (PTH), tartrate-resistant acid phosphatase (TRAP), and bone mineral density (BMD), were measured before and during the treatment period. Glucocorticoids significantly reduced BMD of the lumbar spine in the 6 month treatment period (p < 0.01). Serum OPG was decreased significantly by glucocorticoids within 2 weeks (p < 0.001), and serum TRAP, a marker of bone resorption, was markedly increased (p < 0.001). On the other hand, there were no remarkable changes in serum PTH. Serum OC and bAP, markers of bone formation, were transiently reduced during the treatment period (p < 0.01). Furthermore, only serum OPG was positively and independently correlated with percentage BMD of age-matched reference (%AMR). These findings imply that glucocorticoid-induced bone loss develops rapidly via enhanced bone resorption and suppressed bone formation. Moreover, the increased bone resorption caused by glucocorticoids may be, at least in part, mediated by inhibition of OPG, not increment of PTH.

Plasma calcitonin gene-related peptide levels in patients with various hypertensive diseases.

OBJECTIVE: To clarify the pathophysiological role of calcitonin gene-related peptide (CGRP) in hypertensive diseases. METHOD: Using a sensitive radioimmunoassay established in our laboratory, plasma CGRP levels were evaluated in control subjects and in patients with essential hypertension, phaeochromocytoma or primary aldosteronism. RESULTS: The CGRP levels in the three hypertensive groups were significantly higher than in normal controls, but no statistically significant difference was observed among CGRP levels in the three hypertensive groups. In the three cases of secondary hypertensives (one patient with phaeochromocytoma and two with primary aldosteronism), a significant decrease in plasma CGRP levels and a marked reduction in blood pressure were observed after adrenalectomy. CONCLUSION: These results suggest that increased plasma CGRP levels in hypertensive patients could be a compensatory reaction to elevated blood pressure.

Myocardial distribution of indium-111-antimyosin Fab in acute inferior and right ventricular infarction: comparison with technetium-99m-pyrophosphate imaging and histologic examination.

In a postmortem study of a 69-yr-old female patient who had suffered 2 yr previously a non-Q-wave anterior infarction and who had sustained just seven days earlier a left inferior and right ventricular infarction, the distribution of 111In-antimyosin Fab was compared to the results of 99mTc-pyrophosphate imaging and histologic examination. Indium-111-antimyosin Fab imaging could not be performed because of cardiogenic shock. However, postmortem gamma scintillation counting revealed increased activities of antimyosin Fab in the inferoapical and right ventricular infarcted regions in which 99mTc-pyrophosphate positive imagings were observed; in contrast, a histologically confirmed old subendocardial anterior infarction had no definite activity. Thus, the myocardial distribution of 111In-antimyosin Fab corresponded well to the results of 99mTc scintigrams and histologic examinations in a human heart, suggesting that this technique could be useful in vivo for detecting several-day-old myocardial infarction of the right ventricle as well as the left ventricle. Tissue from the 2-yr-old infarction was not identified by this technique.

Myocardial accumulation of monoclonal antimyosin Fab in hypertrophic cardiomyopathy and postpartum cardiomyopathy.

Indium-111-antimyosin Fab scan was performed in patients with hypertrophic and postpartum cardiomyopathies to assess whether or not myocardial damage can be delineated. In two patients with hypertrophic cardiomyopathy, intense and diffuse antimyosin uptake was observed, although there was no evidence of acute myocardial damage or wall motion abnormality. A patient with postpartum cardiomyopathy showed a dense and relatively localized accumulation in the left ventricular anterior wall in association with thallium perfusion and wall motion abnormalities. Thus, antimyosin scanning can delineate not only manifested but also subclinical myocardial damage in hypertrophic and postpartum cardiomyopathies which may not be detectable by other techniques.

Detection of impaired fatty acid metabolism and dyskinesis in hypertrophic cardiomyopathy with iodine-123-BMIPP.

Metabolic imaging using 123I-labeled 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) and Fourier phase analysis of gated blood-pool data were performed in a 60-yr-old woman with idiopathic hypertrophic cardiomyopathy. Dyskinetic wall motion was identified as a markedly delayed phase angle in the left ventricular apex, which was well perfused but highly hypertrophied like other ventricular segments. Fatty acid imaging, however, clearly demonstrated highly reduced activities in the apex, although there were no abnormalities in regional systolic function or in 201TI uptake in other hypertrophied regions. Contrast left ventriculography revealed a midventricular collapse of the left ventricle at end-systole due to markedly hypertrophied ventricular walls and dyskinesis at the apex. Thus, dyskinetic wall motion in the apex closely correlated not only with cardiac hypertrophy but also with impaired fatty acid uptake. These findings were unrelated to the myocardial perfusion state per se. Fatty acid imaging using BMIPP may contribute to the detection of myocyte degeneration not visible using conventional imaging modalities. It may also provide etiological information on regional dysfunction in hypertrophic cardiomyopathy.

Cardiac sympathetic denervation in transthyretin-related familial amyloidotic polyneuropathy: detection with iodine-123-MIBG.

In familial amyloidotic polyneuropathy (FAP), the peripheral nervous system is predominantly impaired. Cardiac sympathetic function has not been directly assessed. A 65-yr-old man with severe peripheral neuropathy due to primary systemic amyloidosis was studied. Echocardiograms and scintigraphic examinations with 20Tl and 99mTc-pyrophosphate demonstrated highly thickened but normally perfused left ventricular walls with intense diffuse amyloid deposits. No definite myocardial activity of [123I]metaiodobenzylguanidine (MIBG) was detected in any cardiac region, indicating lack of sympathetic nerve endings. Despite maintained cardiac contractility, left ventricular diastolic performance and heart rate variability assessed by power spectral analysis were markedly depressed. Thus, the myocardial defect of MIBG activity may provide direct evidence of impaired cardiac sympathetic nerve endings due to amyloid deposits in FAP.

Regional cardiac sympathetic nerve dysfunction and the diagnostic efficacy of metaiodobenzylguanidine tomography in stable coronary artery disease.

The present study endeavors to correlate regional myocardial sympathetic nerve dysfunction with reversible and persistent perfusion abnormalities and depressed regional wall motion, and to determine the diagnostic efficacy of radio-iodinated metaiodobenzylguanidine (MIBG) tomography for detecting coronary artery disease. In 28 consecutive patients with stable coronary artery disease and 7 patients with atypical chest pain but no coronary stenosis, regional MIBG uptake was semiquantitatively evaluated in 13 left ventricular segments early (30 minutes) and late (4 hours) after injection. Regional MIBG uptake was reduced in 68 of 90 segments (76%) showing reversible perfusion abnormality and 72 of 81 segments (89%) showing persistent abnormality 4 hours after injection. Although the sensitivity and negative predictive values of late MIBG scanning for detecting myocardial perfusion abnormalities were relatively high (82% and 85%, respectively), the specificity, positive predictive value, and kappa value were low (63%, 57%, and 0.41, respectively). Right coronary lesions were detected by late MIBG scanning with a high sensitivity (85%) but a low specificity (41%). Conversely, the sensitivities for detecting lesions in the other 2 major left coronary arteries were low (55%). The overall diagnostic accuracy of late MIBG scanning was 66% and the positive and negative predictive values and kappa value were low; 60%, 70%, and 0.31, respectively. Similarly, regional sympathetic dysfunction was observed in 42 of 49 asynergic segments (86%) on late MIBG scans, of which 32 segments were viable and 10 nonviable; but the low specificity (73%) and positive predictive value (44%) reduced the kappa value (0.43). Thus, regional cardiac sympathetic innervation is impaired in ischemic, asynergic but noninfarcted myocardium as well as in myocardium which is infarcted or has a persistent perfusion abnormality. The diagnostic efficacy of MIBG tomography to detect coronary artery disease, however, is limited probably because of nonspecific reductions of MIBG uptake in the inferior and posterolateral regions.

Postischemic functional recovery and BMIPP uptake after primary percutaneous transluminal coronary angioplasty in acute myocardial infarction.

To correlate asynergic wall motion after primary percutaneous transluminal coronary angioplasty with myocardial perfusion and fatty acid metabolism, quantitative tomographies using thallium and radioiodinated 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) were performed during the acute and recovery stages in 56 consecutive patients with acute myocardial infarction, of whom 32 underwent primary percutaneous transluminal coronary angioplasty (group A) and 24 were conservatively treated (group B); 44 patients (79%) had 1-vessel disease. Reduced myocardial uptakes of thallium and BMIPP and regional wall motion were quantified with a bull's eye technique and a centerline method using contrast left ventriculography, respectively. BMIPP activity was significantly lower than that of thallium at an acute stage in both groups. Abnormal BMIPP activities and the difference in thallium and BMIPP abnormalities (perfusion metabolism mismatch) at an acute stage decreased significantly during follow-up in group A (111 +/- 13 to 99 +/- 12 and 30 +/- 10 to 15 +/- 10, respectively), and not in group B (129 +/- 31 vs 118 +/- 29 and 29 +/- 13 vs 30 +/- 10, respectively). Improvement in regional wall motion abnormality correlated closely with the improved uptakes of thallium and BMIPP (y = 0.64x + 26.4, r = 0.56, p < 0.05; y = 1.1x + 11.1, r = 0.81, p < 0.001; respectively). The mismatched uptake of both tracers at an acute stage was significantly related to recovery from asynergic wall motion during follow-up in group A (y = 0.45x + 13.9, r = 0.65, p < 0.005). In conclusion, despite restored myocardial perfusion by primary coronary angioplasty, BMIPP uptake is impaired in salvaged myocardium at an acute stage of infarction. However, the degree and improvement of perfusion metabolism mismatch in acute myocardial infarction may reflect subsequent recovery from postischemic wall motion abnormality in metabolically impaired but viable myocardium after coronary reperfusion.

Efficacy and safety of ramipril (HOE 498) in the treatment of hypertension: dose finding study.

An open-label, prospective multicenter trial of ramipril was performed. The agent was administered once daily at an initial dosage of 1.25 mg and this was increased, when necessary, up to 10 mg with intervals of 2 weeks for 8 weeks. Effectiveness in 46 patients with mild to moderate essential hypertension was 28.1% at a dosage of 1.25 mg, 52.2% at 2.5 mg, 69.6% at 5 mg and 78.3% at 10 mg of ramipril alone. In 27 patients receiving baseline therapy with a thiazide diuretic, a subsequent administration of ramipril showed effectiveness in 11.1% for 1.25 mg, 48.1% for 2.5 mg and 70.4% for 5 mg. Adverse effects occurred in 11.7% of patients overall and were not serious. One patient was withdrawn because of severe headache; the other patients tolerated the treatment well. A dosage of 2.5 to 10 mg of ramipril will probably be appropriate for further evaluation of the effectiveness of this agent in a double-blind study.

Effect of ramipril, a new angiotensin converting enzyme inhibitor, on diurnal variations of blood pressure in essential hypertension.

The effect of ramipril on diurnal variations of blood pressure was studied in patients with mild to moderate essential hypertension in groups given once- (n = 18) and twice-daily (n = 21) administration with daily dosages ranging from 2.5 to 10 mg. After ramipril treatment, the blood pressure of patients in both groups was significantly reduced, and no significant differences in diurnal variation of blood pressure were observed between the 2 groups. The pulse rate did not change after administration of ramipril and no serious side effects were observed. In consideration of patient compliance, once-daily administration of ramipril seems to be optimal for the treatment of essential hypertension.

Dose-effect relationship of carvedilol in essential hypertension. An open study.

This study was performed to find the optimal dose of carvedilol, in terms of efficacy and safety, in Japanese patients with mild to moderate essential hypertension. 134 patients with blood pressure greater than 160/95 mm Hg after a 4-week placebo run-in period were initially given carvedilol 5mg once daily. The dose was increased to 10 and 20mg at 4-weekly intervals if the target blood pressure was not achieved. The duration of treatment was 12 weeks. After 12 weeks' administration, the average blood pressure was significantly (p less than 0.001) reduced from 170/101 to 150/91 mm Hg. The hypotensive activity of carvedilol 5mg was mild, but sufficient hypotensive effect was observed in 65% of patients receiving up to 20 mg/day. No significant postural changes in blood pressure were observed. Although heart rate was significantly decreased (77 to 66 beats/min, p less than 0.001), no patient was judged to have bradycardia. Side effects occurred in 5.2% of patients. Carvedilol 10 to 20mg once daily is considered to be an effective and safe treatment for essential hypertension.