Biomedical subjects

K Kugiyama

Publications and source records attributed to K Kugiyama.

At least 91 records · Page 5Linked to original sources

PubMed1997

Supersensitive dilator response to nitroglycerin but not to atrial natriuretic peptide in spastic coronary arteries in coronary spastic angina.

It has been shown that there is the supersensitivity of the dilator effect of nitrovasodilators in the coronary arteries of patients with coronary spastic angina. This study was aimed to elucidate its mechanism(s) by examination of dilator response of spastic coronary arteries to atrial natriuretic peptide (ANP), which is known to dilate arteries by the same final common pathway through cyclic guanosine monophosphate (cGMP) as nitrovasodilators. Effects of infusion of nitroglycerin and ANP on epicardial coronary diameter of left coronary arteries were thus examined by quantitative coronary angiography in 20 patients with coronary spastic angina, who had spasm in left coronary arteries, and in 27 control subjects. Dilator response of coronary diameter to intracoronary infusion of ANP (0.5 microgram/kg) was found to be comparable between spastic coronary arteries and control arteries, whereas dilator response to nitroglycerin (250 micrograms) was enhanced in the spastic arteries compared with control arteries. The results indicate that spastic coronary arteries exhibit supersensitive dilator response to nitroglycerin but not to ANP. There is a possibility that dilator response to cGMP may be comparable between spastic and control coronary arteries and that soluble guanylate cyclase activity and/or conversion of nitric oxide bio-activity from nitroglycerin may be enhanced in spastic coronary arteries.

Adult↗

PubMed1997

Long-lasting abnormalities in cardiac sympathetic nervous system in patients with coronary spastic angina: quantitative analysis with iodine 123 metaiodobenzylguanidine myocardial scintigraphy.

Quantitative analysis of iodine 123 metaiodobenzylguanidine (MIBG) myocardial tomographic imaging showed that the regional uptake reduction and abnormally high washout of MIBG in the myocardial territories of the coronary artery with spasm were observed in 33 (75%) and in 30 (68%) of 44 patients with coronary spastic angina, whereas it was observed in two (7%) and in four (15%) of 27 control subjects, respectively. The patients with higher disease activity of the anginal attack and those with life-threatening ventricular arrhythmias were frequently associated with either the uptake reduction or the abnormally high washout of MIBG (91% in patients with high disease activity, 100% in patients with ventricular arrhythmias). The repeated studies of MIBG myocardial tomographic imaging at 2 and 6 months after suppression of anginal attacks by medical treatments showed that the scintigraphic abnormalities still remained in 85% of the patients at 2 months and 32% at 6 months. Thus the abnormalities in sympathetic nervous system assessed with MIBG scintigraphy has been shown to be highly associated with patients with coronary arteries with spasm, particularly high-risk patients, and lasted for several months despite suppression of anginal attack.

3-Iodobenzylguanidine↗

PubMed1997

Flow-mediated, endothelium-dependent dilatation of the brachial arteries is impaired in patients with coronary spastic angina.

Coronary spasm is induced by acetylcholine, serotonin, ergonovine, or histamine, all of which cause vasodilation when the endothelium is intact, and is promptly relieved by nitroglycerin, which vasodilates through the direct action on smooth muscle. Endothelial dysfunction is therefore possibly involved in the pathogenesis of coronary artery spasm. The aim of this study was to determine whether endothelium-dependent vasodilation is impaired in the peripheral arteries of patients with coronary spastic angina. Flow-dependent vasodilation of the brachial arteries during reactive hyperemia after the transient arterial occlusion was examined by using the high-resolution ultrasound technique in 35 patients with coronary spastic angina and 35 controls. Flow-dependent vasodilation of the brachial arteries was impaired in patients with coronary spastic angina compared with controls (5.9% +/- 4.2% vs 9.6% +/- 3.4%, p < 0.001) although the percent increase in blood flow during reactive hyperemia was not different between the two groups. The dilator response to nitroglycerin was preserved in patients with coronary spastic angina compared with controls (18.6% +/- 5.1% vs 16.2% +/- 3.9%, p < 0.04). The results indicate that endothelium-dependent vasodilation of the brachial arteries is impaired in patients with coronary spastic angina. Thus endothelial vasomotor dysregulation may also be present in the systemic arteries as well as coronary arteries in patients with coronary spastic angina.

Adult↗

PubMed1997

Impairment of endothelium-dependent relaxation of rabbit aortas by cigarette smoke extract--role of free radicals and attenuation by captopril.

The aim of this study was to examine the effects of the water soluble component of cigarette smoke extract (CSE) on endothelium-dependent relaxation (EDR) of isolated rabbit aortas. The incubation with CSE was found to inhibit EDR in a dose-dependent manner. Co-incubation of the aortic strips with superoxide dismutase (SOD), N-acetylcysteine, glutathione or dimethyl sulfoxide (DMSO), free radical scavengers, attenuated the CSE-induced inhibition of the arterial relaxation. Co-incubation of the strips with captopril (3 mM), an angiotensin converting enzyme inhibitor, also attenuated CSE-induced impairment of vasorelaxation. In parallel experiments using cultured human endothelial cells, CSE suppressed endothelial release of NOx, stable metabolites of nitric oxide (NO). SOD, DMSO and captopril attenuated the suppression of NO production by CSE in association with reduction of free radicals, superoxide anions and hydroxyl radicals, in CSE solution. Neither lactate dehydrogenase release from the cultured endothelial cells nor cell death estimated by trypan blue exclusion test was found after the incubation of the cultured endothelial cells with CSE. The results indicate that free radicals in CSE induce the impairment of EDR, which may be partly due to suppression of NO production and is not due to non-specific cytotoxicity by CSE. Captopril attenuates CSE-induced endothelial dysfunction partly through scavenging free radicals.

Acetylcysteine↗

PubMed1997

Gender difference in improvement of endothelium-dependent vasodilation after estrogen supplementation.

OBJECTIVES: We examined whether there is a gender difference in the improvement of endothelium-dependent vasodilation after estrogen supplementation. BACKGROUND: Estrogen therapy reduces the risk of cardiovascular events in postmenopausal women, and the augmented release of endothelium-derived nitric oxide (NO) by estrogens has been suggested to be one of the mechanisms for the cardioprotective effects of estrogen. METHODS: With ultrasound technique, we measured the diameter and blood flow of the brachial artery at rest, during reactive hyperemia after transient occlusion and after nitroglycerin administration before and after estradiol supplementation in 15 postmenopausal women (mean 63 years) and in 15 men matched for age and risk factors for atherosclerosis. RESULTS: Estradiol supplementation augmented the flow-mediated vasodilation and serum level of nitrite/nitrate (metabolites of NO) in women (respectively, from mean +/- SEM of 8.0 +/- 0.6% to 12.9 +/- 0.6% [p < 0.01 by analysis of variance (ANOVA)] and from 64.9 +/- 8.7 to 93.7 +/- 9.4 mumol/liter [p < 0.05 by ANOVA]) but not in men (respectively, from 8.1 +/- 0.6% to 8.3 +/- 0.7% and from 57.8 +/- 6.7 to 60.8 +/- 5.4 mumol/liter). The increases in blood flow during reactive hyperemia and in diameter after nitroglycerin administration were not affected by estradiol supplementation in either men or women. CONCLUSIONS: Estradiol supplementation improves endothelium-dependent vasodilation in women, probably because of augmented NO production/release, but not in men. Thus, there may be gender differences in the effects of estrogen therapy on endothelial functions and NO production/release.

Analysis of Variance↗

PubMed1997

Nitric oxide-mediated flow-dependent dilation is impaired in coronary arteries in patients with coronary spastic angina.

OBJECTIVES: This study sought to examine whether flow-dependent dilation is impaired at the site of coronary artery spasm in patients with coronary spastic angina. BACKGROUND: Physiologic stimuli such as exercise and exposure to cold have been shown to cause an increase in coronary blood flow, leading to flow-dependent dilation of coronary arteries in normal subjects, but cause coronary constriction in patients with coronary spastic angina. METHODS: A maximal increase in blood flow was induced selectively in the left anterior descending coronary artery (LAD) by infusion of adenosine through a Doppler flow catheter tip in the midportion of the LAD in 10 patients with coronary spastic angina, all with angiographically demonstrated spasm of the LAD, and in 11 control patients. Coronary artery diameter at the proximal site of the LAD (exposed to increased flow but not to adenosine) was measured by quantitative angiography. RESULTS: Flow-dependent dilation of the proximal LAD was found to be less in spasm arteries than in control arteries. Infusion of NG-monomethyl-L-arginine (L-NMMA) in the proximal LAD suppressed flow-dependent dilation in control arteries but had no significant effect on spasm arteries. The dilator response to nitroglycerin was not impaired in spasm coronary arteries. CONCLUSIONS: Our results indicate that flow-dependent coronary dilation is impaired in spasm arteries, partly due to a deficiency in endothelial nitric oxide bioactivity, which in turn may contribute to the increase in coronary tone during physiologic stimuli in patients with coronary spastic angina.

Adenosine↗

PubMed1997

Complexes of apoA-1 with phosphatidylcholine suppress dysregulation of arterial tone by oxidized LDL.

The aim of this study was to determine whether apolipoprotein A-1 (apoA-1) may suppress the vasomotor dysregulation by oxidized low-density lipoprotein (ox-LDL), which is known to be an atherogenic lipoprotein. The isolated porcine coronary arterial rings and the cultured endothelial cells from the porcine coronary arteries were exposed to ox-LDL in the presence or absence of complexes of apoA-1 with dimyristoylphosphatidylcholine (DMPC/apoA-1), apoA-1 alone, or DMPC alone. DMPC/apoA-1 but not apoA-1 alone or DMPC alone was found to suppress both impairment of endothelium-dependent arterial relaxation and vasocontraction caused by ox-LDL in the isolated porcine coronary arterial rings suspended in organ chambers. DMPC/apoA-1 absorbed lysophosphatidylcholine (LPC) from ox-LDL and decreased the transfer of LPC from ox-LDL to the surface membrane of the cultured endothelial cells, but apoA-1 alone and DMPC alone had no effect. High-density lipoprotein exerted the protective actions mimicking those observed in DMPC/apoA-1. Thus DMPC/apoA-1 decreased the transfer of LPC from ox-LDL to surface membrane by absorbing LPC, leading to the suppression of ox-LDL-induced dysregulation of endothelium-dependent arterial tone. Therefore, apoA-1 appears to require formation of the complexes with phospholipids to prevent the endothelial dysfunction caused by ox-LDL.

Analysis of Variance↗

PubMed1997

Endothelium-dependent vasodilation in the brachial artery is impaired in smokers: effect of vitamin C.

Cigarette smoking has been shown to cause endothelial dysfunction. To examine the effects of vitamin C and cigarette smoking on endothelium-dependent vasodilation, we measured the lumen diameter and flow velocity of the brachial arteries at rest, during reactive hyperemia following transient arterial occlusion, and after sublingual nitroglycerin (0.3 mg) in smokers (n = 20) and nonsmokers (n = 20) with high-resolution ultrasound after infusion of saline or saline plus vitamin C (10 mg/min for 20 min). We also performed the same study in smokers (n = 15) before and 10 min after cigarette smoking. In addition, we measured the serum levels of vitamin C and the plasma levels of thiobarbituric acid-reactive substances (TBARS) as an index of lipid peroxidation. The smokers had lower vitamin C levels, higher TBARS levels, and showed impairment of flow-dependent vasodilation (5.3 +/- 1.9 vs. 9.2 +/- 1.5%, P < 0.0001) compared with nonsmokers. Vitamin C administration improved the impairment of flow-dependent vasodilation (5.3 +/- 1.9 to 9.0 +/- 3.2%, P < 0.001) and decreased TBARS in smokers but not in nonsmokers. Furthermore, cigarette smoking acutely worsened the impairment of flow-dependent vasodilation (5.4 +/- 1.8 to 1.5 +/- 1.3%, P < 0.01) and increased TBARS. We conclude that 1) endothelium-dependent vasodilation in the brachial arteries is impaired in smokers and this impairment is improved by vitamin C administration in association with a decrease in TBARS and 2) cigarette smoking produces acute impairment of endothelium-dependent vasodilation in smokers in association with an increase in TBARS.

Adult↗

PubMed1997

Coronary spasm: clinical features and pathogenesis.

Coronary artery spasm (coronary spasm) is an abnormal contraction of an epicardial coronary artery resulting in myocardial ischemia and its incidence is relatively high in Japanese as compared with Caucasians. Coronary spasm occurs most often from midnight to early morning when the patient is at rest and it is usually not induced by exercise in the daytime. Coronary spasm can be induced by acetylcholine, an endothelium-dependent vasodilator which causes vasodilatation in the normal coronary artery. Spasm artery is hyperresponsive to the vasodilator effect of nitroglycerin, an nitric oxide (NO) donor and is deficient in NO activity. The major risk factor for coronary spasm is cigarette smoking. Coronary spasm can be a cause of not only variant angina but also ischemic heart disease in general, including unstable angina, acute myocardial infarction and sudden ischemic death.

Acetylcholine↗

PubMed1996

Deficiency in nitric oxide bioactivity in epicardial coronary arteries of cigarette smokers.

OBJECTIVES: This study sought to examine nitric oxide-mediated regulation of epicardial coronary arterial tone in cigarette smokers. BACKGROUND: Cigarette smoking is a major risk factor for coronary artery disease and is highly prevalent in patients with coronary spastic angina. Long-term exposure to cigarette smoking has been recently reported to suppress endothelium-dependent arterial relaxation in vivo humans. METHODS: Responses of epicardial coronary artery diameter to single or combined infusion of acetylcholine and NG-monomethyl-L-arginine (L-NMMA) into the left main coronary artery were examined in 11 current smokers and 17 nonsmokers using quantitative coronary angiography. RESULTS: Acetylcholine dilated one-third of the proximal segments and most of the distal segments of coronary arteries in nonsmokers, whereas it constricted most of the proximal and distal segments in smokers. L-NMMA decreased the basal diameter of coronary arteries in nonsmokers but had minimal effect on the basal diameter in smokers. L-NMMA abolished the dilator response to acetylcholine in the coronary arteries of nonsmokers but had minimal effect on the constrictor response to acetylcholine in the arteries of smokers. The dilator response to nitroglycerin was significantly increased in the coronary arteries of smokers compared with in those of nonsmokers. The constrictor response to L-NMMA at rest was significantly correlated with the dilator response to nitroglycerin and with the diameter changes to acetylcholine in both smokers and nonsmokers. CONCLUSIONS: Nitric oxide bioactivity at rest and at acetylcholine-stimulated conditions in smokers was decreased, leading to the supersensitivity of the artery to the dilator effect of nitroglycerin as well as the constrictor effect of acetylcholine in smokers. Cigarette smoking affects nitric oxide-mediated regulation of coronary artery tone.

Acetylcholine↗

PubMed1996

Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina.

BACKGROUND: Coronary spasm can be induced by acetylcholine, serotonin, ergonovine, or histamine, all of which cause vasodilation when the endothelium is intact by releasing nitric oxide (NO). Coronary spasm is promptly relieved by nitroglycerin, which vasodilates through its conversion to NO. It is thus possible that NO release may be deficient in the spasm arteries in patients with coronary spastic angina (CSA). The aim of this study was to determine whether NO release is deficient in coronary arteries of patients with CSA. METHODS AND RESULTS: NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, was infused into coronary arteries in 21 patients with coronary spastic angina (CSA) and in 28 control patients. Coronary spasm was induced by intracoronary injection of acetylcholine and was documented angiographically in all patients with CSA. L-NMMA dose-dependently decreased basal luminal diameter of coronary arteries in control patients, whereas it had no effect on basal diameter of the spasm arteries in patients with CSA. L-NMMA abolished the dilator response to acetylcholine and enhanced the constrictor response to acetylcholine in control arteries, whereas it had no effect on the constrictor response to acetylcholine in spasm arteries. Intracoronary infusion of L-arginine did not affect the diameter of spasm or control arteries. The dilator response to nitroglycerin was increased markedly in spasm arteries compared with control arteries, whereas response to diltiazem did not differ between them. CONCLUSIONS: There is a deficiency in endothelial NO activity in spasm arteries, which leads to the supersensitivity of the artery to the vasodilator effect of nitroglycerin and to the vasoconstrictor effect of acetylcholine in patients with CSA. This deficient endothelial NO activity plays an important role in the pathogenesis of coronary spasm.

Acetylcholine↗

PubMed1996

Neutral endopeptidase 24.11 in neutrophils modulates protective effects of natriuretic peptides against neutrophils-induced endothelial cytotoxity.

This study was performed to determine effects of atrial and brain natriuretic peptides (ANP, BNP) on neutrophils-induced endothelial injury which is known to play a role in the pathophysiology of ischemia/reperfusion myocardial injury and to examine whether the effects of ANP and BNP on neutrophils are modulated by neutral endopeptidase 24.11 (NEP) in neutrophils themselves. The incubation of human neutrophils with ANP and BNP inhibited the neutrophils-induced detachment of cultured human endothelial cells (HEC). The inhibitory effect of ANP and BNP was associated with the suppressions of the neutrophils adhesiveness to HEC, CD18 expression on the neutrophils and elastase release from the neutrophils. Coincubation with UK73967 or phosphoramidon, inhibitors of NEP, potentiated all of the effects of ANP and BNP on the neutrophil functions, and the NEP inhibitors protected degradation of ANP and BNP by the neutrophils. NEP enzymatic activity in the particulate fractions and immunoreactive NEP expression were found to increase in the neutrophils from patients with early phase of acute myocardial infarction (AMI) by 5.2- and by 4.2-fold of the neutrophils from patients with late phase of AMI, respectively. In an in vivo canine model of myocardial ischemia/reperfusion, the intravenous administration of UK73967 suppressed the neutrophil adherence to endothelium and the neutrophil accumulation in the ischemic/reperfused myocardium. The results indicate that ANP and BNP, which are known to increase in AMI, modulate the neutrophil functions and exert protective effects against the neutrophils-induced endothelial cytotoxity. But the effects are suppressed due to their degradation by the neutrophil own NEP. Thus, neutrophil NEP, which also increases in AMI, may play a role in the pathophysiology of neutrophils-mediated ischemia/reperfusion endothelial and myocardial injury.

Animals↗

PubMed1996

Heart period variability in patients with variant angina.

To clarify how cardiac autonomic control is affected in variant angina, we analyzed heart period variability in 35 patients with variant angina and in 19 control subjects. Patients with variant angina were divided into 1-vessel (group S, n = 17) and multivessel spasm groups (group M, n = 18) according to the site(s) of ST elevation on the electrocardiogram during attacks. The 24-hour Holter electrocardiogram recorded 6 +/- 3 days after the treatment with calcium antagonist was analyzed to avoid the possible influence of spontaneous attacks. In 5 group M patients, the electrocardiogram recorded 1 month after the treatment was also analyzed. There was no difference in the number of spontaneous attacks between groups S and M. The standard deviation of all normal RR intervals (SDNN) and the percentage of differences between adjacent normal RR intervals >50 (pNN50) in variant angina were slightly but significantly lower than those in controls. There were no differences in other indexes between variant angina and controls. When the data were analyzed separately in groups S and M, averaged RR intervals (MN), SDNN, pNN50, high-frequency power, and low-frequency power in group M were significantly lower than those in group S and controls, and the ratio of low- to high-frequency power in group M was significantly higher than that in group S and controls. There was no difference in any index between group S and controls. All abnormal indexes in group M recovered to levels similar to those in controls 1 month after the treatment. In conclusion, depressed cardiac vagal control and sympathetic-dominant sympathovagal interaction were present in patients with variant angina, especially in those with multivessel spasm.

Aged↗

PubMed1996

Diffuse disorder of coronary artery vasomotility in patients with coronary spastic angina. Hyperreactivity to the constrictor effects of acetylcholine and the dilator effects of nitroglycerin.

OBJECTIVES: We examined the vasomotility of the entire epicardial coronary artery system in patients with and without coronary spastic angina. BACKGROUND: The coronary arteries of patients with variant angina are hyperreactive to diverse constrictor stimuli. It is unclear whether the abnormal responses to constrictive or dilative stimuli, or both, result from a localized or diffuse disorder in the coronary artery tree. METHODS: Coronary artery diameter responses to intracoronary acetylcholine and nitroglycerin were examined at the proximal, middle and distal segments of three principal coronary arteries in 36 patients with coronary spastic angina without significant stenosis and in 12 young (< or = 30 years old) and 20 older control subjects (> 30 years old) with normal coronary arteriographic findings. In 10 patients with significant coronary stenosis, the responses of the prestenotic segments were also examined. RESULTS: In patients with coronary spastic angina, coronary spasm was induced in 23 left anterior descending, 13 left circumflex and 17 right coronary arteries by acetylcholine. Multivessel spasm was observed in 15 patients. Acetylcholine had a dilator effect on most segments in young control subjects and a mild constrictor effect in older control subjects and in patients with significant stenosis. Comparison of the responses to acetylcholine among groups demonstrated that the constrictor response of the artery with spasm was enhanced significantly and diffusely. That of the artery without spasm also tended to be enhanced. Coronary artery diameters after nitroglycerin did not differ in any segment among patients with coronary spastic angina and both control groups. In patients with coronary spastic angina, nitroglycerin significantly enhanced dilation in all segments of the artery with spasm compared with that observed in both control groups and in most segments of the artery without spasm. Patients with significant coronary stenosis had a reduced response compared with that in control subjects. CONCLUSIONS: Hyperreactive responses not only to the constrictor effects of acetylcholine, but also the dilator effects of nitroglycerin were detected diffusely in the epicardial coronary arteries of patients with coronary spastic angina. This finding indicates that a diffuse, not localized, disorder in vasomotility is involved in the pathogenesis of coronary spastic angina.

Acetylcholine↗

PubMed1996

Increased plasma levels of B-type natriuretic peptide in patients with unstable angina.

This study was designed to examine the plasma levels of B-type or brain natriuretic peptide (BNP), as well as A-type or atrial natriuretic peptide (ANP) in patients with unstable angina as compared with those in patients with stable exertional angina and control subjects. We measured the plasma levels of BNP and ANP in 33 patients with unstable angina, 20 patients with stable exertional angina, and 20 control subjects. The plasma levels of BNP were significantly increased in patients with unstable angina compared with those in patients with stable exertional angina and control subjects, respectively (39.5 +/- 29.4 pg/ml vs 15.1 +/- 8.0 pg/ml; p < 0.01 and 39.5 +/- 29.4 pg/ml vs 10.3 +/- 6.4 pg/ml; p < 0.01, respectively). On the other hand, there was no significant difference in the plasma levels of ANP among the three groups. Furthermore, in patients with unstable angina, the plasma levels of BNP decreased significantly after the medical treatment (from 39.5 +/- 29.4 pg/ml to 15.8 +/- 11.0 pg/ ml; p < 0.01), whereas the plasma levels of ANP did not change. We conclude that the plasma levels of BNP are increased in the majority of patients with unstable angina and that the increased levels decrease toward normal after treatment.

Adult↗

PubMed1996

Role of adenosine in pathogenesis of syndrome X: assessment with coronary hemodynamic measurements and thallium-201 myocardial single-photon emission computed tomography.

OBJECTIVES: This study was performed 1) to examine the role of adenosine in the pathogenesis of syndrome X in patients with this syndrome and abnormal results on myocardial scintigrams during exercise, and 2) to determine the susceptibility to myocardial ischemia in this subset of patients with syndrome X. BACKGROUND: A role for adenosine in the pathogenesis of syndrome X has recently been postulated, but there are few clinical data supporting this hypothesis. METHODS: Exercise thallium-201 myocardial scintigraphy after intravenous administration of aminophylline, an adenosine receptor blocking agent, or saline solution and adenosine thallium-201 scintigraphy were performed in 26 patients with syndrome X. Hemodynamic variables during exercise and perfusion defect size after aminophylline and saline infusions were compared. At cardiac catheterization, coronary hemodynamic variables during separate infusions of adenosine and doubutamine were also examined and were compared among patients with abnormal or normal scintigrams and 10 control subjects. RESULTS: Perfusion abnormalities on exercise-thallium-201 scintigraphy occurred in 14 of 26 patients with syndrome X. Intravenous infusion of aminophylline suppressed the scintigraphic perfusion defect and prolonged the time to 1-mm ST segment depression in patients with syndrome X with abnormal exercise scintigrams. Intravenous infusion of adenosine induced a perfusion defect in the same myocardial area where the perfusion defect was observed at exercise in 7 of the 14 patients with syndrome X. At cardiac catheterization, patients with syndrome X with abnormal exercise scintigrams had lower coronary flow reserve and a greater frequency of myocardial lactate production and ST segment depression in response to the infusions of adenosine and doubtamine than did the other two groups. During adenosine infusion, great cardiac vein blood flow and oxygen content were significantly increased and myocardial oxygen consumption and lactate extraction were significantly reduced from baseline without a significant increase in rate-pressure product in this subset of patients with syndrome X. CONCLUSIONS: Patients with syndrome X with abnormal exercise scintigrams have high susceptibility to myocardial ischemia during exercise or pharmacologic stress tests, probably owing to reduced coronary flow reserve. A heterogeneous response to endogenous adenosine may contribute to scintigraphic perfusion abnormalities and myocardial ischemia during exercise in this subset of patients with syndrome X.

Adenosine↗

PubMed1996

Suppression of atherosclerotic changes in cholesterol-fed rabbits treated with an oral inhibitor of neutral endopeptidase 24.11 (EC 3.4.24.11).

Neutral endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter various functions of cells present in the arterial wall. Recently NEP has been found to exist in the vascular endothelium. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (candoxatril), an orally active NEP inhibitor (NEPI), on the development of atherosclerotic changes in high-cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks as follows: normal rabbit diet (Normal, n = 15), 1.5% cholesterol diet (Cholesterol, n = 15), or 1.5% cholesterol diet containing NEPI (20 mg.kg-1.d-1) (Cholesterol+NEPI, n = 15). At the end of the dietary period, NEPI treatment was found to suppress the surface area of the aorta covered by plaques (% surface area: Cholesterol, 59 +/- 6 versus Cholesterol+NEPI, 36 +/- 7, P < .01) and decreased contents of cholesterol and cholesterol esters in the aortas. NEPI also reduced plasma total cholesterol by 27% of Cholesterol rabbits (1781 +/- 130 mg/dL). The endothelial function, estimated by the endothelium-dependent relaxation of the isolated aortas in response to acetylcholine, was preserved in Cholesterol+NEPI rabbits compared with that in Cholesterol rabbits. NEP enzymatic activities in plasma and the particulate fraction of the homogenates from the aortas in Cholesterol rabbits were both increased, 3.1- and 3.9-fold, respectively, above those in Normal rabbits, but the activities in Cholesterol+NEPI rabbits were significantly lower than those in Cholesterol rabbits. UK73967, an active form of UK79300, or phosphoramidon partly reversed the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings from Cholesterol rabbits in response to exogenous additions of C-type natriuretic peptide (CNP) and substance P, which are NEP substrates known to exist endogenously in the vascular endothelium. The results suggest that the increased NEP activity plays a significant role in atherogenesis, and NEPIs might be therapeutically useful in the prevention of atherosclerosis. Reduction of plasma cholesterol and suppression of degradations in the arteries of endogenously released CNP, substance P, or possibly other kinins known to have anti-atherosclerotic actions may at least partially contribute to the inhibitory effects of NEPIs on atherosclerotic changes.

Administration, Oral↗

PubMed1996

Effects of sphingomyelinase and sphingosine on arterial vasomotor regulation.

The sphingomyelin pathway is an important signal transduction system regulating various cellular functions. However, little is known about the effect of sphingomyelin metabolites on vasomotor function. We examined the vascular effects of sphingomyelin, sphingosine, and sphingomyelinase (SPMase) in vitro. In pig coronary rings precontracted with prostaglandin F2 alpha, sphingosine and SPMase evoked initial contraction and subsequent gradual relaxation; however, sphingomyelin did not influence the tone. The initial contractions in response to either SPMase (40 microU/ml to 0.4 U/ml) or sphingosine (0.5-10 microM) treatment were abolished in rings denuded of endothelium. This initial contraction in response to sphingosine treatment was significantly attenuated by a cyclo-oxygenase inhibitor indomethacin, but not altered by either a nitric oxide synthase inhibitor, N omega-monomethyl-L-arginine (L-NMMA), a protein kinase C (PKC) inhibitor staurosporine, or superoxide dismutase (SOD, 100 U/ml). Incubation of coronary rings with sphingosine (10 microM) or SPMase (0.4 U/ml) for 120 min significantly attenuated subsequent endothelium-dependent relaxation in response to thrombin and A23187, but did not affect endothelium-independent relaxation in response to sodium nitroprusside. In contrast, sphingomyelin (10 microM) did not alter the endothelium-dependent relaxation. In conclusion, in the sphingomyelin pathway, sphingosine induces vasoconstriction in coronary arteries that seems to be mediated by the release of cyclooxygenase-sensitive vasoconstrictor prostanoids from the endothelium. Sphingosine also induced endothelial dysfunction characterized by impaired endothelium-dependent relaxation. Thus, the sphingomyelin pathway may be an important regulator of vascular function.

Animals↗