Shigeru Hishida

Relationship between facial flushing and blood acetaldehyde levels after alcohol intake

Normal subjects were divided into two groups, i.e., those showing, and those not showing, facial flushing after consuming a small amount of alcohol. In the flushing group, increases of pulse rate, facial skin temperature and carotid arterial pressure and blood flow rate, as well as changes of digital plethysmogram and electrocardiogram, were found together with a conspicuous rise in blood acetaldehyde levels after the drinking. However, significant changes of the signs as mentioned above and elevation of blood acetaldehyde did not occur in the non-flushing group. The maximum blood alcohol levels and the rate of alcohol elimination showed not difference between these two groups. Furthermore, urinary excretions of epinephrine and norepinephrine increased in the flushing cases after the drinking.

Alcohol sensitivity related to polymorphism of alcohol-metabolizing enzymes in Japanese

Normal Japanese subjects were divided into two groups, i.e., one with both low and high Km isozymes of aldehyde dehydrogenase for acetaldehyde, and the other deficient in the low Km isozyme. After intake of 0.4 g/kg alcohol, the deficient subjects showed high level of blood acetaldehyde, facial flushing and the other dysphoric symptoms, including increase of pulse rate, decrease of diastolic blood pressure, changes of pulse wave in the fingertip, and elevation of the arterial pressure and blood flow rate in common carotid arteries as well as increase of plasma catecholamines level. In contrast, subjects with normal ALDH did not show these changes. From the observation of liver specimens obtained at autopsy, the frequency of deficient phenotype of ALDH in Japanese was presumed to be about 36%.

Impairment of endothelium-dependent relaxation in human basilar artery after subarachnoid hemorrhage.

Background and Purpose The goal of this study was to determine the alterations in vascular reactivity of human basilar artery after subarachnoid hemorrhage. Methods Human basilar arteries were obtained from subjects who died within 1 day after subarachnoid hemorrhage and control subjects who died from causes other than brain involvement. Basilar artery strips were suspended for isometric tension recording in Krebs-Ringer solution. Morphometric study was also carried out on paraffin-embedded sections stained with van Giesons elastica stain of preselected sites from the basilar arteries. The intimal and medial area and the intimal index ([intimal area/area circumscribed by internal elastic lamina] × 100) were evaluated. Results Contractile responses to KCl, norepinephrine, and 5-hydroxytryptamine did not differ between subarachnoid hemorrhage and control groups. The endothelium-dependent relaxation responses to thrombin, bradykinin, and calcium ionophore A23187 were less for the subarachnoid hemorrhage group than for the control group. However, the endothelium-independent response to sodium nitroprusside of the subarachnoid hemorrhage group did not differ from that of the control group. Morphometric measurements were comparable between the two groups. Conclusions These results suggest that the decreased relaxation responses to thrombin and bradykinin occur at the level of endothelial cells and not smooth muscle cells and that decreased relaxation may be involved in delayed vasospasm after subarachnoid hemorrhage. Although the decreased relaxation was observed within 1 day after subarachnoid hemorrhage, a period in which delayed spasm does not occur, this time difference may be dependent on the severity of bleeding after rupture of an aneurysm.

Effect of aging on endothelium-dependent vascular relaxation of isolated human basilar artery to thrombin and bradykinin.

Using strips of human basilar arteries mounted in organ chambers to record isometric tension, we investigated vascular reactivity to thrombin and bradykinin. Both agents produced endothelium-dependent relaxation of basilar artery strips precontracted with phenylephrine but had no effect on resting tension in strips with or without endothelium. The relaxations caused by thrombin were abolished by antithrombin III/heparin, hirudin, and MD805. Thrombin but not bradykinin caused complete tachyphylaxis toward a second exposure. Indomethacin did not inhibit the relaxations induced by thrombin or bradykinin, whereas bromophenacyl bromide and methylene blue did. Aging decreased the relaxation induced by thrombin but did not affect the concentration needed to reach 50% maximal relaxation, nor did it affect the maximal relaxation in response to bradykinin, calcium ionophore A23187, and sodium nitroprusside. Our results suggest that thrombin and bradykinin produce endothelium-dependent relaxations mediated by an endothelium-derived relaxing substance and that the relaxation caused by thrombin is mediated by a proteolytic action on endothelial cells. The decrease in relaxations in response to thrombin with increasing age might be due to a decrease in the number or sensitivity of thrombin receptors on endothelial cells.

Inhibitory effect of ethanol on endothelium-dependent vascular responsiveness.

The effect of ethanol was studied on the endothelium-dependent vascular responses in isolated rat aortic strips. Ethanol depressed the endothelium-dependent relaxation induced by acetylcholine and ATP but not that induced by the calcium ionophore, A23187. Endothelium-independent relaxation in response to sodium nitroprusside, a soluble guanylate cyclase activator, was not depressed by ethanol. On the other hand, ethanol significantly enhanced the contractile response to clonidine, an alpha 2-adrenoceptor agonist, in endothelium-intact strips and depressed it in endothelium-denuded strips. These results suggest that ethanol can inhibit endothelium-dependent relaxation by acting on endothelial cells but not on smooth muscle cells, and can also suppress an inhibitory effect of the endothelium on alpha 2-adrenoceptor-mediated vasoconstriction.

Possible involvement of kinins in cardiovascular changes after alcohol intake

Japanese healthy male subjects were divided into two groups, i.e., a normal aldehyde dehydrogenase (ALDH) group with a low Km isozyme of ALDH for acetaldehyde, and a deficient group without it. After intake of 0.4 g/kg alcohol, the deficient group showed high levels of blood acetaldehyde, facial flushing including an increased pulse rate and a fall in diastolic blood pressure, while the normal group did not manifest these changes. In the deficient group, the total kininogen concentration gradually decreased after alcohol intake due to a reduction in low molecular weight kininogen, and plasma prekallikrein remained unchanged. The normal group showed no significant changes in any of these values after alcohol intake. In an in vitro study with pooled plasma, the low concentrations of urinary kallikrein caused a decrease in the low molecular weight kininogen only. These results suggest that kinins released by acetaldehyde-induced activation of glandular kallikreins are associated with the changes in cardiovascular symptoms in deficient group which display flushing after alcohol intake.

Endothelium-dependent relaxation resistant to NG-nitro-L-arginine in rat aorta

Experiments were designed to determine whether cyclic GMP-independent relaxation is involved in the endothelium-dependent vascular relaxation response of rat aortic strip to acetylcholine. The relaxation response to acetylcholine in the presence of 3 x 10(-4) M NG-nitro-L-arginine was apparent when the precontraction was induced by norepinephrine at 5 x 10(-9) M or 10(-8) M. The relaxation response to acetylcholine resistant to NG-nitro-L-arginine was abolished by 10(-6) M atropine, 10 mM tetraethylammonium, or endothelium removal, but was not inhibited by 10(-5) M indomethacin, 3 x 10(-6) M oxyhemoglobin or 10(-5) M glibenclamide. The response was virtually abolished when the vascular strips had been preconstricted with 20 mM KCl. The increase in vascular cyclic GMP levels induced by 10(-5) M acetylcholine was completely abolished by 3 x 10(-4) M NG-nitro-L-arginine. These results suggest that acetylcholine-induced endothelium-dependent relaxation resistant to NG-nitro-L-arginine in rat aorta is unmasked when the precontractile force is caused by lower concentrations of norepinephrine and the relaxation is mediated by a cyclic GMP-independent mechanism, possibly an endothelium-derived hyperpolarizing factor.

Mechanism of inhibitory action of ethanol on endothelium-dependent relaxation in rat aorta

Using isolated rat aortic strips, we investigated the inhibitory effect of ethanol on endothelium-dependent relaxation induced by acetylcholine, especially on that mediated by endothelium-derived relaxing factor. Ethanol depressed the relaxation induced by acetylcholine and inhibited the increase in the content of intravascular cyclic GMP induced by acetylcholine, but not that induced by sodium nitroprusside or calcimycin. Ethanol also inhibited the acetylcholine-induced relaxation resistant to nitro-L-arginine. These results suggest that ethanol can inhibit the cyclic GMP-dependent relaxation mediated by endothelium-derived relaxing factor. Furthermore, ethanol seems to depress the cyclic GMP-independent relaxation mechanism.

An autopsy case of combined drug intoxication involving verapamil, metoprolol and digoxin

We present here a fatal poisoning case involving verapamil, metoprolol and digoxin. A 39-year-old male was found dead in his room, and a lot of empty packets of prescribed drugs were found near the corpse. The blood concentrations of verapamil, metoprolol and digoxin were 9.2 microg/ml, 3.6 microg/ml and 3.2 ng/ml, respectively. The cause of death was given as cardiac failure, hypotension and bradycardia due to a mixed drug overdose of verapamil, metoprolol and digoxin, based on the results of the autopsy and toxicological examination. We speculate that the toxicity of verapamil is potentiated by drug interaction with metoprolol and digoxin.

Effects of methamphetamine and ethanol on learning and brain neurotransmitters in rats.

The interactions of methamphetamine (MAMP) and ethanol (EtOH) on multiple active/passive avoidance performance and neurotransmitters in different brain regions were examined. After the acquisition schedules, rats were retrained under the influence of MAMP (2 mg/kg/day, IP), EtOH (2 g/kg/day, IP), and in combination over 20 days in rats (n = 6 per group). As a function of progress of drug treatment, MAMP-EtOH mixtures disrupt the learned avoidance performance and produced severe impairment of discriminative behavior caused by enhancement of excitability induced by MAMP when compared with MAMP only. At withdrawal, MAMP-EtOH-induced impairments of performance significantly persisted, whereas MAMP-only-induced impairments slightly recovered. At the eleventh day drug withdrawal, MAMP-only-induced alterations of neurotransmitter levels at different regions were alleviated by EtOH, but these did not return to normal levels. These data provide support for the direct antagonistic and indirect additive interactions following constant daily treatment with a combination of MAMP and EtOH. EtOH may be an important factor in MAMP abuse to MAMP-induced psychosis or neurotoxicity.