Katsuhiko Hatake

Diminution of contractile response of the aorta from endotoxin-injected rats

The contractility of a helical strip of the thoracic aorta was studied in rats injected intraperitoneally with endotoxin. The contractile response to any of the agonistic agents, KCl, norepinephrine or 5-hydroxytryptamine was time dependently diminished in the endotoxin-injected rats compared to the controls. This diminution preceded the depression of blood pressure. When the external calcium concentration was increased from 2.5 to 7.5 mM after the KCl (80 mM)-induced contractile response reached a plateau, the diminished contractile response was reversed in the endotoxin-injected group. The strips from the endotoxin-injected rats showed a higher 45CaCl2 uptake into the vascular tissue with the KCl-stimulated contraction. These findings suggest that the blood pressure depression during endotoxic shock may be attributed partially to the diminished contractility of the blood vessels and that this diminution is induced by a disorder of calcium utilization within vascular smooth muscle during vascular contraction.

Modulation of vascular tonus by the endothelium in experimental diabetes

The role of the vascular endothelium in the contractile response of aortas from streptozotocin-induced diabetic rats was investigated using selected agents. Contractile response to KCl was not affected by removal of the endothelium in both diabetic and control groups, but was diminished in the diabetic rats compared to the control rats. Contractile response to clonidine markedly increased after removal of the endothelium in the control group, with the increment being less in the diabetic group. After removal of the endothelium, contractile response to clonidine was poorer in the diabetic group than the control group. Vascular relaxation induced by acetylcholine disappeared when the endothelium was removed in both diabetic and control groups. The degree of reaction to acetylcholine did not significantly differ between the two groups. These results suggest that in diabetic rats, abnormality of the endothelium-dependent vascular relaxation is specific for alpha 2 receptor while that of the vascular smooth muscle reactivity is not receptor-specific.

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.

Effect of age on contractile response to angiotensin II in rat aorta

The effects of aging on contractile response to angiotensin II and tachyphylaxis to it were investigated using aortic strips from rats aged 1.5, 4 and 22 months. Whether the endothelium was present or not, the contractile response to angiotensin II was greater and tachyphylaxis to it was less in 1.5-month-old rats than in 4- and 22-month-old rats. The differences between 4- and 22-month-old rats were not significant. Removal of the endothelium enhanced angiotensin II-induced maximal contraction and depressed the tachyphylaxis, these endothelial effects being greater in 4- rather than in 1.5-month-old rats. When the contractile force of angiotensin II was adjusted to a similar level for 1.5- and 4-month-old rats, the endothelial effect on the tachyphylaxis was greater in the 4-month-old rats, but no significant difference was noted in the endothelial effect on the contractile force. These results suggest that during growth, the contractile response of rat aorta to angiotensin II decreases while the endothelial effect on it increases.

Alcohol addiction of methamphetamine abusers in Japan

Fifty-eight methamphetamine (MAMP) abusers were surveyed to demonstrate the types of nature of MAMP abuse. In-depth interviews using psychophysiological techniques assessed the subjects to be truthful or deceptive about their abuse histories. Research diagnostic criteria determined the subjects clinical symptoms. The results show that three factors characterize MAMP abuse: significant correlation was found between the years of abuse; the manifestation of somatic or mental disorders or both, and alcohol (Alc) addiction. MAMP abusers who were nondrinkers or light drinkers developed a tendency to dislike Alc after MAMP abuse, while there was no change in Alc consumption in heavy drinkers. The findings suggest that the combined abuse of MAMP and Alc aggravates somatic and mental disorders and that Alc plays an important role in the fatal effect of MAMP, especially from small doses. This provides support for the synergistic effects between MAMP and Alc. Coadministration of MAMP and Alc appears to produce long-acting and more complicated changes in the brains neurotransmitter function.