Biomedical subjects

Ichiro Wakabayashi

Publications and source records attributed to Ichiro Wakabayashi.

At least 19 recordsLinked to original sources

PubMed2006

Upregulation of enzymes metabolizing 5-fluorouracil in colorectal cancer.

BACKGROUND: The purpose of this study was to compare the activities of various enzymes, participating in the metabolism of 5-fluorouracil, between colorectal cancer and nontumor tissues and to investigate the association of the enzyme activities with clinicopathological backgrounds. METHODS: Activities of seven enzymes involved in nucleic acid metabolism--orotate phosphoribosyltransferase (OPRT), ribonucleotide reductase (RNR), thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, uridine phosphorylase and thymidine kinase (TK)--were measured in tumor and nontumor tissues from 28 patients who were operated on for colorectal cancers. RESULTS: OPRT, thymidylate synthase, RNR, thymidine phosphorylase, uridine phosphorylase and thymidine kinase activities were significantly higher in tumor areas than in nontumor areas. OPRT showed the highest T/N ratio (the ratio of each enzyme activity in tumor areas to that in nontumor areas). The T/N ratio of RNR activity showed a tendency to be associated with lymph node metastasis and Dukes classification. CONCLUSION: The results suggest that OPRT is a main enzyme participating in the phosphorylation of 5-fluorouracil and has an important role in tumor growth. The T/N ratio of RNR may be predictive of tumor progression.

Adult↗

PubMed2006

Enhancement of vascular smooth muscle cell migration by urotensin II.

The effects of urotensin II (UII) on migration of human aortic smooth muscle cells (HASMCs) were investigated. UII (1-100 nM) significantly increased velocity of HASMC motility in a concentration-dependent manner. Stress-fiber formation and ERK (p44/p42) activity were also increased by UII. U0126 and PD 98059, MEK inhibitors, abolished the effects of UII on motility velocity and stress-fiber formation. These results suggest that UII enhances HASMC migration through activation of an ERK-dependent pathway.

Aorta↗

PubMed2006

Lipoprotein (a) as a determinant of arterial stiffness in elderly patients with type 2 diabetes mellitus.

BACKGROUND: Lipoprotein (a) [Lp(a)] is known to be a risk factor for atherosclerotic disease. However, the relationship between Lp(a) and arterial stiffness has not been clarified. We investigated whether atherosclerotic risk factors, including serum Lp(a), are associated with aortic stiffness in elderly patients with type 2 diabetes mellitus. METHODS: Aortic stiffness, evaluated by using aortic pulse wave velocity, and major atherosclerotic risk factors were measured in elderly (> or =65 years) patients with type 2 diabetes mellitus. Relationships between aortic pulse wave velocity, Lp(a) and other atherosclerotic risk factors were analyzed. RESULTS: Among the atherosclerotic risk factors measured, age, pulse pressure, hemoglobin A1c (HbA1c), uric acid, fibrinogen, sialic acid and Lp(a) showed significant positive correlations with aortic pulse wave velocity. Lp(a) also showed significant positive correlations with pulse pressure, fibrinogen, sialic acid, apolipoprotein B and apolipoprotein B/apolipoprotein A-I ratio. The correlation between Lp(a) and aortic pulse wave velocity was independent of age, sex, blood hemoglobin A1c, uric acid and fibrinogen, history of diabetic nephropathy and therapy with lipid-lowering drugs. Apolipoprotein A-II showed a significant negative correlation with both aortic pulse wave velocity and Lp(a). The median level of Lp(a) in the highest tertile group of subjects divided by aortic pulse wave velocity was significantly higher than the median Lp(a) level in the lowest tertile. The middle and highest tertile groups of subjects divided by aortic pulse wave velocity showed significantly high odds ratios of high Lp(a) levels (> or =30 mg/dl) vs the lowest tertile. CONCLUSIONS: Lp(a) is an independent determinant of aortic stiffness in elderly patients with type 2 diabetes mellitus.

Aged↗

PubMed2006

Intracellular pH as a determinant of vascular smooth muscle function.

Intracellular pH (pHi) is a physiological parameter that is intimately linked to contractility, growth and proliferation of vascular smooth muscle (VSM). Regarding contractility, no general unifying concept of pHi regulation but a rather complex relation between pHi signals and vascular tone has been revealed so far. The modulation of vasotone by pHi depends on the type of blood vessel as well as on the pattern of regulatory input signals. In addition, changes in pHi have been recognized as an important cellular signal to determine the fate of cells in terms of proliferation or apoptosis. Cellular sensors for pHi include a variety of ion transport systems which control intracellular Ca2+ gradients and are likely to serve as a link between pHi and cell functions. Here we provide an overview on the potential targets and mechanisms that transduce pHi signals in VSM. The role of pHi-sensing signaling complexes and localized pHi signaling as the basis of diversity of pHi regulation of VSM function is discussed.

Animals↗

PubMed2006

TRPC4 expression determines sensitivity of the platelet-type capacitative Ca2+ entry channel to intracellular alkalosis.

The present study was designed to analyze the molecular basis of the intracellular pH-dependent capacitative Ca2+ entry (CCE) of human platelets and megakaryocytic cells, specifically to test the hypothesis that members of the classical transient receptor potential (TRPC) protein family are involved in the CCE pathway that is promoted by intracellular alkalosis. Human platelets as well as the tested megakaryocytic cell lines (CMK cells, MEG-01 cells) and HEK293 cells displayed thapsigargin-induced CCE and responded to monensin with comparable elevation in intracellular pH. Promotion of CCE by monensin-induced intracellular alkalosis, however, was profound in mature platelets, moderate in CMK cells and lacking in MEG-01 cells as well as in HEK293 cells. Analysis of the TRPC expression pattern by immunoblotting revealed that mature platelets and CMK cells express TRPC4 along with TRPC1 and TRPC3, while TRPC4 is lacking in MEG-01 cells. HEK293 cells displayed CCE characteristics as well as lack of TRPC4 expression similar to MEG-01 cells. Over-expression of TRPC4 in HEK293 cells was found to result in a gain of pH-sensitivity of CCE with clearly detectable promotion of CCE in response to monensin. These results suggest that platelet CCE channel complexes contain TRPC4 as a molecular component that determines sensitivity of CCE to intracellular alkalosis.

Alkalosis↗

PubMed2006

[Effects of age on the relationship between cardio-ankle vascular index and atherosclerotic progression in patients with type 2 diabetes mellitus].

AIM: A new indicator of arterial stiffness, cardio-ankle vascular index (CAVI), has recently been developed, instead of conventional pulse wave velocity. CAVI is proposed as a blood pressure-independent indicator of atherosclerosis, however, there have been few studies on the association of CAVI with atherosclerosis. The purpose of this study was to investigate effects of age on the relationship between CAVI and atherosclerotic risk in patients with diabetes mellitus. METHODS: The relationship between CAVI and atherosclerotic risk was investigated in 105 subjects with type 2 diabetes mellitus (mean age, 65.1 years old). The mean intima-media thickness (IMT) of the carotid artery was used as an indicator of atherosclerotic progression. RESULTS: In 55.2% of the subjects, CAVI was abnormally high (> or =9.0). In simple regression analysis, CAVI showed significant correlations with age, duration of diabetes and IMT. In logistic regression analysis, crude odds of abnormally high values of CAVI were significant for highest versus lowest tertile groups of mean arterial pressure (MAP) and IMT. Age-and sex-adjusted odds of abnormally high values of CAVI were significant for highest versus lowest tertile groups of mean arterial pressure (MAP) and serum total cholesterol. In multiple regression analysis, CAVI showed significant correlation with IMT independently of MAP but not independently of age, while the significant correlation of ankle-brachial pressure index (ABPI) with IMT was independent of age, sex and MAP. CONCLUSIONS: CAVI reflects atherosclerotic risk and the relationship between CAVI and atherosclerotic progression is strongly confounded by age. Thus, age should be taken into account when CAVI is used as an indicator of atherosclerotic progression.

Adult↗

PubMed2006

[Relationship between drinking alcohol and atherosclerotic risk factors in female Japanese workers of different ages].

AIM: To determine whether age influences the relationships of drinking alcohol with blood pressure and lipids in women. METHODS: The subjects were 53,911 female Japanese workers (20-69 years old) receiving annual health checkups at each workplace. The subjects were divided into three groups by daily average amount of ethanol consumed (non-drinkers; light drinkers, less than 30g ethanol/day; heavy drinkers, 30g ethanol/day or more). Blood pressure, body mass index (BMI) and total and HDL cholesterol were measured. RESULTS: In the age groups from twenties to fifties, BMI was significantly lower in light drinkers than in non-drinkers. In the forties and fifties age groups, systolic blood pressure in heavy drinkers was higher than that in non-drinkers, while no significant difference was found between non- and heavy drinkers in the twenties and thirties age groups. Diastolic blood pressure was higher in heavy drinkers than in non-drinkers in all age groups. Blood total cholesterol tended to be lower in drinkers than in non-drinkers at ages less than 60 years, while this relation was not observed in the sixties age group. Blood HDL cholesterol and atherogenic index tended to become higher and lower, respectively, with an increase in the amount of alcohol drinking in all age groups. CONCLUSION: In elderly women, the elevating effect of drinking on systolic blood pressure is increased and the lowering effects on BMI and blood total cholesterol are decreased. These results imply that drinking alcohol has less beneficial and more harmful effects on atherosclerotic risk in elderly women.

Adult↗

PubMed2006

[Alcohol abuse as a risk factor for ARDS].

Morbidity and mortality rates of ARDS (acute respiratory distress syndrome) are high in patients with a history of chronic alcohol abuse. In addition to susceptibility to lung infection, alteration of local cellular functions in the lung has recently been proposed as a new mechanism of exacerbation of ARDS in patients with a history of chronic alcohol abuse. Clinical studies and studies using animal experiments have shown that a decrease in lung glutathione levels is associated with exacerbation of ARDS in chronic alcohol abuse. In the alcoholic lung, depletion of glutathione increases oxidative stress derived from activated neutrophils, resulting in decreased surfactant production, apoptosis and increased permeability of alveolar epithelial type II cells, in which TGF-beta1 may be involved. Acetoaldehyde has been suggested to be involved in the mechanism of exacerbation of ARDS by inducing lung remodeling through stimulation of fibronectin expression following nicotinic acetylcholine receptor stimulation and CREB activation in chronic alcohol abuse. More recently, antagonists of angiotensin II type-1 receptor (AT1 receptor) have been shown to prevent glutathione depletion, increase in TGF-beta1 expression and lung edema in endotoxemic rats with chronic alcohol administration. On the other hand, macrophage-derived prostaglandin E2 plays a protective role at an initial phase of ARDS by inhibiting cytokine production by macrophages and extravascular invasion of activated neutrophils. Our recent studies have shown that LPS-induced COX-2 expression and subsequent prostaglandin E2 production in rat alveolar macrophages are inhibited by ethanol incubation in vitro and ethanol administration in vivo. Only a decade has passed since alcohol abuse was demonstrated to be associated with increased mortality of ARDS and future studies are needed to clarify the mechanism underlying alcohol-induced exacerbation of ARDS.

Alcoholism↗

PubMed2005

Inhibitory action of daunorubicin on lipopolysaccharide-stimulated inducible-type nitric oxide synthase induction in alveolar macrophages.

The purpose of this study was to investigate the effects of daunorubicin on lipopolysaccharide (LPS)-stimulated inducible-type nitric oxide synthase (iNOS) expression in macrophages. LPS-stimulated iNOS expression and NO production were significantly inhibited in alveolar macrophages from rats administrated daunorubicin (4 mg/kg body weight per day) for 5 consecutive days. Incubation of macrophages with daunorubicin at 1 muM but not at 0.1 and 0.5 muM significantly inhibited LPS-stimulated NO production and iNOS induction. Activation of extracellular regulated kinase (ERK) by LPS was markedly attenuated in both macrophages isolated from in vivo daunorubicin-treated rats and those incubated in vitro with daunorubicin at 1 microM. ERK activation, iNOS induction, and NO production following LPS stimulation were all markedly inhibited in the presence of U0126, an ERK inhibitor. The viability of macrophages was decreased by incubation with daunorubicin at 0.5 and 1 microM, while treatment of rats with daunorubicin did not affect viability of macrophages isolated from the rats. These results suggest that in vivo treatment of rats with daunorubicin attenuates LPS-induced iNOS expression of macrophages through inhibition of ERK activation, while inhibition of iNOS induction by in vitro incubation with daunorubicin may be mainly due to its cytotoxicity.

Animals↗

PubMed2005

5-Hydroxytryptamine as a potent migration enhancer of human aortic endothelial cells.

The purpose of the present study was to investigate whether 5-hydroxytryptamine (5-HT, serotonin) affects migration of vascular endothelial cells. 5-HT significantly enhanced migration of human aortic endothelial cells (HAECs), and this enhancement was completely inhibited by GR 55562, a 5-HT1 receptor antagonist, and fluoxetine, a 5-HT transporter inhibitor, but was not affected by ketanserin, a 5-HT2 receptor antagonist. 5-HT stimulation increased RhoA and ERK activity of HAECs, and inhibitors of RhoA (Y-27632 and H-1152) and inhibitors of MEK (U0126 and PD98059) abolished the 5-HT-induced increase in migration velocity. Inhibition of Rho kinase by Y-27632 blocked stress fiber formation and rear release of HAECs. Thus, 5-HT has a potent enhancing action on migration of HAECs through activating the RhoA and ERK pathways following 5-HT1 receptor stimulation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2005

Enhancement of alcohol dehydrogenase activity in vitro by acetylsalicylic acid.

The interaction of acetylsalicylic acid with alcohol dehydrogenase was investigated. Horse liver alcohol dehydrogenase bound to a p-hydroxyacetophenone affinity column was eluted by acetylsalicylic acid. In vitro enzymatic activity of alcohol dehydrogenase in the presence of ethanol as a substrate was significantly increased by incubation with acetylsalicylic acid. These results suggest that acetylsalicylic acid has an affinity with alcohol dehydrogenase and enhances its activity.

Alcohol Dehydrogenase↗

PubMed2005

5-Hydroxytryptamine augments migration of human aortic smooth muscle cells through activation of RhoA and ERK.

The purpose of this study was to elucidate the mechanism of 5-hydroxytryptamine (5-HT, serotonin) action on migration of vascular smooth muscle cells. Migration of cultured human aortic smooth muscle cells (HASMCs), evaluated using time-lapse microscopy, was significantly enhanced by 5-HT at concentrations of 1-100 nM. The enhancing effect of 5-HT on cell migration was markedly inhibited in the presence of ketanserin, a 5-HT2 receptor antagonist, but not by GR 55562, a 5-HT1 receptor antagonist. Activities of RhoA and ERK were increased by 5-HT, and the increase in cell migration by 5-HT was abolished in the presence of U0126, a MEK1/2 inhibitor, or Y-27632, a Rho-kinase inhibitor. Activation of ERK was strongly inhibited by Y-27632. 5-HT-induced formation of stress fiber and detachment of uropod (trailing edge) were abolished by Y-27632. Thus, 5-HT has a potent enhancing action on migration of HASMCs due to an increase in stress fiber formation by 5-HT2 receptor stimulation followed by activation of the Rho-kinase and ERK pathways.

Aorta↗

PubMed2005

Association of acute-phase reactants with arterial stiffness in patients with type 2 diabetes mellitus.

BACKGROUND: The relationship between chronic low-grade inflammation and atherosclerotic progress in patients with diabetes mellitus has not been confirmed. We determined whether acute-phase reactants are associated with arterial stiffness in diabetic patients. METHODS: Relationships of blood inflammatory markers [high-sensitivity C-reactive protein (CRP), amyloid A protein (SAA), sialic acid, fibrinogen and white blood cells (WBC)] with atherosclerosis were investigated in a cross-sectional study using 114 subjects with type 2 diabetes. The degree of atherosclerosis was evaluated by arterial stiffness measured using cardio-ankle vascular index (CAVI), a new index of arterial stiffness, which is compatible with conventional aortic pulse-wave velocity. RESULTS: CRP, SAA, sialic acid, fibrinogen and WBC showed significant correlations with CAVI. CAVI was significantly higher in the highest tertile of sialic acid, fibrinogen and WBC compared with the lowest tertile or lowest and middle tertiles. This association was independent of age, sex and smoking. By logistic regression analysis, the highest levels of these acute-phase reactants showed increased risk of high CAVI, while CRP and SAA were not associated with an increased risk in this analysis. CAVI was also significantly correlated with duration of diabetes, blood pressure and serum total cholesterol. CONCLUSIONS: Acute-phase reactants, such as CRP, SAA, sialic acid, fibrinogen and WBC, are associated with arterial stiffness in patients with type 2 diabetes mellitus.

Acute-Phase Reaction↗

PubMed2005

Monensin augments capacitative Ca2+ entry and subsequent aggregation of platelets via an intracellular alkalosis-mediated mechanism.

Effects of monensin, an ionophore that facilitates the transmembrane exchange of Na+ for H+, on capacitative Ca2+ entry (CCE) of platelets were investigated. CCE of human platelets was induced by addition of Ca2+ to a nominally Ca2+-free medium after release of intracellular stored Ca2+ caused by thapsigargin. CCE was strongly inhibited by SKF-96365 (1-[beta-(3-[4-methoxyphenyl]propoxy)-4-methoxyphenethyl]-1H-imidazole hydrochloride). Monensin significantly increased SKF-96365-sensitive CCE and subsequent platelet aggregation. Monensin also induced a sustained increase in intracellular pH. The augmenting effect of monensin on CCE and subsequent platelet aggregation was not observed in the presence of sodium propionate, which canceled intracellular alkalinization induced by monensin. These results suggest that monensin augments CCE of platelets by a mechanism mediated by intracellular alkalosis.

Alkalosis↗

PubMed2005

Sensitivity of circulatory response to alcohol influences the relationship between alcohol consumption and blood pressure in Orientals.

There is a genetic difference in sensitivity to alcohol in Orientals, which is known to be mainly due to polymorphisms of alcohol-metabolizing enzymes such as aldehyde dehydrogenase. Habitual alcohol drinking is a risk factor for hypertension. However, it has not been determined whether individual sensitivity to alcohol influences the relationship between alcohol consumption and blood pressure. In this study, the relationship between amount of alcohol consumption and blood pressure was compared between groups of subjects with low and high sensitivities of circulatory response to alcohol. Sensitivity to alcohol in subjects (306 male workers) was evaluated by a self-administered questionnaire on symptoms (skin flushing and palpitation) that appear when drinking alcohol. Weight, height and blood pressure were measured. In subjects with high sensitivity to alcohol, systolic blood pressure was significantly higher in the subgroup of moderate-to-heavy drinkers (30 g/day or more) than in the subgroups of non-drinkers and light drinkers (less than 30 g/day). On the other hand, in subjects with low sensitivity to alcohol, systolic blood pressure in the subgroup of non-drinkers was not significantly different from that in the subgroups of light drinkers and moderate-to-heavy drinkers. The amount of daily alcohol consumption was significantly correlated with both systolic and diastolic blood pressures in subjects with high sensitivity to alcohol but not in subjects with low sensitivity to alcohol. Pressor effects of alcohol drinking on blood pressure were significant only in subjects with high sensitivity to alcohol, suggesting that there is a greater risk of development of hypertension from drinking large amounts of alcohol in people with high sensitivity to alcohol.

Adult↗

PubMed2005

Effects of acute ethanol administration on LPS-induced expression of cyclooxygenase-2 and inducible nitric oxide synthase in rat alveolar macrophages.

BACKGROUND: Activation of alveolar macrophages acts as a primary defense mechanism of lung with immunologic and inflammatory processes. Incidence of respiratory distress syndrome (ARDS) has been reported to be higher in alcoholics than that in nonalcoholics. Both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are induced by inflammatory stimuli such as LPS and cytokines and are involved in host defense. COX-2 and iNOS have been reported to play important roles in pathophysiology of ARDS. The aim of the present study was to elucidate whether acute ethanol administration to rats affects on COX-2 and iNOS expression in isolated alveolar macrophages. METHODS: Ethanol (4.5 g per kg body weight as a 20% solution) was intraperitoneally injected to male Wistar rats. At 2.5 hrs after the injection, alveolar macrophages were collected from rats by bronchoalveolar lavage and were stimulated with lipopolysaccharide (LPS, 1 mug/ml). Expression of COX-2 and iNOS and activation of MAPKs was evaluated by Western blotting. RESULTS: In alveolar macrophages isolated from ethanol-treated rats, LPS-stimulated production of both prostaglandin E2 and nitrite was significantly lower than that in macrophages isolated from vehicle-treated control rats. LPS-induced expression of both COX-2 and iNOS was significantly lower in macrophages from ethanol-treated rats than that in macrophages from the control rats, while expression of beta-actin was not different in these groups. LPS increased phosphorylation of both extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). The levels of phosphorylated ERK and p38 were significantly lower in macrophages from ethanol-treated rats compared with those from the control rats. Treatment of macrophages with ethanol (100 - 400 mM) in vitro significantly inhibited expression of COX-2 in a concentration-dependent manner, while only a high concentration (400 mM) of ethanol significantly inhibited expression of iNOS. Ethanol also inhibited COX-2 expression in the presence of Tiron. Expression of COX-2 and iNOS was significantly inhibited by U0126 but not by SB203580. CONCLUSION: In rat alveolar macrophages, LPS-induced expression of COX-2 and iNOS is mediated by ERK MAPK but not by p38 MAPK. Acute ethanol administration to rats attenuates induction of both COX-2 and iNOS in alveolar macrophages by inhibiting phosphorylation of ERK.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗

PubMed2005

Interactions of alcohol dehydrogenase to p-hydroxyacetophenone-sepharose and p-acetamidophenol-sepharose.

BACKGROUND: p-Hydroxyacetophenone (HAP)-sepharose is known to be an effective ligand for isolation of aldehyde dehydrogenase and chloramphenicol acetyltransferase. In this study, we investigated ligand specificities to alcohol dehydrogenase (ADH) using p-HAP-sepharose and p-acetamidophenol (AAP)-sepharose. METHODS: p-HAP and p-AAP were coupled to epoxy-activated sepharose and used as ligands for affinity chromatography to detect binding proteins. Fractions of affinity chromatography were collected and separated by SDS-PAGE. Commassie brilliant blue staining was carried out for detecting proteins. For determining protein sequences, polypeptide was separated by HPLC after cleavage of Lys-specific protease digestion. RESULTS: p-HAP ligands have the ability to bind to seven proteins, including class I ADH extracted from a rat cytosolic fraction as well as HLADH (horse liver ADH). p-HAP, p-AAP and benzaldehyde (10 mM each) could elute HLADH from the complex of HLADH-pHAP-sepharose column. On the other hand, p-AAP-sepharose has no ability to bind to HLADH, although three proteins from a rat liver cytosolic fraction were found to be able to bind to p-AAP-sepharose. CONCLUSIONS: p-HAP binds to ADH in a structure-specific manner and this binding is nonspecific to species of origin of ADH.

Acetaminophen↗

PubMed2005

Diminution of angiotensin II-induced contraction of the abdominal aorta isolated from Watanabe heritable hyperlipidemic rabbits.

The purpose of this study was to investigate the changes in vasocontractile responses in atherosclerosis, using abdominal aortic strips isolated from Watanabe heritable hyperlipidemic (WHHL) rabbits and Japanese White (control) rabbits. The aortic strips from WHHL rabbits showed a significantly lower contractile response to angiotensin II than that in strips from control rabbits. The contractile responses to phenylephrine and 5-hydroxytryptamine were not different in WHHL and control groups. The contractile response to angiotensin II was higher in endothelium-denuded aortic strips than in endothelium-intact strips, but to a greater extent in the control group than in the WHHL group. The contractile response to angiotensin II in the absence of the endothelium was also lower in the WHHL group than in the control group. Pretreatment with N(G)-nitro-L-arginine significantly increased the contractile response to angiotensin II in the endothelium-intact aortic strips in both the WHHL and control groups, while pretreatment with diclofenac did not affects the aortic contractile response to angiotensin II. The contractile responses to angiotensin II in the presence of N(G)-nitro-L-arginine and diclofenac were lower in the WHHL group than in the control group. The contractile response to angiotensin II in the presence of PD123319 was also lower in the WHHL group than in the control group. Endothelium-dependent relaxation by acetylcholine occurred to the some extent in the WHHL and control groups. These results suggest that the WHHL rabbit abdominal aorta displays attenuated angiotensin II-induced contraction, mainly due to an abnormality in the angiotensin II-specific contractile pathway of the medial smooth muscle.

Angiotensin II↗