Arterial stiffness of the aorta and iliofemoral artery and their responses to nitroglycerin administration in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits.

OBJECTIVES: The role of hypercholesterolemia in arterial stiffness, which usually reflects the progression of atherosclerosis has not been fully investigated. To clarify the meaning of arterial stiffness in hypercholesterolemia, we evaluated arterial stiffness in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits by using new arterial stiffness indices of the aorta and common iliac to femoral artery. The new arterial stiffness indices of both arteries were determined by the application of the theory of cardio-ankle vascular index (CAVI) to the aorta (aBeta) and ilio-femoral artery (ifBeta). Furthermore, the responses of both indices to nitroglycerin (NTG) administration were compared between WHHHMI and normal rabbits. DESIGN AND METHODS: aBeta and ifBeta of WHHLMI and normal rabbits were measured under anesthesia. Pulse wave velocity in the whole aorta (aPWV) and ilio-femoral artery (ifPWV), blood pressure, and other parameters were measured before and after administration of NTG (50-120 µg/kg/min) every 1 for 5 min. RESULTS: Atherosclerotic lesions were observed in the aorta, but a little in the ilio-femoral artery in WHHLMI rabbits. Compared with normal rabbits, aBeta was significantly higher, but ifBeta was lower in WHHLMI rabbits. When NTG was administered, ifBeta decreased significantly in both groups; however, aBeta increased in normal rabbits, but remained unchanged in WHHIMI rabbits. CONCLUSION: These findings suggested that hereditary hypercholesterolemia in rabbits did not uniformly enhance arterial stiffness in elastic artery and muscular artery. The responses to NTG were also different between two arteries. The mechanism of these different responses needs further studies.

Estimation of Central Systolic Blood Pressure from Peripheral Pressure Waves using a Novel Second Systolic Pressure-Based Method in Normal and Heritable Hypercholesterolemic Rabbits.

AIM: Central systolic blood pressure (cSBP) was closely related to hypertension-related organ damage rather than peripheral systolic blood pressure (pSBP). We aimed to estimate cSBP from pSBP without generalized transfer function in normal and Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits aged 12 months. METHODS: Two catheter-tip transducers were advanced into the ascending aorta (AA) and distal end of the right brachial artery (Br) through the right common carotid and right radial arteries, respectively, under pentobarbital anesthesia. Pressure waves in response to the intravenous administration of angiotensin II and sodium nitroprusside were simultaneously recorded in AA and Br under regular cardiac pacing. RESULTS: The first (pSBP) and second peaks (pSBP2) of the brachial blood pressure and their average (pSBPm) were significantly correlated with cSBP, despite Murgo's wave pattern of central pressure waves in both rabbit groups. In Bland-Altman plot and its modification as a function of the peripheral augmentation index (pAI) analyses, the differences between pSBP and cSBP decreased, and those between pSBP2 and cSBP increased significantly in their average- or pAI-dependent manner, with undeniable mean biases in both rabbit groups. When the same analyses for SBPm were performed instead, the mean bias was around zero, with reduced variance in the two rabbit groups. The observed pressure or pAI-dependent systematic biases for pSBP and pSBP2 disappeared, representing the precise feature of pSBPm as a cSBP estimate. CONCLUSIONS: We conclude that pSBPm could be more precise than pSBP2 as a cSBP estimate, irrespective of blood pressure levels, pAI, or the presence of atherosclerosis.

Opposing Responses of the Calcium Channel Blocker Nicardipine to Vascular Stiffness in the Elastic and Muscular Arteries in Rabbits.

AIM: The cardio-ankle vascular index (CAVI) consists of intrinsic and functional arterial stiffness mainly regulated by vasoactive compounds. A new stiffness index of the aorta (aBeta) and iliac-femoral arteries (ifBeta) was determined by applying the CAVI theory to the whole aorta and iliac-femoral arteries. We investigated the changes in aBeta and ifBeta in response to decreased blood pressure (BP) induced by the Ca2＋ channel blocker nicardipine to elucidate the involvement of Ca2＋ in aBeta and ifBeta. METHODS: Pressure waves at the origin of the aorta (oA), distal end of the abdominal aorta (dA), and left femoral artery (fA) as well as flow waves at the oA were simultaneously recorded before and after the infusion of nicardipine (50 µg/kg/min) for 2 min in 12 male rabbits under pentobarbital anesthesia. Beta was calculated using the following formula: Beta=2ρ / PP×ln (SBP / DBP)×PWV2, where ρ, SBP, DBP, and PP denote blood density and systolic, diastolic, and pulse pressures, respectively. aBeta, ifBeta, and aortic-iliac-femoral Beta (aifBeta) were calculated using aPWV, ifPWV, and aifPWV, respectively. RESULTS: SBP, mean arterial pressure (MAP), DBP, and total peripheral vascular resistance significantly decreased during the administration of nicardipine, whereas cardiac output significantly increased. aBeta and ifBeta significantly increased and decreased, respectively, whereas aifBeta did not change despite the decrease in BP. ifBeta and aBeta positively and negatively correlated with BP, respectively, whereas aifBeta did not correlate with SBP. CONCLUSIONS: There were contradictory arterial responses to nicardipine between the elastic and muscular arteries. Unknown vasoconstriction mechanisms that are not involved in Ca2＋ influx may function in the aorta in response to decreased BP.

Different Responses of Arterial Stiffness between the Aorta and the Iliofemoral Artery during the Administration of Phentolamine and Atenolol in Rabbits.

AIM: The mechanism underlying the stiffness of the aorta and iliofemoral artery that is required to maintain blood pressure (BP) is unclear. A new stiffness index of the aorta (aBeta) and iliac-femoral arteries (ifBeta) was defined by applying the cardio-ankle vascular index (CAVI). We compared changes in stiffness of the two arteries in response to reduced BP, due to the non-selective α adrenergic blocker phentolamine and the ß1 adrenergic blocker atenolol, in rabbits. METHODS: Pressure waves at the origin (oA) and distal ends of the aorta (dA) and the distal end of the left femoral artery (fA) were recorded simultaneously using three pressure sensors in 25 anesthetized rabbits. Phentolamine (50 µg/kg/min) and atenolol (10 mg/kg/min) were infused for 2 min. The pulse wave velocity (PWV) in each artery was determined; aBeta, ifBeta, and whole Beta (aifBeta) were calculated by the following formula; Beta=2ρ/PP×ln(SBP/DBP)×PWV2 (ρ: blood density; SBP, SBP, and PP: systolic, diastolic, and pulse pressures, respectively). RESULTS: SBP and DBP at oA, dA, and fA decreased by the administration of phentolamine and atenolol, with and without decreased total peripheral vascular resistance. After phentramine infusion, cardiac output (CO), aBeta, and aifBeta increased, while ifBeta decreased. After infusion of atenolol, CO decreased, while aBeta, ifBeta, and aifBeta remained unchanged. CONCLUSION: The contradictory reactions of aBeta and ifBeta to phentolamine suggest that the stiffness of the aorta and ilio-femoral artery is regulated separately during decreased BP induced by phentolamine, but not by atenolol.

Spaceflight affects postnatal development of the aortic wall in rats.

We investigated effect of microgravity environment during spaceflight on postnatal development of the rheological properties of the aorta in rats. The neonate rats were randomly divided at 7 days of age into the spaceflight, asynchronous ground control, and vivarium control groups (8 pups for one dam). The spaceflight group rats at 9 days of age were exposed to microgravity environment for 16 days. A longitudinal wall strip of the proximal descending thoracic aorta was subjected to stress-strain and stress-relaxation tests. Wall tensile force was significantly smaller in the spaceflight group than in the two control groups, whereas there were no significant differences in wall stress or incremental elastic modulus at each strain among the three groups. Wall thickness and number of smooth muscle fibers were significantly smaller in the spaceflight group than in the two control groups, but there were no significant differences in amounts of either the elastin or collagen fibers among the three groups. The decreased thickness was mainly caused by the decreased number of smooth muscle cells. Plastic deformation was observed only in the spaceflight group in the stress-strain test. A microgravity environment during spaceflight could affect postnatal development of the morphological and rheological properties of the aorta.

Local pulse wave velocity directly reflects increased arterial stiffness in a restricted aortic region with progression of atherosclerotic lesions.

We investigated local pulse wave velocity (LPWV) in different aortic segments with respect to the rheological properties of the aorta with age-related progression of atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. Normal and KHC rabbits aged 10-12, 22-24 and 34-36 months were anesthetized with pentobarbital sodium (30 mg kg(-1), intravenous). Pulse waves at the ascending aorta were recorded simultaneously with those at the proximal, middle and distal thoracic and abdominal aortas by moving a catheter with three micromanometers (40-mm intervals) at 80-mm intervals from the origin of the descending thoracic aorta. The aortic diameter was measured using an intravascular imaging system at the same aortic position at which the pulse waves were measured. LPWV was the greatest in the aortic arch, decreased gradually in the thoracic aorta and increased again in the abdominal aorta in KHC rabbits, whereas it was the lowest in the aortic arch, increased slightly in the thoracic aorta and increased gradually in the abdominal aorta in normal rabbits. LPWV increased significantly with age in most aortic segments. The change pattern of LPWV resembled that of the percent fractional lesioned area where LPWV was determined. The significant increase in LPWV with age was mainly due to the increase in the elastic modulus of the aortic wall with atherosclerotic progression as well as the increase in wall thickness. LPWV accurately detected the presence of atherosclerotic lesions and alteration in the rheological properties of the aortic regions through which pulse waves travelled.

Chronic phencyclidine treatment induces long-lasting glutamatergic activation of VTA dopamine neurons.

Use of phencyclidine (PCP) can mimic some aspects of schizophrenia. However, the underlying mechanism is unclear. Administration of PCP is known to activate mesolimbic dopamine pathway. In this study, we focused on ventral tegmental area (VTA) of mesolimbic dopamine pathway as target of PCP for inducing schizophrenia-like symptoms. Single VTA neuron was isolated and its neural activity was monitored by measuring cytosolic Ca(2+) concentration ([Ca(2+)]i) followed by immunocytochemical identification of dopamine neurons. Administration of glutamate increased [Ca(2+)]i in dopamine neurons from control rats, and the [Ca(2+)]i increase was inhibited in the presence of PCP. In contrast, in VTA dopamine neurons from rats chronically treated with PCP for 7 days, administration of glutamate was able to induce [Ca(2+)]i increase in the presence of PCP. Furthermore, this glutamate-induced [Ca(2+)]i increase in the presence of PCP continued even after washout of glutamate and this effect lasted as long as PCP was present. This long-lasting glutamate-induced [Ca(2+)]i increase in the presence of PCP was not observed or significantly attenuated under Ca(2+) free condition and by N-type Ca(2+) channel blocker ω-conotoxin. The results indicate that chronic treatment with PCP reverses the acute PCP effect on VTA dopamine neurons from inhibitory to stimulatory tone, and consequently induces long-lasting activation of dopamine neurons by glutamate.

Subservient relationship of the peripheral second systolic pressure peak to the central hemodynamic parameters is preserved, irrespective of atherosclerosis progression in hypercholesterolemic rabbits.

We investigated whether the subservient relationship of peripheral to central hemodynamic parameters, such as the augmentation index (AI) and the second systolic (SBP2) and pulse pressures, were preserved with the progression of atherosclerosis in the Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbit, an animal model for hypercholesterolemia and atherosclerosis. Male KHC rabbits, aged 12 and 24 months, were anesthetized with pentobarbital sodium. Two catheter-tip transducers were introduced to the central (ascending aorta) and peripheral (distal region of the right brachial artery) arteries through the left common carotid and the right radial arteries, respectively. Pressure waves were simultaneously recorded under regular atrial pacing to investigate changes in response to the intravenous infusion of angiotensin II (Ang II) (30-40 ng kg(-1) min(-1)) and sodium nitroprusside (NTP) (20-30 µg kg(-1) min(-1)). Central systolic blood pressure (cSBP) and diastolic blood pressure (DBP), peripheral systolic blood pressure (pSBP) and DBP, and peripheral second systolic blood pressure (pSBP2) showed no significant difference between the 12- and 24-month-old groups before the administration of vasoactive drugs. There was no significant difference in central AI (cAI) between the two age groups before the drug infusion, even though atherosclerosis progressed with aging. Peripheral AI (pAI) changed in parallel with cAI in response to vasopressor and depressor actions due to the infusion of Ang II and NTP, respectively. We conclude that the subservience of pSBP2 to cSBP and pAI to cAI, in addition to the regression relationship of these parameters between peripheral and central arteries, were well preserved, irrespective of the progression of atherosclerosis.

Basis of monitoring central blood pressure and hemodynamic parameters by peripheral arterial pulse waveform analyses.

In hypertension clinics, central blood pressure (CBP) should be estimated, instead of directly measured, by the "signal processing" of a noninvasive peripheral pressure waveform. This paper deals with the data obtained in our three separate studies focusing on a major estimation method, i.e., radial artery late systolic shoulder pressure (rSBP2)-based CBP estimation. Study 1: Using a wave separation analysis of precise animal data of pressure wave transmission along the upper-limb arteries, we first demonstrate that pulse pressure amplification is largely attributable to local wave reflection alone. Study 2: A frequency component analysis of simultaneously recorded human central and radial artery pressure waveforms showed a predominance of lower (1st+2nd) harmonic components in determining the central augmentation peak amplitude. The features of a central pressure waveform, including its phase property, may contribute to the less-altered transmission of augmentation peak pressure to rSBP2. Study 3: Comparisons of noninvasive rSBP2 with direct or estimated central systolic blood pressure (cSBP) revealed broad agreement but also augmentation-dependent biases. Based on the features of the biases as well as the counterbalanced relationship between pulse pressure amplification and the transmission-induced alterations of augmentation peak amplitude observed in Study 2, we propose an improved cSBP estimate, SBPm, the simple arithmetic mean of rSBP2 and peripheral systolic blood pressure.

Does the augmentation index of pulse waves truly increase with progression of atherosclerosis? An experimental study with hypercholesterolemic rabbits.

BACKGROUND: Recently, the central augmentation index (AIx) has been reported to show a nonlinear correlation with age. We investigated whether the AIx of the central artery changes with the progression of atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. METHODS: We simultaneously recorded pressure and flow waves in the ascending aorta in normal and KHC rabbits aged 10-12, 22-24, and 34-36 months, under pentobarbital anesthesia. RESULTS: The systolic, diastolic, and mean arterial pressures and total peripheral vascular resistance were significantly higher in KHC rabbits than in their age-matched controls. The systolic pressure of the KHC rabbits increased with age. Additionally, the AIx of the KHC rabbits was significantly higher than that of their age-matched controls, although the AIx did not show a significant age-dependent increase in either of the two rabbit groups. However, the development of atherosclerotic lesions progressed markedly in KHC rabbits, and the early and late (pulse pressure [PP]) systolic waves increased progressively in amplitude with age in the KHC rabbits. On the other hand, no significant differences were seen in the normal and KHC rabbits' cardiac output (CO), stroke volume (SV), or heart rate (HR) at any age, nor did the two strains show significant age-related changes in these variables. Aortic compliance (SV/PP) was significantly lower in the 22-24- and 34-36-month-old KHC rabbits than in their age-matched controls, and decreased with age in the KHC rabbits. CONCLUSIONS: Although the progression of atherosclerosis stiffened the aortic wall, it did not affect the AIx. This was partly the result of the decreased distensibility of the wall, in which the pressure waves used to determine AIx were measured.

Differences in rates of decrease of environmental radiation dose rates by ground surface property in Fukushima City after the Fukushima Daiichi nuclear power plant accident.

After the Great East Japan Earthquake on 11 March 2011, the environmental radiation dose in Fukushima City increased. On 11 April, 1 mo after the earthquake, the environmental radiation dose rate at various surfaces in the same area differed greatly by surface property. Environmental radiation measurements continue in order to determine the estimated time to 50% reduction in environmental radiation dose rates by surface property in order to make suggestions for decontamination in Fukushima. The measurements were carried out from 11 April to 11 November 2011. Forty-eight (48) measurement points were selected, including four kinds of ground surface properties: grass (13), soil (5), artificial turf (7), and asphalt (23). Environmental radiation dose rate was measured at heights of 100 cm above the ground surface. Time to 50% reduction of environmental radiation dose rates was estimated for each ground surface property. Radiation dose rates on 11 November had decreased significantly compared with those on 11 April for all surface properties. Artificial turf showed the longest time to 50% reduction (544.32 d, standard error: 96.86), and soil showed the shortest (213.20 d, standard error: 35.88). The authors found the environmental radiation dose rate on artificial materials to have a longer 50% reduction time than that on natural materials. These results contribute to determining an order of priority for decontamination after nuclear disasters.

To what extent does aortic pulse wave velocity estimate early atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic rabbits?

Pulse wave velocity (PWV), an index of arterial stiffness, is dependent not only on structural alterations in arterial wall but also on distending pressure, which could be related to wall distensibility. We investigated the efficacy of aortic PWV (AoPWV) for detecting early to moderate atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. Pressure waves were recorded at the ascending, and proximal and distal abdominal aortas in 13 male normal and KHC rabbits aged 12 months under pentobarbital anesthesia when angiotensin II or sodium nitroprusside was infused intravenously. AoPWV was compared between the two rabbit groups at different mean arterial pressure (MAP) levels. Vascular diameter (D(m)) was measured using an intravascular ultrasound imaging system in the proximal thoracic and proximal abdominal aortas to determine pressure-strain elastic modulus (E(p)). AoPWV was correlated to MAP in the two rabbit groups (P < 0.001). AoPWV was slightly but significantly greater (< 0.5 m s(-1)) in the KHC rabbit group than in the normal rabbit group at MAP level >80 mm Hg (P < 0.01). The value of h/D(m) (h, wall thickness) was significantly high in the KHC rabbit group at any MAP level (P < 0.001) in these aortic regions. There was no significant difference in E(p) and D(m) between the two rabbit groups at any MAP level. AoPWV showed only a slight but significant increase in the young KHC rabbits at different MAP levels, which was mainly due to the increased h/D(m). AoPWV could underestimate aortic stiffness due to early to moderate atherosclerosis if AoPWV was adjusted for arterial pressure level.

Safflower seed polyphenols (N-(p-coumaroyl)serotonin and N-feruloylserotonin) ameliorate atherosclerosis and distensibility of the aortic wall in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits.

Pulse wave velocity (PWV) has been used clinically as a direct measure of arterial stiffness. We investigated the inhibitory effects of defatted safflower seed extract (SSE) and serotonin derivatives (N-(p-coumaroyl)serotonin, N-feruloylserotonin; CS+FS), which are the active components in SSE, on hypercholesterolemia and atherosclerosis, using PWV in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. SSE and CS+FS were supplemented with a commercial diet containing 0.5% cholesterol for 8 weeks in male KHC rabbits, aged 2 months. Pulse waves were recorded at different aortic positions using two catheters with micromanometers under pentobarbital anesthesia. The atherosclerotic lesioned area in the aorta was significantly reduced in the SSE and CS+FS groups, without significant changes in serum cholesterol and triglyceride levels among the three groups after supplementation. Local PWV (LPWV) in the middle thoracic and distal abdominal aortas was significantly smaller in the SSE and CS+FS groups than in the control group. PWV in the entire aorta was also significantly lower in the SSE and CS+FS groups, compared with that in the control group. Pressure-strain elastic modulus, an index of wall distensibility, was significantly lower in the middle thoracic and middle abdominal aortas in the SSE and CS+FS groups than in the control group. Wall thickness was also significantly smaller in the middle thoracic aorta in the SSE and CS+FS groups compared with that in the control group. Serotonin derivatives inhibited the progress of atherosclerosis and ameliorated wall distensibility, which contributed, in part, to the lowering of LPWV. Serotonin derivatives may be beneficial in improving vascular distensibility and in reducing cardiovascular risk.

Correlation between augmentation index and pulse wave velocity in rabbits.

PURPOSE: Pulse wave velocity (PWV) is a direct measure of large arterial stiffness. Augmentation index (AIx) is a surrogate measure of arterial rigidity that could be affected by the ventricular ejection and peripheral haemodynamics in addition to the properties of large arteries. In clinical studies, it is still controversial whether PWV depends on AIx or not. We investigated a relationship between PWV and AIx in young normal rabbits when mean arterial pressure (MAP) level was altered using vasoactive drugs. MATERIALS AND METHODS: Pulse waves were simultaneously recorded in the ascending, proximal and distal abdominal aortas in response to intravenous infusion of angiotensin II or sodium nitroprusside in fifteen normal rabbits anaesthetized with pentobarbital sodium. Changes in intravascular diameters were measured using an intravascular ultrasound imaging system in the proximal thoracic and proximal abdominal aortas to determine pressure-strain elastic modulus (Ep). RESULTS: PWV from the ascending aorta to the bifurcation of the common iliac arteries and AIx at the ascending aorta were changed with MAP level in response to vasoactive drugs. Significant and positive correlation was observed between PWV and MAP. AIx was correlated significantly with systolic, diastolic and mean arterial pressures. PWV and AIx showed significant and positive correlation mainly with Ep in the proximal thoracic and proximal abdominal aortas, respectively. There was significant correlation between PWV and AIx (r = 0.66, P < 0.001). CONCLUSION: AIx was changed dependently on PWV when the MAP level was changed with vasoactive drugs, which was partly associated with the change in Ep.

Deep-sea water improves cardiovascular hemodynamics in Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits.

Deep-sea water is rich in minerals, e.g., Mg, Ca, and K which have been considered to be associated with prevention of cardiovascular disease. We investigated the effect of deep-sea water on cardiovascular hemodynamics in Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits. Deep-sea water was pumped in the offing of Cape Muroto in Japan and the mineral constituents were refined to a degree of hardness of 1,000. Twenty four 4-month-old KHC rabbits were given refined deep-sea water (n=12) and tap water (n=12) for 6 months. Pressure and flow waves at the ascending aorta were recorded under pentobarbital anesthesia. Systolic, diastolic, pulse and mean arterial pressures and total peripheral resistance were significantly lower in the deep-sea water group than in the control group. There were no significant differences in changes in serum lipid levels, plasma renin and angiotensin converting enzyme activities and electrolyte levels except for Mg(2+) after the feeding of the water between the two groups. A slight increase in serum Mg(2+) level in the deep-sea water group may not account for the inhibition of mild hypertension. From our results, we conclude that deep-sea water could improve cardiovascular hemodynamics, even though the factors which affect the blood pressure are still unknown.

Mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits.

The coexistence of hypertension and hypercholesterolaemia from youth may increase the prevalence of and mortality from cardiovascular disease and stroke. We thus investigated haemodynamics of mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits aged 10-12 months old, as models of heritable hypercholesterolaemia. Pressure and flow waves were simultaneously recorded at the ascending aorta with a catheter-tip micromanometer and ultrasonic flow meter under pentobarbital anaesthesia, respectively. Systolic (119.3 +/- 6.5 and 138.4 +/- 7.4 mmHg (mean +/- SD) for control and KHC rabbit groups; p < 0.001), diastolic (95.7 +/- 6.1 and 109.8 +/- 5.2; p < 0.001), mean (105.8 +/- 6.5 and 122.5 +/- 4.9; p < 0.001) and pulse (23.7 +/- 2.5 and 28.6 +/- 4.0; p < 0.001) pressures as well as total peripheral vascular resistance (0.32 +/- 0.02 and 0.37 +/- 0.03 mmHg/ml/min; p < 0.001) were significantly greater in the KHC rabbit group than those in the age-matched control rabbit group, respectively, while there were no significant differences in the mean aortic flow, heart rate or stroke volume between the two rabbit groups. Aortic input impedance (p < 0.05) and reflection coefficient (p < 0.05) were significantly greater at lower frequency in the KHC rabbit group than in the control rabbit group, whereas there was no significant difference in the characteristic impedance between the two rabbit groups. Plasma angiotensin I (p < 0.01) and II (p < 0.01) levels and serum angiotensin converting enzyme activity (p < 0.05) were significantly greater in the KHC rabbit group than in the age-matched control rabbit group. Atheromatous plaque was in the early stage and composed mainly of abundant foam cells. Neither sclerotic lesions nor stenosis were observed in main peripheral arteries. The mild hypertension in young KHC rabbits was due partly to the increased activity of the renin-angiotensin system. These findings may be thought provoking in elucidating the mechanism and developing preventive and therapeutic strategies in young patients with coexistent hypertension and hypercholesterolaemia.

Action mechanism of an angiotensin I-converting enzyme inhibitory peptide derived from chicken breast muscle.

In a previous study, we isolated the inhibitory peptide (P4 peptide, Gly-Phe-Hyp-Gly-Thr-Hyp-Gly-Leu-Hyp-Gly-Phe) for angiotensin I-converting enzyme (ACE) from chicken breast muscle extract possessing hypotensive activity for spontaneously hypertensive rats (SHRs). This study was performed to elucidate the peptide's action mechanisms of inhibiting ACE. Intravenous administration of synthetic P4 peptide resulted in significant drops in the blood pressures of SHRs. As Dixon plots indicate, the P4 peptide showed high affinity toward ACE (K(i) = 11.48 microM) and only 10% of the total amount of the P4 peptide was decomposed. The analyses of the relationship between the ACE inhibitory activity and structure of the P4 peptide clarified that Hyp-Gly-Leu-Hyp-Gly-Phe showed a stronger activity (IC50 = 10 microM) than the P4 peptide (IC50 = 46 microM). When Phe at the C-terminus of the P4 peptide was deleted, IC50 changed to 25000 microM, indicating that Phe at the C-terminus of the peptide is very important for ACE inhibitory activity.

Suppressive effects of cacao liquor polyphenols (CLP) on LDL oxidation and the development of atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic rabbits.

We investigated the properties of cacao liquor polyphenols (CLP), which have an antioxidative effect on low-density lipoprotein (LDL) and an anti-atherosclerotic effect in the spontaneous familial hypercholesterolemic model, the Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbit. After 6 months of dietary administration of CLP at 1% (w/w) to the KHC rabbits, a higher total cholesterol concentration was observed in the treatment group compared to the control group. However, no other effects were noted in lipid profiles in plasma or lipoproteins. The plasma concentration of thiobarbituric acid reactive substances (TBARS), which is a lipid-peroxidation index, was significantly decreased 1 month after the start of CLP administration compared to that of the control group. The antioxidative effect of CLP on LDL was observed from 2 to 4 months of administration. The area of atherosclerotic lesions in the aorta in the CLP group (32.01+/-1.58%) was significantly smaller than that in the control group (47.05+/-3.29%), and the tissue cholesterol and TBARS concentrations were lower in the CLP group than in the control group. The anti-atherosclerotic effect of CLP was confirmed both rheologically and histopathologically. An in vitro study using KHC rabbit-derived LDL revealed that CLP significantly prolonged the lag time of LDL oxidation that was induced by a lipophilic azo-radical initiator, 2,2'-azobis(4-methoxy)-2,4-dimethylvaleronitrile (V-70), or Cu(2+) from a low concentration of 0.1 microg/mL. The antioxidative effect of CLP was superior to those of the well-known antioxidative substances, vitamin C, vitamin E and probucol. Therefore, CLP suppressed the generation of atherosclerosis, and its antioxidative effect appeared to have an important role in its anti-atherosclerotic activity.

Suppressive effect of cocoa powder on atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic rabbits.

We investigated the suppressive effect of cocoa powder (cacao polyphenol content: 7.8%) on atherosclerosis in a spontaneous familial hypercholesterolemic model, Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. Six-month dietary administration of cocoa powder had no effects on body weight, hematology or blood chemistry parameters or a lipid profile in KHC rabbits. Antioxidative activity of low-density lipoprotein (LDL) was observed in the 2nd month and 3rd month of administration. Thiobarbituric acid reactive substances (TBARS), the marker of lipid peroxidation, in plasma were decreased in the cocoa powder treated group from the 2nd month of administration during the study period compared to that in the control group. The area of atherosclerotic lesions in th aorta was significantly smaller in the cocoa powder group (30.87%) than in the control (52.39%). Tissue cholesterol content also tended to decrease. Distensibility of the aortic wall was improved significantly in the cocoa powder treated group due to decreases in fatty streaks and intimal thickening compared to that in the control group. These results suggest that cocoa powder has suppressive effect on development of atherosclerotic lesions. We consider that antioxidative activity of polyphenols rich in cocoa powder may be a key factor for the anti-atherosclerotic effect.

Effects of space flight on the histological characteristics of the aortic depressor nerve in the adult rat: electron microscopic analysis.

The effects of microgravity on the histological characteristics of the aortic depressor nerve, which is the afferent of the aortic baroreflex arc, were determined in 10 female adult rats. The rats were assigned for nursing neonates in the Space Shuttle Columbia or in the animal facility on the ground (NASA Neurolab, STS-90), and were housed for 16 days under microgravity in space (microg, n=5) or under one force of gravity on Earth (one-g, n=5). In the Schwann cell unit in which the axons of unmyelinated fibers are surrounded by one Schwann cell, the average number of axons per unit in the microg group was 2.1 +/- 1.6 (mean +/- SD, n=312) and significantly less than that in the one-g group (3.0 +/- 2.9, n=397, p<0.05). The proportion of unmyelinated fibers in the aortic depressor nerve in the microg group was 64.5 +/- 4.4% and significantly less than that in the one-g group (74.0 +/- 7.3%, p<0.05). These results show that there is a decrease in the number of high-threshold unmyelinated fibers in the aortic depressor nerve in adult rats flown on the Shuttle Orbiter, suggesting that the aortic baroreflex is depressed under microgravity during space flight.