Hypertension: Takeshita S

Asaba Y, Ito M, Fumoto T, Watanabe K, Fukuhara R, Takeshita S, Nimura Y, Ishida J, Fukamizu A, Ikeda K. · Department of Bone and Joint Disease, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. · J Bone Miner Res. · Pubmed #18847324 No free full text.

Abstract: Hypertension and osteoporosis are two major age-related disorders; however, the underlying molecular mechanism for this comorbidity is not known. The renin-angiotensin system (RAS) plays a central role in the control of blood pressure and has been an important target of antihypertensive drugs. Using a chimeric RAS model of transgenic THM (Tsukuba hypertensive mouse) expressing both the human renin and human angiotensinogen genes, we showed in this study that activation of RAS induces high turnover osteoporosis with accelerated bone resorption. Transgenic mice that express only the human renin gene were normotensive and yet exhibited a low bone mass, suggesting that osteoporosis occurs independently of the development of hypertension per se. Ex vivo cultures showed that angiotensin II (AngII) acted on osteoblasts and not directly on osteoclast precursor cells and increased osteoclastogenesis-supporting cytokines, RANKL and vascular endothelial growth factor (VEGF), thereby stimulating the formation of osteoclasts. Knockdown of AT2 receptor inhibited the AngII activity, whereas silencing of the AT1 receptor paradoxically enhanced it, suggesting a functional interaction between the two AngII receptors on the osteoblastic cell surface. Finally, treatment of THM mice with an ACE inhibitor, enalapril, improved osteoporosis and hypertension, whereas treatment with losartan, an angiotensin receptor blockers specific for AT1, resulted in exacerbation of the low bone mass phenotype. Thus, blocking the synthesis of AngII may be an effective treatment of osteoporosis and hypertension, especially for those afflicted with both conditions.

Ito S, Akutsu K, Tamori Y, Sakamoto S, Yoshimuta T, Hashimoto H, Takeshita S. · Department of Medicine, National Cardiovascular Center, Osaka, Japan. · Am J Cardiol. · Pubmed #18308024 No free full text.

Abstract: Differences in atherosclerotic profiles between patients with thoracic aortic aneurysm (TAA) and patients with abdominal aortic aneurysm (AAA) have not been studied. We retrospectively studied the clinical records of 343 consecutive patients (132 TAA and 211 AAA) who were admitted to our hospital for elective repair of aortic aneurysms between July 2001 and December 2004. Clinical variables were compared between patients with TAA and those with AAA by using a univariate analysis, and those achieving statistical significance were subsequently assessed in a multivariate analysis. The incidence of coronary artery disease (CAD) (53% vs 23%, p <0.0001), 3-vessel coronary disease (41% vs 10%, p <0.0001), male gender (86% vs 74%, p <0.01), smoker (88% vs 76%, p <0.01), chronic obstructive pulmonary disease (COPD) (30% vs 15%, p <0.01), and diabetes mellitus (39% vs 23%, p <0.01) were significantly higher in patients with AAA than in those with TAA. In contrast, the incidence of hypertension (91% vs 81%, p <0.05), saccular-type aneurysm (61% vs 7%, p <0.0001), and body mass index (24.1 +/- 3.1 vs 23.2 +/- 3.5, p <0.05) were significantly higher in patients with TAA than in those with AAA. Multivariate stepwise logistic analysis revealed that CAD (odds ratio [OR] 3.65; 95% confidence interval [CI] 2.12 to 6.42; p <0.0001), COPD (OR 2.05; 95% CI 1.11 to 3.89; p <0.05), and diabetes mellitus (OR 1.85; 95% CI 1.06 to 3.27; p <0.05) were associated with AAA, and that body mass index (OR 9.39; 95% CI 2.0 to 46.8; p <0.01), hypertension (OR 3.09; 95% CI 1.48 to 6.87; p <0.01), and cerebral infarction (OR 2.83; 95% CI 1.25 to 6.50; p <0.05) were associated with TAA. In conclusion, atherosclerotic profiles are significantly different between patients with TAA and patients with AAA. This result suggests the possibility that mechanisms underlying the development of aortic aneurysms may differ between TAA and AAA, and, from the perspective of prevention, provides further stimulus for the modification of key risk factors for atherosclerosis.

Obata H, Sakai Y, Ohnishi S, Takeshita S, Mori H, Kodama M, Kangawa K, Aizawa Y, Nagaya N. · Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. · Am J Respir Crit Care Med. · Pubmed #17975203 links to  free full text

Abstract: RATIONALE: Although prostacyclin is recognized as a therapeutic breakthrough for pulmonary hypertension, it needs continuous infusion because of its short action. Therefore, we developed a new drug delivery system for prostacyclin. We prepared ONO-1301MS, a novel sustained-release prostacyclin analog polymerized with poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres. OBJECTIVES: We examined whether ONO-1301MS attenuates monocrotaline (MCT)-induced pulmonary hypertension in rats, and attempted to elucidate the underlying mechanisms responsible for the beneficial effects of ONO-1301MS. METHODS: After MCT injection, rats were randomized to receive a single subcutaneous injection of 100 mg/kg ONO-1301MS or vehicle. MEASUREMENTS AND MAIN RESULTS: We prepared ONO-1301MS, which was polymerized with PLGA to release ONO-1301 for 3 weeks. A single administration of ONO-1301MS achieved sustained elevation of its circulating level and plasma cyclic adenosine 3',5'-monophosphate level for 3 weeks, and attenuated an increase in a metabolite of thromboxane A(2) level. Rats had developed pulmonary hypertension 3 weeks after MCT injection; however, treatment with ONO-1301MS significantly attenuated the increases in right ventricular systolic pressure and right ventricular weight to body weight ratio. ONO-1301MS significantly inhibited hypertrophy of pulmonary arteries. Phosphorylation of extracellular signal-regulated protein kinase (ERK) in the lung was significantly increased in the control group, whereas this increase was markedly attenuated by treatment. CONCLUSIONS: We developed a new drug delivery system for prostacyclin using PLGA and ONO-1301. A single injection of ONO-1301MS resulted in sustained activity for 3 weeks, and attenuated pulmonary hypertension, partly through its antiproliferative effect on vascular smooth muscle cells via inhibition of ERK phosphorylation.

Takeshita S, Tomiyama H, Yokoyama N, Kawamura Y, Furukawa T, Ishigai Y, Shibano T, Isshiki T, Sato T. · Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, 173-8605, Tokyo, Japan. · Cardiovasc Res. · Pubmed #11684080 links to  free full text

Abstract: OBJECTIVES: Natural angiogenesis has been shown to be impaired in spontaneously hypertensive rats (SHR). The purpose of this study was to determine whether pathological angiogenesis in the setting of tissue ischemia is also impaired in SHR, and to what extent it is modified by angiotensin-converting enzyme (ACE) inhibition. METHODS: Ischemia was induced in the hindlimb of SHR by excision of the femoral artery, after which the animals were randomly assigned to receive low-dose perindopril (sub-antihypertensive, 0.2 mg/kg/day), high-dose perindopril (antihypertensive, 2.0 mg/kg/day), or vehicle for 3 weeks. Wistar-Kyoto rats (WKY) with femoral artery excision served as a control group. RESULTS: Tissue ACE activity in SHR was significantly increased compared to WKY (49.4+/-6.2 vs. 34.0+/-14.2 IU/mg, P<0.01). Administration of perindopril significantly reduced ACE activity in SHR (low dose: 12.4+/-2.3; high dose: 11.0+/-2.1 IU/mg, P<0.005). Angiogenesis of the ischemic limb muscles was significantly impaired at 4 weeks in SHR versus WKY as indicated by the lower capillary density in the former (364.5+/-43.0 vs. 463.8+/-63.0/mm(2), P<0.05) as well as the reduced hindlimb perfusion assessed by laser Doppler imaging (0.86+/-0.08 vs. 1.03+/-0.09, P<0.05). Administration of perindopril significantly augmented both the capillary density (low dose: 494.3+/-69.8; high dose: 543.9+/-76.9/mm(2), P<0.005) and the limb perfusion (low dose: 1.06+/-0.15; high dose: 1.05+/-0.12, P<0.05) of the ischemic limb in SHR. CONCLUSIONS: These findings indicate that pathological angiogenesis in the setting of tissue ischemia is impaired in SHR compared with WKY, and that this impairment can be reversed by ACE inhibition. The angiogenic properties of an ACE inhibitor may benefit patients with essential hypertension presenting with lower limb vascular insufficiency.

Suzuki N, Kozuma K, Ueno Y, Nagaoka K, Kyono H, Ishikawa S, Watanabe H, Yokoyama N, Takeshita S, Isshiki T. · Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan. · Ann Thorac Surg. · Pubmed #18222257 No free full text.

Abstract: BACKGROUND: A paucity of data exists with respect to changes in whole saphenous vein grafts (SVGs) despite accelerated atherosclerosis within grafted saphenous vein conduits. In the present study, we evaluated the one-year change in SVGs by means of quantitative coronary analysis. METHODS: This study enrolled consecutive 52 patients with 109 SVGs, who underwent coronary artery bypass graft surgery successfully. A follow-up study was performed in 33 patients with 65 SVGs after one year because 16 SVGs were obstructed (baseline, 8; follow-up period, 8), and 15 patients with 28 SVGs dropped out within one year. RESULTS: Both minimal and mean lumen diameters decreased significantly (3.17 +/- 0.64 mm vs 2.41 +/- 0.57 mm, p < 0.001; 3.70 +/- 0.69 mm vs 2.92 +/- 0.70 mm, p < 0.001; respectively). Graft length also decreased significantly (107.1 +/- 25.8 vs 100.6 +/- 25.2 mm, p < 0.001). The graft shortening rate (graft shortening length/baseline graft length x 100) was greater than 5% in 33 vessels (51%) and greater than 10% in 23 vessels (35%). Coronary risk factors (smoking, diabetes mellitus, hypertension, dyslipidemia) did not reveal significant relationship with late loss of minimal and mean lumen diameters. CONCLUSIONS: The present study showed a considerable and uniform lumen loss of SVGs after one year, irrespective of coronary risk factors. Graft length shortening was seen more than elongation.