Hypertension: Isshiki T

Furukawa T, Nukada T, Namiki Y, Miyashita Y, Hatsuno K, Ueno Y, Yamakawa T, Isshiki T. · Department of Internal Medicine, Teikyo University School of Medicine, Kaga, Tokyo, Japan. · Eur J Pharmacol. · Pubmed #19401195 No free full text.

Abstract: 1,4-dihydropyridine (DHP) Ca(2+) antagonists have recently been shown to block T-type Ca(2+) channels, which may render favorable actions on cardiovascular systems. However, this evaluation remains to be done systematically for each T-type Ca(2+) channel subtype except for the Ca(v)3.1 (alpha(1G)) subtype. To address this issue at the molecular level, blocking effects of 14 kinds of DHPs (amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nitrendipine), which are clinically used for treatments of hypertension, on 3 subtypes of T-type Ca(2+) channels [Ca(v)3.2 (alpha(1H)), Ca(v)3.3 (alpha(1I)), and Ca(v)3.1 (alpha(1G))] were investigated in the Xenopus oocyte expression system using the two-microelectrode voltage-clamp technique. These 3 kinds (alpha(1H), alpha(1I) and alpha(1G)) of T-type channels were blocked by amlodipine, manidipine and nicardipine. On the other hand, azelnidipine, barnidipine, benidipine and efonidipine significantly blocked alpha(1H) and alpha(1G), but not alpha(1I) channels, while nilvadipine and nimodipine apparently blocked alpha(1H) and alpha(1I), but not alpha(1G) channels. Moreover, aranidipine blocked only alpha(1H) channels. By contrast, cilnidipine, felodipine, nifedipine and nitrendipine had little effects on these subtypes of T-type channels. The result indicates that the blockade of T-type Ca(2+) channels by derivatives of DHP Ca(2+) antagonist was selective for the channel subtype. Therefore, these selectivities of DHPs in blocking T-type Ca(2+) channel subtypes would provide useful pharmacological and clinical information on the mode of action of the drugs including side-effects and adverse effects.

Furukawa T, Hatsuno T, Ueno Y, Nagaoka K, Watari Y, Yamakawa T, Sagawa T, Isshiki T. · Department of Internal Medicine, School of Medicine, Teikyo University, Teikyo, Japan. · Clin Drug Investig. · Pubmed #19301939 No free full text.

Abstract: BACKGROUNDS AND METHODS: A higher degree of clinical efficacy with olmesartan compared with other angiotensin receptor blockers, has been reported by several sources. In this study of 31 examples of cases of essential hypertension, Holter electrocardiogram, ambulatory blood pressure monitoring and pulse wave velocity (PWV) measurements were performed before and after substituting olmesartan 20 mg for candesartan 8 mg antihypertensive drug therapy. RESULTS: Following the therapeutic change, daily average systolic and diastolic blood pressures were decreased by 6.7 +/- 9.3 mmHg and 3.6 +/- 8.3 mmHg, respectively, with olmesartan 20 mg; PWV was also significantly decreased. Holter electrocardiogram heart rate variability spectral analysis demonstrated that none of the very low frequency (VLF), high frequency (HF) and low frequency (LF)/HF components were significantly altered. However, a significant correlation was observed between the LF/HF component and blood pressure difference, when blood pressure and heart rate variability components in each individual case were studied. CONCLUSION: This study shows that olmesartan has a stronger antihypertensive effect in comparison to candesartan, and does not generate reflex sympathoexcitatory activity.

Furukawa T, Nukada T, Miura R, Ooga K, Honda M, Watanabe S, Koganesawa S, Isshiki T. · Department of Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan. · J Cardiovasc Pharmacol. · Pubmed #15725949 No free full text.

Abstract: Recent reports show that efonidipine, a dihydropyridine Ca2+ antagonist, has blocking action on T-type Ca2+ channels, which may produce favorable actions on cardiovascular systems. However, the effects of other dihydropyridine Ca2+ antagonists on T-type Ca2+ channels have not been investigated yet. Therefore, in this study, we examined the effects of dihydropyridine compounds clinically used for treatment of hypertension on a T-type Ca2+ channel subtype, alpha1G, expressed in Xenopus oocytes. These effects were compared with those on T-type Ca2+ channel. Rabbit L-type (alpha1Calpha2/deltabeta1a) or rat T-type (alpha1G) Ca2+ channel was expressed in Xenopus oocytes by injection of cRNA for each subunit. The Ba currents through expressed channels were measured by conventional 2-microelectrode voltage-clamp methods. Twelve DHPs (amlodipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nitrendipine) and mibefradil were tested. Cilnidipine, felodipine, nifedipine, nilvadipine, minodipine, and nitrendipine had little effect on the T-type channel. The blocks by drugs at 10 microM were less than 10% at a holding potential of -100 mV. The remaining 6 drugs had blocking action on the T-type channel comparable to that on the L-type channel. The blocking actions were also comparable to that by mibefradil. These results show that many dihydropyridine Ca2+ antagonists have blocking action on the alpha1G channel subtype. The action of dihydropyridine Ca2+ antagonists in clinical treatment should be evaluated on the basis of subtype selectivity.

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.