K022: Effect of combination therapy (ANG II antagonist, valsartan and a calcium channel blocker) in a hypertensive model of diabetic nephropathy

Recently, it has been suggested that in the context of diabetes and hypertension, more aggressive blood pressure targets should be considered. To achieve these levels of blood pressure control, it is likely that combination therapy will need to be used. The present study has explored the role of the addition of either a dihydropyridine or a non-dihydropyridine calcium channel blocker (CCB) to Ang II antagonist based treatment in an experimental model of hypertension and diabetes. The doses chosen for the combination therapy groups were lower than those used with monotherapy in order to achieve similar antihypertensive efficacy. Diabetic (streptozotocin induced) SHR were randomised to no treatment, valsartan (30 mg/kg/day), the non-dihydropyridine CCB verapamil (20 mg/kg/day), the dihydropyridine CCB amlodipine (6 mg/kg/day), a combination of valsartan and amlodipine (20 mg + 4 mg/kg/day respectively) or valsartan and verapamil (20 mg + 15 mg/kg/day respectively). Serial measurements of systolic blood pressure (BP) and albumin excretion rate (AER) were performed monthly (data are shown at week 16 for AER and mean of wk 20-28 for BP). This model was associated with hypertension (control, 217 ± 8, diabetic, 200 ± 5 mmHg) which was reduced by most treatments to a similar degree (valsartan 165 ± 3, amlodipine 164 ± 2, verapamil 182 ± 4, valsartan + amlodipine 151 ± 3 and valsartan + verapamil 169 ± 5 mmHg). Diabetes was associated with a progressive increase in AER (control 1.5 vs diabetic 17 mg/24 hr). Valsartan retarded the increase in AER (11 mg/24 hr). Similar efficacy was observed in the valsartan + amlodipine combination (9 mg/24 hr) but not with amlodipine alone (16 mg/24 hr) despite similar effects on blood pressure. No advantage of verapamil versus amlodipine either as monotherapy or in combination with valsartan was observed. The present study indicates that the combination of an Ang II antagonist and a dihydropyridine CCB is an effective regimen at reducing blood pressure and albuminuria in the context of diabetes and hypertensio

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Angiotensin II-receptor subtypes in human atria and evidence for alterations in patients with cardiac dysfunction

Angiotensin II (All) has been implicated as an important factor in the pathophysiology of heart diseases. Following the recent identification of two subtypes of the All receptor in cardiac tissue of animals, we investigated the possible occurrence of these, or similar, subtypes in human atrial tissue. In right-atrial tissue from patients undergoing heart surgery, we determined the All-receptor profile in receptor binding studies, using [125I]-angiotensin as radioligand and All as well as two compounds selective for the receptor subtypes to identify and quantify All-receptor subpopulations. In 35 patients (23 requiring coronary bypasses, 10 vaivular surgery and two combined coronary and valvular surgery), the left-ventricular ejection fraction was determined in the preoperative phase, and right- and left-atrial pressure during surgery. In membranes of human right atria, All receptors are present in high density (median: Bmax= 294 fmol. mg−1 protein, range: 111-2073) and two different subtypes can be distinguished. Type-1 receptors (AT1) accounted for 33 ± l0% of the population whereas type-2 receptors (AT2) made up 67 ± 10% of the population. There was no correlation between any of the measured cardiac functions and total All-receptor density or receptor affinity. However, the percentage of AT1 receptors was higher in the atria of patients with normal right-atrial pressure; left-ventricular ejection fraction was positively and right-atrial pressure inversely correlated with the percentage of AT1 receptors (r=0·740 and -0·901, respectively; P<0·001, for both). Moreover, the percentage of AT receptors was directly correlated with the levels of left-atrial pressure (r=0·853; P<0·001). It is concluded that the ratio of AT1 to AT2 receptors correlates well with right-atrial pressure and left-ventricular function. This is a first indication of a possible involvement of All-receptor subtypes in the pathophysiology of cardiac dysfunction

Angiotensin II Receptor Subtypes and Cardiac Function

All the components of the renin-angiotensin system have been identified in the heart including the angiotensin II receptor subtypes AT1 and AT2 In the normal human heart, there is a decreasing receptor density from the right atrium to the left ventricle. In right atrial membranes prepared from pathological hearts, the percentage of AT1 receptor decreases with the severity of cardiac dysfunction whereas that of AT2 receptor increases. Treatment of hypertrophic rats with AT1 receptor antagonists inhibits cardiac hypertrophy and reverses the increase receptor density, indicating involvement of this Ang II receptor subtype. The role of the AT2 receptor is still largely unknown but it may be involved in cell growth and proliferation. The cloning of both AT1 and AT2 receptors as well as the availability of potent and selective antagonists will help us to understand better the functional role of Angiotensin II in cardiovascular disorder

A deep Large Binocular Telescope view of the Canes Venatici I dwarf galaxy

We present the first deep color-magnitude diagram of the Canes Venatici I (CVnI) dwarf galaxy from observations with the wide field Large Binocular Camera on the Large Binocular Telescope. Reaching down to the main-sequence turnoff of the oldest stars, it reveals a dichotomy in the stellar populations of CVnI: it harbors an old (> 10 Gyr), metal-poor ([Fe/H] ~ -2.0) and spatially extended population along with a much younger (~ 1.4-2.0 Gyr), 0.5 dex more metal-rich, and spatially more concentrated population. These young stars are also offset by 64_{-20}^{+40} pc to the East of the galaxy center. The data suggest that this young population, which represent ~ 3-5 % of the stellar mass of the galaxy within its half-light radius, should be identified with the kinematically cold stellar component found by Ibata et al. (2006). CVnI therefore follows the behavior of the other remote MW dwarf spheroidals which all contain intermediate age and/or young populations: a complex star formation history is possible in extremely low-mass galaxies.Comment: 4 pages, 3 figures, accepted for publication in ApJL. Minor changes, conclusions unchange

Hybrid Newton-type method for a class of semismooth equations

In this paper, we present a hybrid method for the solution of a class of composite semismooth equations encountered frequently in applications. The method is obtained by combining a generalized finite-difference Newton method to an inexpensive direct search method. We prove that, under standard assumptions, the method is globally convergent with a local rate of convergence which is superlinear or quadratic. We report also several numerical results obtained applying the method to suitable reformulations of well-known nonlinear complementarity problem

The Blue Straggler population in the globular cluster M53 (NGC5024): a combined HST, LBT, CFHT study

We used a proper combination of multiband high-resolution and wide field multi-wavelength observations collected at three different telescopes (HST, LBT and CFHT) to probe Blue Straggler Star (BSS) populations in the globular cluster M53. Almost 200 BSS have been identified over the entire cluster extension. The radial distribution of these stars has been found to be bimodal (similarly to that of several other clusters) with a prominent dip at ~60'' (~2 r_c) from the cluster center. This value turns out to be a factor of two smaller than the radius of avoidance (r_avoid, the radius within which all the stars of ~1.2 M_sun have sunk to the core because of dynamical friction effects in an Hubble time). While in most of the clusters with a bimodal BSS radial distribution, r_avoid has been found to be located in the region of the observed minimum, this is the second case (after NGC6388) where this discrepancy is noted. This evidence suggests that in a few clusters the dynamical friction seems to be somehow less efficient than expected. We have also used this data base to construct the radial star density profile of the cluster: this is the most extended and accurate radial profile ever published for this cluster, including detailed star counts in the very inner region. The star density profile is reproduced by a standard King Model with an extended core (~25'') and a modest value of the concentration parameter (c=1.58). A deviation from the model is noted in the most external region of the cluster (at r>6.5' from the center). This feature needs to be further investigated in order to address the possible presence of a tidal tail in this cluster.Comment: 25 pages, 9 figures, accepted for publication on Ap

Electronic sculpting of ligand-GPCR subtype selectivity:the case of angiotensin II

GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (<i>K</i>_i = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range

Effect of valsartan on angiotensin II-induced plasminogen activator inhibitor-1 biosynthesis in arterial smooth muscle cells

Previous studies have shown that angiotensin II stimulates the synthesis of plasminogen activator inhibitor-1 in cultured vascular cells, which suggests that activation of the renin-angiotensin system may impair fibrinolysis. We have investigated the effects of angiotensin II and of valsartan, a recently developed angiotensin II antagonist that is highly specific and selective for the angiotensin II subtype 1 receptor, on plasminogen activator inhibitor-1 secretion by smooth muscle cells isolated from rat and human vessels. Angiotensin II induced a time- and concentration-dependent increase of plasminogen activator inhibitor activity in supernatants of rat aortic cells, which reached a plateau after 6 hours of incubation with 100 nmol/L angiotensin II (2.4+/-0.6-fold over control value; P:<0.001). The angiotensin II-induced plasminogen activator inhibitor activity was inhibited, in a concentration-dependent manner, by valsartan with an IC(50) value of 21 nmol/L. Valsartan fully prevented the angiotensin II-induced increase in plasminogen activator inhibitor-1 protein and mRNA. Furthermore, angiotensin II doubled the secretion of plasminogen activator inhibitor-1 by smooth muscle cells obtained from human umbilical and internal mammary arteries, and valsartan fully prevented it. Angiotensin II did not affect the secretion of tissue plasminogen activator antigen by any of the cell systems tested. Thus, valsartan effectively inhibits angiotensin II-induced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activator in arterial rat and human smooth muscle cells