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

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

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

Angiotensin receptors in GtoPdb v.2023.1

The actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [63, 155]), which have around 30% sequence similarity. The decapeptide angiotensin I, the octapeptide angiotensin II and the heptapeptide angiotensin III are endogenous ligands. losartan, candesartan, olmesartan, telmisartan, etc. are clinically used AT1 receptor blockers

Angiotensin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [61, 152]), which have around 30% sequence similarity. The decapeptide angiotensin I, the octapeptide angiotensin II and the heptapeptide angiotensin III are endogenous ligands. losartan, candesartan, telmisartan, etc. are clinically used AT1 receptor blockers

The performance of the blue prime focus Large Binocular Camera at the Large Binocular Telescope

We present the characteristics and some early scientific results of the first instrument at the Large Binocular Telescope (LBT), the Large Binocular Camera (LBC). Each LBT telescope unit will be equipped with similar prime focus cameras. The blue channel is optimized for imaging in the UV-B bands and the red channel for imaging in the VRIz bands. The corrected field-of-view of each camera is approximately 30 arcminutes in diameter, and the chip area is equivalent to a 23x23 arcmin2 field. In this paper we also present the commissioning results of the blue channel. The scientific and technical performance of the blue channel was assessed by measurement of the astrometric distortion, flat fielding, ghosts, and photometric calibrations. These measurements were then used as input to a data reduction pipeline applied to science commissioning data. The measurements completed during commissioning show that the technical performance of the blue channel is in agreement with original expectations. Since the red camera is very similar to the blue one we expect similar performance from the commissioning that will be performed in the following months in binocular configuration. Using deep UV image, acquired during the commissioning of the blue camera, we derived faint UV galaxy-counts in a ~500 sq. arcmin. sky area to U(Vega)=26.5. These galaxy counts imply that the blue camera is the most powerful UV imager presently available and in the near future in terms of depth and extent of the field-of-view. We emphasize the potential of the blue camera to increase the robustness of the UGR multicolour selection of Lyman break galaxies at redshift z~3.Comment: Accepted for publication in A&A. Uses aa.cls, 10 pages, 10 figures. Zero points changed in Table

Prevention and Intervention Studies with Telmisartan, Ramipril and Their Combination in Different Rat Stroke Models

The effects of AT1 receptor blocker, telmisartan, and the ACE inhibitor, ramipril, were tested head-to head and in combination on stroke prevention in hypertensive rats and on potential neuroprotection in acute cerebral ischemia in normotensive rats. Normotensive Wistar rats were treated s.c. 5 days prior to middle cerebral artery occlusion (MCAO) for 90 min with reperfusion. Groups (n = 10 each): (1) sham, (2) vehicle (V; 0,9% NaCl), (3) T (0,5 mg/kg once daily), (4) R (0,01 mg/kg twice daily), (5) R (0,1 mg/kg twice daily) or (6) T (0,5 mg/kg once daily) plus R (0,01 mg/kg twice daily). Twenty-four and 48 h after MCAO, neurological outcome (NO) was determined. Forty-eight h after MCAO, infarct volume by MRI, neuronal survival, inflammation factors and neurotrophin receptor (TrkB) were analysed.Stroke incidence was reduced, survival was prolonged and neurological outcome was improved in all treated SHR-SP with no differences between treated groups. In the acute intervention study, T and T+R, but not R alone, improved NO, reduced infarct volume, inflammation (TNFα), and induced TrkB receptor and neuronal survival in comparison to V.T, R or T+R had similar beneficial effects on stroke incidence and NO in hypertensive rats, confirming BP reduction as determinant factor in stroke prevention. In contrast, T and T+R provided superior neuroprotection in comparison to R alone in normotensive rats with induced cerebral ischemia