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

Interaction between Angiotensinase Activities in Pituitary and Adrenal Glands of Wistar–Kyoto and Spontaneously Hypertensive Rats under Hypotensive or Hypertensive Treatments

In the present study, we analyzed the activity of several aminopeptidases (angiotensinases) involved in the metabolism of various angiotensin peptides, in pituitary and adrenal glands of untreated Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) or treated with the antihypertensive drugs captopril and propranolol or with the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). Intra- and inter-gland correlations between angiotensinase activities were also calculated. Membrane-bound alanyl-, cystinyl-, and glutamyl-aminopeptidase activities were determined fluorometrically using aminoacyl-β-naphthylamide as substrates. Depending on the type of angiotensinase analyzed, the results reflect a complex picture showing substantial differences between glands, strains, and treatments. Alanyl-aminopeptidase responsible for the metabolism of Ang III to Ang IV appears to be the most active angiotensinase in both pituitary and adrenals of WKY and particularly in SHR. Independently of treatment, most positive correlations are observed in the pituitary gland of WKY whereas such positive correlations are predominant in adrenals of SHR. Negative inter-gland correlations were observed in control SHR and L-NAME treated WKY. Positive inter-gland correlations were observed in captopril-treated SHR and propranolol-treated WKY. These results may reflect additional mechanisms for increasing or decreasing systolic blood pressure in WKY or SHR

Stress influences brain enkephalinase, oxytocinase and angiotensinase activities: a new hypothesis.

Brain enkephalin and oxytocin are anxiolytic agents involved in the response mechanism to stress. Degrading enzymes such as enkephalinase and oxytocinase could also be associated with this response. The effect of acute immobilization stress on enkephalinase and oxytocinase activities was determined in the soluble and membrane fractions of the medial prefrontal cortex, hippocampus and amygdala using alanyl- and leucyl-beta-naphthylamide as substrates, the latter in the presence and absence of 20 mM L-methionine. No change in aminopeptidase activities was observed in the prefrontal cortex of stressed rats. In contrast, enkephalinase activity decreased in the soluble fraction of the hippocampus but increased in the membrane fraction. In the amygdala, soluble oxytocinase and membrane enkephalinase activities decreased in stressed animals. These results show that acute immobilization stress affects differentially enkephalinase and oxytocinase activities depending on the fraction and brain region analyzed. A reduction in the activity of soluble enkephalinase in the hippocampus and soluble oxytocinase as well as membrane enkephalinase in the amygdala may suggest higher availability/longer action of enkephalin and oxytocin at these locations. This may explain the relative importance of these enzymatic activities in the anxiolytic properties proposed for enkephalins and oxytocin in the hippocampus and amygdala during stress conditions. This interpretation is not applicable to membrane enkephalinase activity in the hippocampus. However, alanyl-beta-naphthylamide hydrolyzing activity not only measures enkephalinase activity, it also reflects the angiotensinase-induced metabolism of angiotensin III to angiotensin IV. Therefore, our results may also mirror an increase in the formation of Ang IV in hippocampus and a decrease in the amygdala in acute stress. In conclusion, aminopeptidase activities in the hippocampus and amygdala may affect enkephalin, oxytocin and angiotensin III metabolism during acute immobilization stress and therefore be involved in the anxiolytic response.Junta de Andalucia CVI-221, CTS 438, 4723/04/200

Brain, Heart and Kidney Correlate for the Control of Blood Pressure and Water Balance: Role of Angiotensinases.

The renin-angiotensin system (RAS) plays a major role in the control of blood pressure (BP) and water balance by coordinating brain, heart and kidney functions, connected with each other by hormonal and neural mechanisms through the autonomic nervous system (ANS). RAS function may be monitored by the study of the enzymes (angiotensinases) involved in the metabolism of its active peptides. In order to study the relationship between the brain-heart-kidney axis and the control of BP and water balance, we analyzed the correlation of angiotensinase activities, assayed as arylamidase activities, between hypothalamus, left ventricle, renal cortex and renal medulla, collected from Wistar-Kyoto and spontaneously hypertensive rats, treated or not treated with L-NAME [N(G)-nitro-L-arginine methyl ester]. This compound not only inhibits the formation of nitric oxide but also disrupts the normal function of the ANS activating the sympathetic nervous system (SNS) to increase BP. In addition, to assess the influence of the SNS, we studied the effect of its blockade by treatment of both strains with propranolol. The present results support the notion that RAS function of the brain-heart-kidney axis, as reflected by the activities of angiotensinases, is reciprocally connected by afferent and efferent mechanisms between these locations, presumably through the ANS. These results reveal new aspects of neuroendocrine regulation possibly involving the ANS.SAF 2008 04685 C02 0

The renin-angiotensin system: new insight into old therapies.

Although the renin-angiotensin system (RAS) is already an old acquaintance, there are often exciting discoveries that improve our knowledge of it and open new therapeutic possibilities. Moreover, well-established drugs, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), or beta-blockers, show that their mechanism of action may be the result of parallel pathways other than the ones initially established. A detailed analysis of the RAS can be carried out in part through the study of the enzymes, named angiotensinases, involved in its cascade, whose activity is a reflection of the functionality of their peptide substrates. The study of these enzymes offers the possibility of controlling the effects of angiotensins through various pharmacological manipulations. For example, angiotensinase inhibitors or activators are being used or have been proposed as antihypertensive agents. They have also been suggested as analgesic and antidepressant drugs or targets for drug development against different pathologies such as Alzheimer's disease, epilepsy or ischemia. On the other hand, the analysis of brain asymmetry has revealed surprising results about the laterality of central and peripheral components of the RAS. Such studies indicate that the neurovisceral integration, already proposed by Claude Bernard (1867) should also be analyzed from a bilateral perspective. In this review, the RAS and the role of various angiotensinases implicated in the cascade are revisited. Therapeutic strategies involving some components of the RAS with an unusual vision resulting from a bilateral perspective added to their study are discussed.SAF-2008 04685 C0

Asymmetric interaction of neuropeptidase activities between cortico-limbic structures, plasma and cardiovascular function after unilateral dopamine depletions of the nigrostriatal system

In emotional processing, dopamine (DA) plays an essential role, and its deterioration involves important consequences. Under physiological conditions, dopamine exhibits brain asymmetry and coexists with various neuropeptides that can coordinate the processing of brain functions. Brain asymmetry can extend into a broader concept of asymmetric neurovisceral integration, including behavior. The study of the activity of neuropeptide regulatory enzymes (neuropeptidases, NPs) is illustrative. We have observed that the left and right brain areas interact intra- and inter-hemispherically, as well as with peripheral tissues or with physiological parameters such as blood pressure or with behaviors such as turning preference. To obtain data that reflect this integrative behavior, we simultaneously analyzed the impact of left or right brain DA depletion on the activity of various NPs in corticolimbic regions of the left and right hemispheres, such as the medial prefrontal cortex, amygdala and hippocampus, as well as on the plasma activity of the same aminopeptidase activities (APs) and on systolic blood pressure (SBP). Intra- and inter-hemispheric interactions as well as the interactions of NPs from the left or right hemispheres were analyzed with the same plasma APs and the SBP obtained from sham and from left or right lesioned rats. The results demonstrate a complex profile depending on the hemisphere considered. They definitively confirm an asymmetric neurovisceral integration and reveal a higher level of inter-hemispheric corticolimbic interactions including with SBP after left dopamine depletion

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