Statins, ACE inhibitors and ARBs in cardiovascular disease

Several trials have indicated that classical cardiovascular risk factors, including hyperlipidemia and hypertension, are not associated with a great number of acute cardiovascular events. Given the crucial role of inflammation in atherogenesis, inflammatory factors have been proposed to better define and predict acute cardiovascular events. In this promising context, treatments with lipid-lowering drugs (statins) and anti-hypertensive drugs (ACE inhibitors and ARBs) have been also investigated from an ‘anti-inflammatory’ point of view, with some encouraging results. At present, statins are recommended by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines as the first-line choice for drug therapy lowering LDL cholesterol in high-risk patients (LDL goal <70 mg/dL, <1.8 mmol/L). In moderate-risk patients (LDL goal <100 mg/dL, <2.6 mmol/L), statin therapy is indicated mainly in metabolic syndrome and in diabetic patients. Treatment with ACE inhibitors or ARBs is recommended in both hypertension and cardiovascular diseases, particularly in diabetic patients. The use of ACE inhibitors is recommended in all patients with ST-elevation myocardial infarction with LVEF ≤40%, with normal LVEF in the presence of well-controlled cardiovascular risk factors and revascularization, hypertension, diabetes or chronic kidney disease. On the other hand, the use of ARBs is recommended in patients intolerant of ACE inhibitors or who have heart failure or hypertension. In the future, these recommendations will probably be frequently updated as the pleiotropic activities of statins, ACE inhibitors and ARB are also taken into account.     

A study of proliferative markers and tumor suppressor gene proteins in different grades of ependymomas

Ependymomas are CNS tumors that originate from the spinal canal and walls of the ventricular system. Considerable controversy continues to exist with regard to their prognostic factors; age and extent of resection are the only statistically significant prognostic factors yet identified. The authors report a retrospective study of a homogenous population of 119 patients harbouring ependymomas between 1991 and 2002. All clinico‐radiological and follow‐up data were analyzed and a pathologic review was performed by two pathologists. Immunohistochemical staining for MIB‐1, Topo IIα, p53 and MDM2 was performed. Histopathologic grades show relationship with MIB1 and Topo IIα labelling indices and cut‐off values of 5% can differentiate between anaplastic and lower grades. p53 and MDM2 proteins expression are not common in ependymomas; however, they are seen in higher grades only and may be involved in the tumor progression.     

Role of the median preoptic nucleus in the chronic hypotensive effect of losartan in sodium-replete normal rats

1. We have shown previously that the chronic hypotensive effect of the angiotensin II AT₁ receptor antagonist losartan is mediated, in part, by the subfornical organ (SFO). However, the neural pathway(s) mediating this central effect of losartan downstream from the SFO has not been completely elucidated.
2. The present study was designed to test the hypothesis that the median preoptic nucleus (MnPO) is a crucial part of the neural pathway necessary for the chronic hypotensive effect of losartan. To test this hypothesis, male Sprague-Dawley rats were subjected to either Sham or electrolytic lesion of the MnPO (MnPOx). Rats were instrumented with radiotelemetric transducers and aortic flow probes for the continuous measurement of mean arterial pressure (MAP) and heart rate and cardiac output (CO), respectively. Total peripheral resistance (TPR) was calculated as MAP/CO. After 3 days of baseline measurements, rats were infused intraperitoneally with losartan (10 mg/kg per day) via an osmotic minipump at a rate of 5 μL/min.
3. The data revealed that, by Day 9 of losartan treatment, MAP had decreased 34 ± 2 mmHg in MnPOx rats ( n  = 9), whereas the MAP of Sham-lesioned rats ( n  = 8) had only decreased 24 ± 3 mmHg. These findings were accompanied by a greater decrease in TPR in MnPOx compared with Sham rats (−0.464 vs −0.237 mmHg/mL per min, respectively), whereas CO remained unchanged throughout the study protocol.
4. These results do not support the hypothesis that an intact MnPO is necessary to mediate the full chronic hypotensive effect of losartan in normal rats. Instead, they appear to suggest that the MnPO may play an important role in buffering the profound hypotension induced by losartan.     

The response of neurons in the bed nucleus of the stria terminalis to serotonin: Implications for anxiety

Substantial evidence has suggested that the activity of the bed nucleus of the stria terminalis (BNST) mediates many forms of anxiety-like behavior in human and non-human animals. These data have led many investigators to suggest that abnormal processing within this nucleus may underlie anxiety disorders in humans, and effective anxiety treatments may restore normal BNST functioning. Currently some of the most effective treatments for anxiety disorders are drugs that modulate serotonin (5-HT) systems, and several decades of research have suggested that the activation of 5-HT can modulate anxiety-like behavior. Despite these facts, relatively few studies have examined how activity within the BNST is modulated by 5-HT. Here we review our own investigations using in vitro whole-cell patch-clamp electrophysiological methods on brain sections containing the BNST to determine the response of BNST neurons to exogenous 5-HT application. Our data suggest that the response of BNST neurons to 5-HT is complex, displaying both inhibitory and excitatory components, which are mediated by 5-HT_1A, 5-HT_2A, 5-HT_2C and 5-HT₇ receptors. Moreover, we have shown that the selective activation of the inhibitory response to 5-HT reduces anxiety-like behavior, and we describe data suggesting that the activation of the excitatory response to 5-HT may be anxiogenic. We propose that in the normal state, the function of 5-HT is to dampen activity within the BNST (and consequent anxiety-like behavior) during exposure to threatening stimuli; however, we suggest that changes in the balance of the function of BNST 5-HT receptor subtypes could alter the response of BNST neurons to favor excitation and produce a pathological state of increased anxiety.     

The kinetics of mercury nucleation from Hg22+ and Hg2+ solutions on vitreous carbon electrodes

The kinetics of the electrochemical nucleation of Hg onto vitreous carbon were studied from analysis of potentiostatic current transients obtained at different overpotentials in Hg₂²⁺ and Hg²⁺ solutions. Similar sizes of critical nuclei and number densities of sites on the surface were found for nucleation of Hg from both solutions, indicating, in agreement with nucleation theory, that the rates of nucleation are controlled by surface energies and deposit–substrate interactions. Saturation number densities of nuclei were deduced from the kinetic analysis, and their relationship with those obtained from direct observation of the electrode surface is discussed. It was found that at low overpotentials, the nuclei deposited from both solutions were uniformly distributed on the electrode surface, whereas their distribution was affected by inhibition of the nucleation rates close to already established nuclei at high overpotentials. This inhibition was enhanced during deposition from Hg²⁺ solution.     

Development of the hepatic mixed function oxidase system in a marsupial, the quokka (Setonix brachyurus).

The development of the mixed function oxidase system has been studied in pouched and young-at-heel joey quokkas. Cytochrome P-450 was first detectable at 35 days, rose sharply to one-third of the adult level by 53 days, and reached levels in the adult range between 155 and 255 days. NADPH-Cytochrome c reductase was approximately one-fifth the adult level at 45 days and , by 80–105 days of life, had reached values within the range for adult animals. Benzpyrene hydroxylase activity was barely detectable at 35 days; its development lagged behind that of the components of the cytochrome P-450 system and adult levels were not seen until 200 days. Electron microscopy showed that hepatocytes in 20- and 35-day joeys contained some short chains of rough endoplasmic reticulum. Areas of smooth endoplasmic reticulum were first evident at 45 days and at subsequent stages (80, 100, and 150 days and adult) increasing concentrations of both smooth and rough endoplasmic reticulum were present. Development of the mixed function oxidase system in the quokka liver is slow and resembles more closely the pattern of development in human fetal liver than that in many common laboratory animals.     

Identification of transmembrane domain 6 & 7 residues that contribute to the binding pocket of the urotensin II receptor

Urotensin II (U-II), a cyclic undecapeptide, is the natural ligand of the urotensin II (UT) receptor, a G protein-coupled receptor. In the present study, we used the substituted-cysteine accessibility method to identify specific residues in transmembrane domains (TMDs) six and seven of the rat urotensin II receptor (rUT) that contribute to the formation of the binding pocket of the receptor. Each residue in the R256^(6.32)-Q283^(6.59) fragment of TMD6 and the A295^(7.31)-T321^(7.57) fragment of TMD7 was mutated, individually, to a cysteine. The resulting mutants were expressed in COS-7 cells, which were subsequently treated with the positively charged methanethiosulfonate-ethylammonium (MTSEA) or the negatively charged methanethiosulfonate-ethylsulfonate (MTSES) sulfhydryl-specific alkylating agents. MTSEA treatment resulted in a significant reduction in the binding of TMD6 mutants F268C^(6.44) and W278C^(6.54) and TMD7 mutants L298C^(7.34), T302C^(7.38), and T303C^(7.39) to ¹²⁵I-U-II. MTSES treatment resulted in a significant reduction in the binding of two additional mutants, namely L282C^(6.58) in TMD6 and Y300C^(7.36) in TMD7. These results suggest that specific residues orient themselves within the water-accessible binding pocket of the rUT receptor. This approach, which allowed us to identify key determinants in TMD6 and TMD7 that contribute to the UT receptor binding pocket, enabled us to further refine our homology-based model of how U-II interacts with its cognate receptor.     

ENDOTHELIN IS BLOOD VESSEL SELECTIVE: STUDIES ON A VARIETY OF HUMAN AND DOG VESSELS IN VITRO AND ON REGIONAL BLOOD FLOW IN THE CONSCIOUS RABBIT

1. Endothelin (Et), a vasoconstrictor peptide, was 5-10-fold more potent (lower EC50) on isolated ring segments of large veins than on large arteries removed from dog coronary, mesenteric, femoral, renal and internal mammary vasculature and from the human internal mammary pedicle. 2. In the dog large coronary artery, Et (10-30 nmol/L) caused transient relaxations partway through the generation of a concentration-contraction curve. These relaxations were endothelium dependent. 3. In conscious rabbits treated with mecamylamine, Et (0.025-0.4 nmol/kg) caused a marked rise in renal vascular resistance but hindquarter vasodilation. Under the same conditions angiotensin II constricted both beds. 4. These studies suggest that Et is vascular bed and large vein selective in activity. It did not appear to be selective for large or small coronary arteries in vitro.     

Ca2+/calmodulin-dependent protein kinase II immunoreactivity in Lewy bodies

Summary Ca²⁺/calmodulin-dependent protein kinase II (CaM kinase II) is one of the predominant protein kinases in the brain. We found that CaM kinase II immunoreactivity was concentrated in the peripheral halos of Lewy bodies (LBs) in Parkinson's disease and Lewy body-like hyaline inclusions (LBHIs) in amyotrophic lateral sclerosis. An immunoelectron microscopic examination of LBs revealed that the filaments at the periphery of LBs were decorated with immunopositive deposits. Since CaM kinase II has a broad substrate specificity and can phosphorylate neurofilaments and other cytoskeletal proteins, it may play some role in the formation of LBs and LBHIs through the aberrant phosphorylation of the cytoskeletal elements in these inclusions.Supported by a Grant-in-Aid for Scientific Research on Priority Areas, No. 02240104, from the Ministry of Education, Science and Culture, Japan     

Inhibition by Brain Natriuretic Peptide of Vasopressin Neurons in the Supraoptic Nucleus and Neurons in the Region of the Anteroventral Third Ventricle in Rat Hypothalamic Slice Preparations

It is not entirely clear whether or not atrial natriuretic peptide (ANP) directly inhibits vasopressin neurons in the supraoptic nucleus (SON) and paraventricular nucleus. Recently, a novel peptide, brain natriuretic peptide (BMP), which has been isolated from the brain, has been shown to have a similar action to ANP on the regulation of vasopressin release. Intracerebroventricular injection of both BNP and ANP inhibits stimulus-evoked increases of plasma vasopressin level. The present study was undertaken: 1) to investigate whether BNP affects the activity of neurons in the region of the anteroventral third ventricle (AV3V) and SON which are involved in the control of body fluid homeostasis and blood pressure regulation, 2) to reassess effects of ANP on SON neurons, and 3) to test whether BNP exerts its effects by mechanisms which are different from those of ANP. Extracellular recordings were made from 213 AV3V and 110 SON spontaneously firing neurons in the rat coronal hypothalamic slice preparation. Of the AV3V neurons tested, BNP inhibited 86 (40%) and excited 2 (1%) while 125 neurons remained unaffected. A dose-response relationship was obtained for 7 AV3V neurons at different BNP concentrations ranging from 10^?11 M to 10^?6 M; the firing rates of all 7 neurons decreased. The threshold concentration to evoke inhibitory responses was approximately 10^?10M in the AV3V. When BNP and ANP were applied to the same neuron, most AV3V neurons which were inhibited by BNP were also inhibited by ANP and the neurons which were unaffected by BNP were also unaffected by ANP. Thus, these two peptides probably have a similar action on AV3V neurons. When BNP and angiotensin II were applied to a group of 60 neurons in the AV3V, most of the responsive neurons showed either inhibitory responses to BNP or excitatory responses to angiotensin II. Both BNP and ANP were applied to a group of 110 SON neurons: BNP (10 ^?7 M) inhibited 52 (75%) of 69 phasic (putative vasopressin) neurons, while BNP affected none of the 41 non-phasic (putative oxytocin) neurons. By contrast, ANP inhibited only 20 (29%) of 69 phasic neurons tested but it also had no effect on 41 non-phasic neurons tested. Our results are consistent with the suggestion that BNP is involved in the regulation of vasopressin release by acting on SON neurons and AV3V neurons.