Plasma brain natriuretic peptide at rest and after adenosine-induced myocardial ischemia in normotensive and essential hypertensive patients with suspected coronary artery disease.

This study investigated plasma brain natriuretic peptide (BNP) levels in normotensive and hypertensive patients with suspected coronary artery disease during radionuclide pharmacological stress testing. Twenty-seven normotensive patients (15 males, aged 63.0+/-4.5 years and 12 females, aged 63.0+/-4.1 years) and 38 essential hypertensive patients (25 males, aged 63.3+/-3.3 years and 13 females, aged 64.6+/-2.6 years) with chest pain and exercise stress testing inconclusive for coronary artery disease underwent myocardial perfusion single-photon emission computed tomography (SPECT) using adenosine infusion. SPECT identified patients without (16 normotensive and 22 hypertensive) and patients with (11 normotensive and 16 hypertensive) transient perfusion defects. Basal BNP levels in normotensive patients without transient myocardial ischemia (3.1+/-1.2 fmol/ml) were significantly (P<0.01) lower than those observed in normotensive patients with transient ischemia (8.2+/-1.2 fmol/ml), whereas BNP levels in hypertensive patients without transient ischemia (8.2+/-1.0 fmol/ml) did not significantly differ from those in hypertensive patients with transient ischemia (8.1+/-2.0 fmol/ml). No significant difference was found in BNP levels between males or females either in normotensive or hypertensive patients without or with ischemia. Adenosine infusion did not significantly change BNP levels in any subject group without or with myocardial perfusion defects. Our findings show that increases in BNP allow early detection of myocardial ischemia in normotensive patients, but not in hypertensive patients with suspected coronary artery disease. Adenosine-induced myocardial ischemia does not affect BNP production already activated by coronary artery disease in normotensive patients and by hemodynamic changes in hypertensive patients.

Imidazo[2,1-b]thiazole system: a scaffold endowing dihydropyridines with selective cardiodepressant activity.

The synthesis, characterization, and functional in vitro assays in cardiac tissues and smooth muscle (vascular and nonvascular) of a number of 4-imidazo[2,1- b]thiazole-1,4-dihydropyridines are reported. The binding properties for the novel compounds have been investigated and the interaction with the binding site common to other aryl-dihydropyridines has been demonstrated. Interestingly, the novel 4-aryl-dihydropyridines are L-type calcium channel blockers with a peculiar pharmacological behavior. Indeed, the imidazo[2,1- b]thiazole system is found to confer to the dihydropyridine scaffold an inotropic and/or chronotropic cardiovascular activity with a high selectivity toward the nonvascular tissue. Finally, molecular modeling studies were undertaken for the most representative compounds with the aim of describing the binding properties of the new ligands at molecular level and to rationalize the found structure-activity relationship data. Due to the observed pharmacological behavior of our compounds, they might be promising agents for the treatment of specific cardiovascular pathologies such as cardiac hypertrophy and ischemia.

Endothelin-1 response to mental stress in early ischemic lesions of the extremities due to systemic sclerosis.

We studied circulating levels of endothelin-1, catecholamines and nitric oxide after a mental arithmetic test in 14 patients with early ischemic lesions of the extremities due to systemic sclerosis and slightly impaired peripheral vascular flow. The test induced an increase (P<0.01) in blood pressure, heart rate, endothelin-1 and catecholamine levels, whereas it did not change the low basal levels of nitric oxide. In healthy subjects (n=20) the test significantly (P<0.01) decreased endothelin-1 without affecting nitric oxide. The low basal levels of nitric oxide and the high plasma concentration of endothelin-1 after psychological stress cannot be explained by an impaired release from the limited ischemic lesions alone. This suggests a diffuse microvascular derangement that aggravates the course of peripheral microvascular ischemic lesions.

Expression of the repressor element-1 silencing transcription factor (REST) is influenced by insulin-like growth factor-I in differentiating human neuroblastoma cells.

The repressor element-1 (RE-1) silencing transcription factor (REST) interacts with an RE-1 cis element and represses the transcription of neuron-specific genes in neuronal progenitors but is down-regulated in post-mitotic neurons. We report that REST expression is modified, in a time-dependent manner, in SH-SY5Y neuroblastoma cells exposed to insulin-like growth factor I (IGF-I), a polypeptide hormone affecting various aspects of neuronal induction and maturation. REST is increased in cells treated with IGF-I for 2 days and then declines in 5-day-treated cells concomitant with a progressive neurite extension. To investigate any role played by REST in neurodifferentiation by IGF-I, we employed an antisense oligonucleotide (AS-ODN) complementary to REST mRNA. In AS-ODN-treated cells, the effects elicited by IGF-I on cell proliferation are not influenced whereas a marked decrease of REST significantly increases neurite elongation without any gross perturbation of neurogenesis. Synapsin I and betaIII-tubulin gene promoters contain an RE-1 motif and their transcription is repressed by REST; both of them are increased in cells exposed to IGF-I for 5 days and further elevated by AS-ODN treatment. A parallel increase of growth cone-associated protein 43, a protein chosen as a neuronal marker not directly regulated by REST, is also observed. Therefore, REST is elevated during early steps of neural induction by IGF-I and could contribute to down-regulate genes not yet required by the differentiation program while it declines later for the acquisition of neural phenotypes. These results suggest a model in which differentiating neuroblastoma cells determine their extent of neurite outgrowth on the basis of REST disappearance.

Opioid peptide response to spinal cord stimulation in chronic critical limb ischemia.

Twelve patients with chronic critical limb ischemia in whom a spinal cord stimulation (SCS) system had been implanted for at least one year had increased microvascular flow and achieved healing of trophic acral lesions. After switching off the system, the clinical improvement persisted for 10 days and the neurohormonal pattern showed high plasma values of beta-endorphin and Met-enkephalin, normal dynorphin B, endothelin-1 and catecholamines, and low nitric oxide. Met-enkephalin levels were further increased (P < 0.01) immediately after switching on the electrical stimulation again. The persistence of high plasma opioid levels after switching off the spinal cord stimulation explains the absence of subjective complaints and suggests an involvement of opioids in the regulation and improvement of the microcirculation.

Biocompatibility and integrin-mediated adhesion of human osteoblasts to poly(DL-lactide-co-glycolide) copolymers.

The biocompatibility of polylactic acid (PLA) and polyglycolic acid (PGA) copolymers, employed in manufacturing bone-graft substitutes, is affected by their chemical composition, molecular weight and cell environment, and by the methods of polymerization and processing. Their in vitro bioactivity on human osteoblasts has been investigated very little. We first evaluated the behavior of primary human osteoblasts cultured in close contact with 75:25 and 50:50 PLA-PGA copolymers for 14 days adopting a cell culture system that allowed us to evaluate the influence of direct contact, and of factors released from polymers. The copolymers had no negative influence on cell morphology, cell viability and proliferation. Alkaline phosphatase (ALP) activity and osteocalcin production were also not affected. The initial adhesion of osteoblasts on implant surfaces requires the contribution of integrins, acting as a primary mechanism regulating cell-extracellular matrix (ECM) interactions. We observed that adhesion of osteoblasts to PLA-PGA copolymers, 2h after plating, was reduced by approximately 70% by antibodies capable to block integrin beta(1) and alpha(5)beta(1) complex and only by approximately 30% by an anti-integrin alpha(v) antibody. Therefore, beta(1) integrins may represent a predominant adhesion receptor subfamily utilized by osteoblasts to adhere to PLA-PGA copolymers. These materials do not show any negative influence on cell proliferation and differentiation.

Regioselective Oligomerization of 3-(Alkylsulfanyl)thiophenes with Ferric Chloride.

The action of FeCl(3) on 3-(alkylsulfanyl)thiophenes (3-(alkylthio)thiophenes) leads to the one-step formation of regioregular alpha-conjugated oligothiophenes, from trimer to octamer, depending on the solvent used and on the length of the alkyl chain. The regiochemistry of these oligomers is characterized by one inner head-to-head linkage between adjacent rings and by a variable number of lateral head-to-tail junctions. The reaction of ferric chloride with the head-to-head and head-to-tail bis(methylsulfanyl)-2,2'-bithiophenes gives the corresponding tetramers, while the reaction with the tail-to-tail counterpart affords a high molecular weight insoluble material. With the aid of theoretical calculations, these results are interpreted on the basis of the joint effects of the orienting power of the substituents and of the stability of the radical cations formed during the oxidative process.