Relaxant effects of antidepressants on human isolated mesenteric arteries

AIMS: The therapeutic action of tricyclic agents may be accompanied by unwanted effects on the cardiovascular system. The evidence for the effects on vascular and nonvascular smooth muscle comes from animal studies. Whether these studies can be extrapolated to human vessels remains to be determined. Therefore, the present study was designed to investigate the influence of amitriptyline, nortriptyline and sertraline on the contractile responses of human isolated mesenteric arteries to electrical field stimulation, noradrenaline and potassium chloride. METHODS: Arterial segments (lumen diameter 0.8-1.2 mm) were obtained from portions of the human omentum during the course of 41 abdominal operations (22 men and 19 women), and rings 3 mm long were mounted in organ baths for isometric recording of tension. In some artery rings the endothelium was removed mechanically. RESULTS: In precontracted artery rings amitriptyline, nortriptyline and sertraline (3x10(-7)-10(-4) m ) produced concentration-dependent relaxation that was independent of the presence or absence of vascular endothelium. Incubation with indomethacin (3x10(-6) m ) reduced the pD2 values thus indicating the participation of dilating prostanoid substances in this response. Amitriptyline and nortriptyline inhibited both the neurogenic-and noradrenaline-induced contractions. In contrast, only the highest concentration of sertraline reduced the adrenergic responses. Amitriptyline, nortriptyline and sertraline inhibited contractions elicited by KCl and produced rightward shifts of the concentration-response curve to CaCl2 following incubation in calcium-free solution. CONCLUSIONS: These results indicate that amitriptyline and nortriptyline could act as adrenoceptor antagonists and direct inhibitors of smooth muscle contraction of human mesenteric arteries, whereas sertraline might principally exert its action only as direct inhibitor of smooth muscle contraction. This relaxant mechanism involves an interference with the entry of calcium.     

Otras dianas terapéuticas distintas a las citocinas

The arrival of anti-TNF-α to the clinic has been the most successful example of translational research. However, clinical experience has shown that these compounds do not induce clinical remission in half of rheumatoid arthritis (RA) patients. Recently, new biological drugs against non-cytokine targets have been available for RA patients. These compounds deplete B cells or interfere with the activation of T cells and have also shown effectiveness in controlling signs, symptoms and structural damage progression in RA. Second generation B-cell depletion therapies are progressing in the pipeline of several pharmaceutical companies. These compounds will likely improve the immunogenicity and formulation of rituximab, but it is improbable that they will improve the remission rate achieved by the anti-TNF-α δρυγσ. Currently, regulation of signal transduction has evolved into an important field of drug research, and small molecule inhibitors for a number of pathways are tested as new anti-inflammatory agents. For rheumatic diseases, specific Jak3 and Syk inhibitors are, so far, the most successful compounds representing a significant advance over p38 mitogen-activated protein kinase (MAPK) inhibitors.     

Uncommon Epiloptogenic Lesions Affecting the Temporal Lobe

There are several processes implicated as uncommon causes of temporal lobe epilepsy. Trauma is the leading cause of epilepsy in young adults, intracerebral blood collection being the most consistent risk factor of seizures, especially subdural hematomas and brain contusions. Infarction is the entity most commonly related to epilepsy in the elderly population. Seizures usually present as complex seizures with high recurrence between 6 months and 2 years after stroke. There are some radiological characteristics of the affectation associated with high risk of early and late seizures. Noninfectious limbic encephalitis is a syndrome characterized by seizures, memory loss, and confusion. It includes paraneoplasic and non-paraneoplasic limbic encephalitis, both presenting as hyperintense lesion affecting temporobasal regions more evident with fluid-attenuated inversion recovery sequences. Paraneoplasic limbic encephalitis is associated with several types of tumor-induced autoimmunity against the nervous system. The tumors most frequently implicated are the lungs, testis, and breast, including Hodgkin's lymphoma, teratoma, and thymoma in young patients. Once a tumor is excluded, non-paraneoplasic limbic encephalitis has to be considered by investigating the presence of antibodies against voltage-gated potassium channels. It is associated with hyponatremia and responds to regimens of steroids, plasma exchange, and intravenous immunoglobulins. Finally, herpetic limbic encephalitis is also associated with seizures, accompanied by fever and neurologic symptoms. It presents characteristic findings and distribution on magnetic resonance imaging, which shows abnormalities in more than 90% of patients with proven Herpes simplex virus type 1.     

Risk Acceptance in Composite Tissue Allotranplantation Reconstructive Procedures

Abstract Composite tissue allotransplantation (CTA) has recently emerged as a new therapeutic modality to reconstruct major tissue defects of the face, larynx, and extremities. However, because the risk-versus-benefit ratio for CTA procedures has not yet been defined, the decision as to whether or not to perform these new reconstructive techniques is based on subjective opinions rather than objective data. To address this problem, the authors developed a reliable and valid instrument to objectively assess the relative risk that individuals are willing to accept in order to receive the benefits of various CTA procedures.     

Heterogeneity in ataxia-telangiectasia: Classical phenotype associated with intermediate cellular radiosensitivity

We identified a subgroup of ataxia-telangiectasia (AT) patients (2 sibs and 1 unrelated case) characterized by typical clinical manifestations of the disease and cellular radiosensitivity intermediate between classical AT and normal subjects. Our data and a literature review of the intermediate radiosensitivity AT cases show that radioresistant DNA synthesis, cellular radiosensitivity (measured in terms of survival and chromosome break-age), and the clinical hallmarks behave independently. This raises a number of interesting questions about the correlation between radiobiological and clinical features, and about the nature of the AT gene(s).     

Familial occurrence of congenital stricture of bulbar urethra

We report on the familial occurrence of congenital bulbar urethral stricture in 2 brothers. Embryological mechanisms are briefly discussed and the literature reviewed.     

Glutamate induces oxidative stress not mediated by glutamate receptors or cystine transporters: protective effect of melatonin and other antioxidants

Glutamate is responsible for most of the excitatory synaptic activity and oxidative stress induction in the mammalian brain. This amino acid is increased in the substantia nigra in parkinsonism due to the lack of dopamine restraint to the subthalamic nucleus. Parkinson's disease also shows an increase of iron levels in the substantia nigra and a decrease of glutathione, the antioxidant responsible for the ascorbate radical recycling. Considered together, these facts could make the antioxidant ascorbate behave as a pro-oxidant in parkinsonism. Since both glutamate and ascorbate are present in the synaptosomes and neurons of substantia nigra, we tested 1) if glutamate is able to induce oxidative stress independently of its excitatory activity, and 2) if ascorbate may have synergistic effects with glutamate when these two molecules co-exist. Brains were homogenized in order to disrupt membranes and render membrane receptors and intracellular signaling pathways non-functional. In these homogenates glutamate induced lipid peroxidation, indicating that this amino acid also may cause oxidative stress not mediated by its binding to glutamate receptors or cystine transporters. Ascorbate also induced lipid peroxidation thus behaving as a pro-oxidant. Both substances together produced an additive effect but they did not synergize. Given that melatonin is a potent physiological antioxidant with protective effects in models of neurotoxicity, we tested the role of this secretory product on the pro-oxidant effect of both compounds given separately or in combination. We also checked the protective ability of several other antioxidants. Pharmacological doses of melatonin (millimolar), estrogens, pinoline and trolox (micromolar) prevented the oxidant effect of glutamate, ascorbate, and the combination of both substances. Potential therapeutic application of these results is discussed.