How New Developments in Pharmacology Receptor Theory Are Changing (Our Understanding of) Hypertension Therapy.

BACKGROUND: Many hypertension therapeutics were developed prior to major advances in drug receptor theory. Moreover, newer drugs may take advantage of some of the newly understood modalities of receptor function. GOAL: The goal of this review is to provide an up-to-date summary of drug receptor theory. This is followed by a discussion of the drug classes recognized for treating hypertension to which new concepts in receptor theory apply. RESULTS: We raise ideas for mechanisms of potential new antihypertensive drugs and whether they may take advantage of new theories in drug-receptor interaction.

Los receptores para imidazolinas I2 como posible marcador de malignidad en tumores gliales humanos / Imidazoline I2 receptors as a possible marker for malignancy in human glial cell tumours

Objetivo. Se pretenden exponer los datos experimentalesque apoyan la hipótesis de que los receptores para imidazolinasdel subtipo I2 podrían valorarse como un marcador biológico demalignidad en los tumores cerebrales humanos de estirpe glial.Desarrollo. Los tumores gliales son el tipo de neoplasia cerebralmás común en humanos. En estos tumores, la clasificación y la determinacióndel grado de malignidad representan elementos clavesa la hora de orientar el tratamiento del paciente. Sin embargo, enalgunas ocasiones, la correcta determinación del tipo de tumorestá limitada por la subjetividad de los criterios histológicos empleados,de ahí que la búsqueda de nuevos marcadores tumoralespara los gliomas sea una tarea imprescindible. En este contexto, seha demostrado un aumento significativo de la densidad de receptores I2 en los gliomas humanos con respecto al tejido cerebral normaly a otros tumores intracraneales de origen no glial. Además,este aumento de densidad se correlaciona con el grado de malignidadde los tumores gliales, siendo la densidad de receptores I2 enlos glioblastomas multiformes 1,4 veces mayor que en los astrocitomasanaplásicos y 2,2 veces mayor que en los astrocitomas debajo grado. Conclusiones. Estos datos indican que la medida de ladensidad de los receptores I2 mediante tomografía por emisión depositrones podría emplearse en un futuro para realizar el diagnósticoy pronóstico de los gliomas humanos sin necesidad de obtenerbiopsias del tumor para su posterior estudio anatomopatológico

Aim. To present the experimental data that support the hypothesis that the imidazoline I2 receptors may beassessed as a biological marker to establish diagnosis and grade of human gliomas. Development. Gliomas constitute themost important group of brain neoplasm in humans. In these tumours accurate histopathologic diagnosis is a first crucialprerequisite for patient treatment. However, current grading schemes are still limited by subjective histologic criteria.Therefore, the search for new molecular and biological markers of gliomas represents a crucial step. In this context, it hasbeen reported a significant increase in I2 density in human gliomas when compared with normal brain tissue and otherintracranial non-glial tumours. Moreover, this increase seems to fit well with the degree of malignancy in human gliomas.Thus, in glioblastomas multiformes the I2 density is 1.4 times higher than in anaplastic astrocytomas and 2.2 higher than inlow-grade astrocytomas. Conclusions. The present results demonstrate that the measurement of the I2 density by positronemission tomography techniques could be used in the future for grading and prognosis of human gliomas. This could avoid thecurrent need for tumour biopsies in order to obtain a histopathologic diagnosis

Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation.

Cannabidiol (CBD), a nonpsychoactive marijuana constituent, was recently shown as an oral antihyperalgesic compound in a rat model of acute inflammation. We examined whether the CBD antihyperalgesic effect could be mediated by cannabinoid receptor type 1 (CB1) or cannabinoid receptor type 2 (CB2) and/or by transient receptor potential vanilloid type 1 (TRPV1). Rats received CBD (10 mg kg(-1)) and the selective antagonists: SR141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) for CB1, SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) for CB2 and capsazepine (CPZ) for TRPV1 receptors. The intraplantar injection of carrageenan in rats induced a time-dependent thermal hyperalgesia, which peaked at 3 h and decreased at the following times. CBD, administered 2 h after carrageenan, abolished the hyperalgesia to the thermal stimulus evaluated by plantar test. Neither SR141716 (0.5 mg kg(-1)) nor SR144528 (3 and 10 mg kg(-1)) modified the CBD-induced antihyperalgesia; CPZ partially at the lowest dose (2 mg kg(-1)) and fully at the highest dose (10 mg kg(-1)) reversed this effect. These results demonstrate that TRPV1 receptor could be a molecular target of the CBD antihyperalgesic action.

Targeted prevention of renal accumulation and toxicity of gentamicin by aminoglycoside binding receptor antagonists.

Receptor-mediated endocytosis plays an important role in accumulation of aminoglycosides in renal proximal tubule. To prevent aminoglycoside-induced nephrotoxicity following concentrated accumulation of gentamicin in the kidney, effect of cationic proteins and their peptide fragments, which could inhibit gentamicin binding to its binding receptor(s), was investigated. Among several substrates for megalin, an endocytic receptor responsible for renal accumulation of aminoglycosides, cytochrome c potently inhibited gentamicin accumulation in renal cortex. Concentration-dependent inhibition by cytochrome c on gentamicin uptake was also observed in OK kidney epithelial cells expressing megalin. In addition, gentamicin-induced increase in urinary excretion of N-acetyl-beta-d-glucosaminidase (NAG), a marker of renal tubular damage, was significantly reduced by cytochrome c. We next attempted to find a peptide fragment with lower molecular size showing inhibitory effect on gentamicin uptake. Cyto79-88 inhibited gentamicin uptake in OK cells, but had little effect on renal accumulation of gentamicin in mice in vivo. On one hand, a peptide fragment of neural Wiskott-Aldrich syndrome protein (N-WASP), which interacts with acidic phospholipids like aminoglycosides, inhibited gentamicin accumulation not only in OK cells but also in mouse kidney. These results show that substrates and/or their peptide fragments for aminoglycoside binding receptor such as megalin might be useful for preventing aminoglycoside-induced nephrotoxicity.

After a decade of intravesical vanilloid therapy: still more questions than answers.

Vanilloid sensitivity is a functional signature of a subset of unmyelinated fibres innervating the urinary bladder. The role that these nerves have in the physiological control of storage and voiding is unclear. However, after the bladder has been disconnected by spinal injury from the pontine micturition centre, vanilloid-sensitive fibres assume a central role in the reflex emptying of the bladder that occurs at low volumes. Intravesical vanilloid (capsaicin or resiniferatoxin) administration is beneficial in this disorder by "desensitising" these nerves. Resiniferatoxin is superior to capsaicin in terms of its tolerability profile. Investigators are moving rapidly to identify the mechanisms by which desensitisation to vanilloids occurs. Vanilloids induce lasting, but fully reversible, changes in gene expression, including downregulation of the vanilloid receptor subtype 1. It is hoped that application of gene chip technologies will address the global profile of vanilloid-induced changes in gene expression and their relative contribution to desensitisation. Drugs that target signalling mechanisms that bring about these changes in gene expression have obvious therapeutic potential.