Nitroprusside─Expanding the Potential Use of an Old Drug Using Nanoparticles.

For more than 70 years, sodium nitroprusside (SNP) has been used to treat severe hypertension in hospital emergency settings. During this time, a few other clinical uses have also emerged such as in the treatment of acute heart failure as well as improving mitral incompetence and in the intra- and perioperative management during heart surgery. This drug functions by releasing nitric oxide (NO), which modulates several biological processes with many potential therapeutic applications. However, this small molecule has a short lifetime, and it has been administered through the use of NO donor molecules such as SNP. On the other hand, SNP also has some setbacks such as the release of cyanide ions, high water solubility, and very fast NO release kinetics. Currently, there are many drug delivery strategies that can be applied to overcome many of these limitations, providing novel opportunities for the use of old drugs, including SNP. This Perspective describes some nitroprusside properties and highlights new potential therapeutic uses arising from the use of drug delivery systems, mainly silica-based nanoparticles. There is a series of great opportunities to further explore SNP in many medical issues as reviewed, which deserves a closer look by the scientific community.

In vitro and in vivo leishmanicidal activity of a ruthenium nitrosyl complex against Leishmania (Viannia) braziliensis.

Leishmaniasis is a parasitic disease caused by protozoa of the genus Leishmania. There are many complications presented by the current treatment, as high toxicity, high cost and parasite resistance, making the development of new therapeutic agents indispensable. The present study aims to evaluate the leishmanicidal potential of ruthenium nitrosyl complex cis-[Ru(bpy)2(SO3)(NO)](PF6) against Leishmania (Viannia) braziliensis. The effect of this metal complex on parasite-host interaction was evaluated by in vitro efficacy test in dermal fibrobast cells in the presence of different concentrations (1, 10, 50 and 100 µM) and by in vivo efficacy tests performed in the presence of two different concentrations of complex (100 µg/kg/day or 300 µg/kg/day) evaluating its effect on the size of the lesion and the number of parasites present in the draining lymph nodes in hamsters. Even at the lowest concentration of 1 µM of ruthenium complex, it was observed a significant decrease of the infected cells, after 24 h exposure in vitro, with total reduction at 50 µM of the ruthenium complex. In the in vivo cutaneous infection model, administration of daily doses of 300 µg/kg/day of complex reduced significantly lesion size by 51% (p < 0.05), with a 99.9% elimination of the parasites found in the lymph nodes (p < 0.001). The results suggest a promising leishmanicidal effect by that ruthenium nitrosyl complex against L. (V.) braziliensis.

The effect of Cratylia floribunda lectin on renal hemodynamics and ion transport

Lectins have been described as glycoproteins that reversibly and specifically bind to carbohydrates. Legume lectins isolated from the subtribe Diocleinae (Canavalia, Dioclea andCratylia) are structurally homologous with respect to their primary structures. The Diocleinae lectins of Canavalia brasiliensis, Dioclea guianensis andCanavalia ensiformis have been shown to distinctly alter physiological parameters in isolated rat kidneys. Thus, the aim of this study was to investigate the effect of Cratylia floribunda lectin (CFL) on renal hemodynamics and ion transport in rats. In isolated perfused kidneys, CFL (10 mg/mL, n=5) increased RPP, RVR and decreased %TK+, but did not change urinary flow, glomerular filtration rate, sodium or chloride tubular transport. In isolated perfused mesenteric bed, CFL (3 and 10 mg/mL/min; n=4) did not alter tissue basal tonus or tissue contraction by phenylephrine (1 mM/mL/min). In conclusion, the seed lectin of Cratylia floribunda increased renal hemodynamic parameters showing a kaliuretic effect. This effect could be of tubular origin, rather than a result from haemodynamic alterations.

As lectinas são descritas como (glico)proteínas que se ligam, especificamente e reversivelmente, a carboidratos. Lectinas de leguminosas isoladas da subtribo Diocleinae (Canavalia, Dioclea eCratylia) são estruturalmente homólogas em relação às suas estruturas primárias. Demonstrou-se que as lectinas de DiocleinaeCanavalia brasiliensis, Dioclea guianensis eCanavalia ensiformis alteram diferentemente parâmetros fisiológicos em rins isolados de ratos. Dessa maneira, o objetivo deste estudo foi investigar o papel da lectina de Cratylia floribunda (CFL) na hemodinâmica renal e no transporte de íons em ratos. Em rins isolados perfundidos, CFL (10 mg/mL, n=5) aumentou a pressão de perfusão renal, a resistência vascular renal e reduziu o percentual do transporte tubular de K+, mas não alterou o fluxo urinário, a taxa de filtração glomerular e o percentual de transporte tubular dos íons sódio e cloreto. No leito mesentérico isolado perfundido, CFL (3 e 10 mg/mL/min, n=4) não alterou o tônus basal ou a contração do tecido induzida por fenilefrina (1 mM/mL/min). Em conclusão, a lectina de sementes de Cratylia floribunda altera parâmetros hemodinâmicos renais, provavelmente de origem tubular, e não por alterações hemodinâmicas.

Identification of mechanisms involved in the relaxation of rabbit cavernous smooth muscle by a new nitric oxide donor ruthenium compound.

PURPOSE: The aim of this study was to evaluate the relaxation in vitro of cavernous smooth muscle induced by a new NO donor of the complex nitrosil-ruthenium, named trans-[Ru(NH3)4(caffeine)(NO)]C13 (Rut-Caf) and sodium nitroprusside (SNP). MATERIALS AND METHODS: The tissues, immersed in isolated bath systems, were pre-contracted with phenilephrine (PE) (1 µM) and then concentration-response curves (10 (-12) - 10(-4) M) were obtained. To clarify the mechanism of action involved, it was added to the baths ODQ (10 µM, 30 µM), oxyhemoglobin (10 µM), L-cysteine (100 µM), hydroxicobalamine (100 µM), glibenclamide, iberotoxin and apamine. Tissue samples were frozen in liquid nitrogen to measure the amount of cGMP and cAMP produced. RESULTS: The substances provoked significant relaxation of the cavernous smooth muscle. Both Rut-Caf and SNP determined dose-dependent relaxation with similar potency (pEC50) and maximum effect (E(max)). The substances showed activity through activation of the soluble guanylyl cyclase (sGC), because the relaxations were inhibited by ODQ. Oxyhemoglobin significantly diminished the relaxation effect of the substances. L-cysteine failed to modify the relaxations caused by the agents. Hydroxicobalamine significantly diminished the relaxation effect of Rut-Caf. Glibenclamide significantly increased the efficacy of Rut-Caf (pEC50 4.09 x 7.09). There were no alterations of potency or maximum effect of the substances with the addition of the other ion channel blockers. Rut-Caf induced production of significant amounts of cGMP and cAMP during the relaxation process. CONCLUSIONS: In conclusion, Rut-Caf causes relaxation of smooth muscle of corpus cavernosum by means of activation of sGC with intracellular production of cGMP and cAMP; and also by release of NO in the intracellular environment. Rut-Caf releases the NO free radical and it does not act directly on the potassium ion channels.

Identification of mechanisms involved in the relaxation of rabbit cavernous smooth muscle by a new nitric oxide donor ruthenium compound

PURPOSE: The aim of this study was to evaluate the relaxation in vitro of cavernous smooth muscle induced by a new NO donor of the complex nitrosil-ruthenium, named trans-[Ru(NH3)4(caffeine)(NO)]C13 (Rut-Caf) and sodium nitroprusside (SNP). MATERIALS AND METHODS: The tissues, immersed in isolated bath systems, were pre-contracted with phenilephrine (PE) (1 µM) and then concentration-response curves (10-12 - 10-4 M) were obtained. To clarify the mechanism of action involved, it was added to the baths ODQ (10 µM, 30 µM), oxyhemoglobin (10 µM), L-cysteine (100 µM), hydroxicobalamine (100 µM), glibenclamide, iberotoxin and apamine. Tissue samples were frozen in liquid nitrogen to measure the amount of cGMP and cAMP produced. RESULTS: The substances provoked significant relaxation of the cavernous smooth muscle. Both Rut-Caf and SNP determined dose-dependent relaxation with similar potency (pEC50) and maximum effect (Emax). The substances showed activity through activation of the soluble guanylyl cyclase (sGC), because the relaxations were inhibited by ODQ. Oxyhemoglobin significantly diminished the relaxation effect of the substances. L-cysteine failed to modify the relaxations caused by the agents. Hydroxicobalamine significantly diminished the relaxation effect of Rut-Caf. Glibenclamide significantly increased the efficacy of Rut-Caf (pEC50 4.09 x 7.09). There were no alterations of potency or maximum effect of the substances with the addition of the other ion channel blockers. Rut-Caf induced production of significant amounts of cGMP and cAMP during the relaxation process. CONCLUSIONS: In conclusion, Rut-Caf causes relaxation of smooth muscle of corpus cavernosum by means of activation of sGC with intracellular production of cGMP and cAMP; and also by release of NO in the intracellular environment. Rut-Caf releases the NO free radical and it does not act directly on the potassium ion channels.

The extract of the jellyfish Phyllorhiza punctata promotes neurotoxic effects.

Phyllorhiza punctata (P. punctata) is a jellyfish native to the southwestern Pacific. Herewith we present the biochemical and pharmacological characterization of an extract of the tentacles of P. punctata. The tentacles were subjected to three freeze-thaw cycles, homogenized, ultrafiltered, precipitated, centrifuged and lyophilized to obtain a crude extract (PHY-N). Paralytic shellfish poisoning compounds such as saxitoxin, gonyautoxin-4, tetrodotoxin and brevetoxin-2, as well as several secretory phospholipase A(2) were identified. PHY-N was tested on autonomic and somatic neuromuscular preparations. In mouse vas deferens, PHY-N induced phasic contractions that reached a peak of 234 ± 34.7% of control twitch height, which were blocked with either 100 µ m of phentolamine or 1 m m of lidocaine. In mouse corpora cavernosa, PHY-N evoked a relaxation response, which was blocked with either L-N(G) -Nitroarginine methyl ester (0.5 m m) or 1 m m of lidocaine. PHY-N (1, 3 and 10 µg ml(-1) ) induced an increase in tonus of the biventer-cervicis neuromuscular preparation that was blocked with pre-treatment of galamine (10 µ m). Administration of 6 mg kg(-1) PHY-N intramuscularly produced death in broilers by spastic paralysis. In conclusion, PHY-N induces nerve depolarization and nonspecifically increases neurotransmitter release.

Disfunção endotelial e nitrérgica: prevenção e/ou reversão por antioxidantes naturais e componetes do mediador putativo da insulina / Endothelial dysfunction and nitrergic: Prevention and / or reversal of natural antioxidants and components of the putative insulin mediator

O endotélio é um órgão endócrino que regula diversas funções importantes para a homeostase vascular, como tônus, trombogênese, aterogênese, angiogênese, migração celular na inflamação, etc. Esse órgão, como qualquer outro, está sujeito a disfunção e até mesmo falência. Entre os principais fatores de risco que causam disfunção endotelial (DE) estão o diabetes (Db) e a senescência. Neste estudo avaliamos a função endotelial através da medida da resposta relaxante endotélio-dependente em vasos de ratos diabéticos e senescentes e de coelhos diabéticos. A administração oral duas vezes ao dia durante 1 mês de antioxidantes naturais (rutina e ácido lipóico-AL) em ratos diabéticos ou senescente foi capaz de prevenir a DE nestes animais. A taxa de DE na aorta ratos diabéticos tratados apenas com veículo foi de 51,9 +- 4,6% enquanto que nos tratados com rutina foi de 14,1 +- 2,4% (p < 0,05) e 44,7 +- 3,7% nos tratados com AL. No leito arteriolar mesentérico (LAM) dos ratos diabéticos a DE foi de 44,6 +- 5,8% comparado com 21,4 +- 2,8% nos tratados com rutina e 24,8 +- 3,7% no grupo tratado com AL. O mesmo padrão de resposta foi observado no leito vascular renal (LVR) corpos cavernosos de coelhos (RbCC) diabéticos. Nestes tecidos a incubação por 1 hora com 1 μM de rutina ou AL foi capaz de reverter a DE. No LVR a resposta relaxante máxima à acetilcolina (ACh) foi de 16,0 +- 2,0% comparada com 42,0 +- 3,4% obtidas nos LVR tratados com rutina e 31,0 +- 3,9% nos tratados com AL...