Insulin attenuates vascular contraction via inhibition of voltage-operated Ca2+ channels and by enhancement of endothelium-dependent vasodilation. Thus it has been suggested that hypertension-associated insulin resistance results from an insensitivity to the hormone’s effects on vascular reactivity. This hypothesis has been strengthened by reports that thiazolidinediones, a class of insulin-sensitizing agents, lower blood pressure and improve insulin responsiveness in hypertensive, insulin-resistant animal models. We tested the hypothesis that troglitazone enhances the vasodilating effect of insulin via inhibition of voltage-operated Ca2+ channels in vascular smooth muscle cells. Rat thoracic aortic rings (no endothelium) were suspended in tissue baths for isometric force measurement. Rings were incubated with 0.1 DMSO vehicle (control), troglitazone (10−5 M), insulin (10−7 U/l), or both troglitazone and insulin (1 h) and then contracted with phenylephrine (PE), KCl, or BAY K 8644. Troglitazone increased the EC50 values for PE and KCl. Contractions to BAY K 8644 in troglitazone-treated rings were virtually abolished. Insulin alone had no effect on contraction. However, when insulin was combined with troglitazone, the EC50 values for PE and KCl were further increased. Additionally, the maximum contractions to both PE (14 ± 4% of control) and KCl (12 ± 2% of control) were reduced. Measurement of Ca2+concentration ([Ca2+]) with fura 2-AM in dispersed vascular smooth muscle cells indicated that neither insulin nor troglitazone alone altered PE-induced increases in intracellular [Ca2+]. However, troglitazone and insulin together caused a significant reduction in PE-induced increases in intracellular [Ca2+] (expressed as percentage of preincubation stimulation to PE: 47 ± 10%, treated; 102 ± 13%, vehicle). These results demonstrate that troglitazone inhibits Ca2+ influx and that it acts synergistically with insulin to attenuate further vascular contraction via inhibition of voltage-operated Ca2+ channels.
Photorelaxation of arteries by ultraviolet (UV) light is hypothesized to result from nitric oxide (NO) released from photoactivable stores. Recently, a study reported enhanced photorelaxation of aortic tissue from rats administered the NO synthase (NOS) inhibitor Nω-nitro-L-arginine (L-NNA). Presumably, the potentiated photorelaxation was due to NO generated from UV-light-induced decomposition of the NO2 moiety of L-NNA. However, we hypothesized that photorelaxation is: (1) not the result of NO synthesis and subsequent activation of guanylate cyclase and (2) not due to hyperpolarization induced by NO or any other factor. Endothelium-denuded rat aortic rings were suspended in isolated baths for isometric force measurement. Rings were exposed to UV light (366 nm) before addition of phenylephrine or KCI, and then at each agonist concentration during a cumulative concentration response curve. NOS inhibition by L-NNA and L-thiocitrulline, which lacks an NO2 group, enhanced photorelaxation of basal myogenic tone and contraction to phenylephrine (EC70). Furthermore, relaxation of a maximum phenylephrine-induced contraction to the NO donor S-nitroso-N-acetyl-D L-penicillamine during UV light exposure was not altered by incubation of rings with L-NNA or tissues from animals fed L-NNA. These data demonstrate that NO is not produced endogenously or from the breakdown of L-NNA to result in photorelaxation. Methylene blue (MB) did not alter photorelaxation, suggesting that cGMP is not essential to the response. MB and L-NNA together potentiated photorelaxation of basal myogenic tone and phenylephrine-induced contraction. Photorelaxation of KCl-induced contraction was unaltered, indicating that hyperpolarization does not contribute to the relaxation. Photorelaxation of basal myogenic tone and KCl-induced contraction excludes the possibility that UV light is interfering with agonist-receptor binding. Collectively, these results refute the hypotheses that photorelaxation results from activation of the NO-cGMP pathway, release of a hyperpolarization factor, or inhibition of drug-receptor interaction. Interestingly, photorelaxation may be inhibited by NO-cGMP pathway activation, uncovering a novel effect of this messenger system on vascular reactivity.
Chronotherapeutics also known as pulsatile drug delivery system deals with the study of the temporal changes in absorption, distribution, metabolism and elimination and thus takes into account the influence of time of administration on these different steps and it focuses on the release of a drug after a lag time at a particular site in order to maintain constant blood levels of a particular drug matching circadian rhythms of various diseases. Circadian time dependent differences are also seen in pharmacokinetics of many classes of medications like cardiovascular active drugs, NSAID's, antidepressants, anti hypertensives, local anesthetics, H 1 and H 2 antagonists etc. The role of circadian rhythms in the mechanisms of disease and the pharmacokinetics and pharmacodynamics of medications constitutes a challenge to drugdiscovery and drug-delivery scientists. We must strive to develop intelligent drug-delivery systems that can affect a target cell or organ system at that circadian time when it is possible to optimize desired therapeutic outcomes and minimize or avert adverse effects. The recent advances in pulsatile drug delivery technology are CODAS, ACCU-BREAK, SODAS, IPDAS, DMDS Technology etc.
Rabeprazole sodium is a proton pump inhibitor used to treat peptic ulcer, duodenal ulcer, gastro oesophageal reflux disease by inhibiting the enzyme H + /K + ATPase, the acidic pump. It is also used to treatZollinger-Ellison syndrome, erosive esophagitis.This study is aimed to develop pharmaceutically equivalent and stable enteric-coated tablets of Rabeprazole sodium which protects it from acidic environment of the stomach. Six Formulations of Rabeprazole core tablets were developed using mannitol as diluents, crospovidone and polyplasdone-XL as super disintegrants, sodium carbonate anhydrous as stabilizer, magnesium stearate and talc as lubricant and glidant in different proportions, and the prepared core tablets were coated with enteric coating using hypromellose phthalate 55, myvacet, pigment blend yellow, ethanol and purified water. Compatibility studies were performed for drug, physical mixture tablet which shows no interaction. From the dissolution the formulation F6 shows highest percentage of drug release.
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