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Both iptakalim (Ipt) and natakalim (Nat) activate the SUR2B/Kir6.1 channel, an ATP-sensitive potassium channel (KATP) subtype, with high selectivity. In this study we investigated the therapeutic effects of Ipt and Nat against isoproterenol-induced chronic heart failure (ISO-CHF) in rats, and demonstrated a new therapeutic approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells. In ISO-CHF rats, oral administration of Nat (1, 3, 9 mg·kg -1 ·d -1 ) or Ipt (3 mg·kg -1 ·d -1 ) for 60 days significantly improved cardiac dysfunction, reversed cardiac remodeling, significantly attenuated the pathological increases in BNP levels, and improved endothelial dysfunction by adjusting the balance between endothelin and NO systems. The therapeutic effects of Nat were prevented by the selective KATP blocker glibenclamine (Gli, 50 mg·kg -1 ·d -1 ), confirming that these effects were mediated through activation of the SUR2B/Kir6.1 channel in endothelial cells. The molecular mechanisms underlying the therapeutic effects of Nat were further addressed using proteomic methods. We identified 724 proteins in the plasma of ISO-CHF rats; 55 proteins were related to Nat. These differentially expressed proteins were mainly involved in single-organism processes and the regulation of biological quality relative to CHF, including proteasome (Psm) and ATP protein clusters. We screened out PRKAR2β, GAS6/eNOS/NO and NO/PKG/VASP pathways involved in the amelioration of CHF among the 24 enriched pathways. We further confirmed 6 protein candidates, including PRKAR2β, GAS6 and VASP, which were involved in the endothelial mechanisms, and ATP, TIMP3 and AGT, which contributed to its cardiovascular actions. This study demonstrates a new pharmacological approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells, and that the eNOS/VASP pathways are involved in its signaling mechanisms.

The activation of β -cell's A- and B-type gamma-aminobutyric acid receptors (GABA A -Rs and GABA B -Rs) can promote their survival and replication, and the activation of α -cell GABA A -Rs promotes their conversion into β -cells. However, GABA and the most clinically applicable GABA-R ligands may be suboptimal for the long-term treatment of diabetes due to their pharmacological properties or potential side-effects on the central nervous system (CNS). Lesogaberan (AZD3355) is a peripherally restricted high-affinity GABA B -R-specific agonist, originally developed for the treatment of gastroesophageal reflux disease (GERD) that appears to be safe for human use. This study tested the hypothesis that lesogaberan could be repurposed to promote human islet cell survival and β -cell replication. Treatment with lesogaberan significantly enhanced replication of human islet cells in vitro , which was abrogated by a GABA B -R antagonist. Immunohistochemical analysis of human islets that were grafted into immune-deficient mice revealed that oral treatment with lesogaberan promoted human β -cell replication and islet cell survival in vivo as effectively as GABA (which activates both GABA A -Rs and GABA B -Rs), perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation.

Aims: The endothelial molecular pathway of a new ATP-sensitive potassium channel (KATP) opener natakalim was investigated in mesenteric arterioles of rats., Main Methods: A DMT wire myograph was used to evaluate the vasorelaxation effects of natakalim. Ca(2+) responses of endothelial cells induced by natakalim were measured by laser confocal fluorescence microscopy. NO assay kits and Western blotting were used., Key Findings: The new KATP opener natakalim significantly produced endothelium-dependent arteriolar dilation and increased endothelial cell intracellular calcium concentration ([Ca(2+)]i) as well as NO release, which could be inhibited by SB366791 and capsazepine, the specific TRPV1 blockers. Additionally, down-regulation of endothelial TRPV1 by RNA interference inhibited the Ca(2+) influx induced by natakalim., Significance: These results suggest that endothelial KATP mediated natakalim-induced vasorelaxation through increasing [Ca(2+)]i and NO production. Activation of endothelial TRPV1 channels and subsequent Ca(2+) entry, and NO release at least partly contribute to endothelium-dependent vasorelaxation induced by natakalim., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Two types of drugs are generally used for treating attention-deficit/hyperactivity disorder or attention-deficit disorder in humans: amphetamines or similar stimulants and the nonamphetamine atomoxetine. We describe the toxicity and treatment of both amphetamines and similar medications and atomoxetine in dogs and cats. Amphetamine intoxication can cause life-threatening stimulatory signs. Treatment is aimed at preventing absorption, controlling the stimulatory signs, and protecting the kidneys; prognosis is generally good. Atomoxetine also has a fast onset of action; stimulatory signs such as hyperactivity and tachycardia are often seen. There are little published data about treatment of atomoxetine toxicity in cats and dogs.

Background: The neurotoxic aldehyde 3-aminopropanal (3-AP) contributes to brain injury following cerebral ischemia. Tiopronin (N-2-mercaptopropionyl-glycine[N-2-MPG]) is a US Food and Drug Administration (FDA)-approved drug for the treatment of cystinuria and a putative neuroprotective agent that has been shown to bind and neutralize 3-AP and reduce infarct volumes., Objective: The objective of this trial was to establish the safety of tiopronin administration in patients with aneurysmal subarachnoid hemorrhage (aSAH) in preparation for further trials of its efficacy as a neuroprotective agent in this disease process., Methods: This Phase I dose-escalation trial enrolled three-patient cohorts using a conventional "3+3" study design. Tiopronin dose began at 1 g/d until aSAH Day 14. Each subsequent cohort received a dose of tiopronin based on predetermined guidelines. A maximum dose of 3 g/d was selected, because this is the maximum FDA-approved dose for long-term cystinuria treatment. Subjects were monitored for known side effects of tiopronin., Results: Nine patients were enrolled, the minimum number required based on the study design. None of these patients experienced serious side effects attributable to tiopronin, and no adverse events were noted that could not be attributed to the pathophysiology of aSAH., Conclusion: The administration of 3 g/d of tiopronin following aSAH for up to 14 days appears to be safe and without the side effects associated with long-term use. Plans for a randomized, placebo-controlled Phase II trial of tiopronin for neuroprotection following aSAH are underway.

We have recently reported in vivo disruption of collagen and elastin architecture within blood vessel walls resulting from the selective inhibition of the enzyme semicarbazide-sensitive amine oxidase (SSAO). This study further investigates the effects of SSAO inhibition on extracellular matrix deposition by smooth-muscle cells (SMCs) cultured from neonatal rat hearts. SMCs were characterized, SSAO activity was measured, and soluble and insoluble collagen and elastin in the extracellular matrix (ECM) were quantified. Cultured neonatal rat heart SMC exhibited a monotypic synthetic phenotype that likely represents a myofibroblast. Detectable levels of SSAO activity present throughout 30-d culture peaked at 7-14 d, coinciding with the production of ECM. The addition of enzyme inhibitors and alternate SSAO substrates (benzylamine) produced varied and, in some cases, marked changes in SSAO activity as well as in the composition of mature and soluble matrix components. Similar to our previous in vivo findings, in vitro SSAO inhibition produced aberrations in collagen and elastin deposition by heart SMC. Because changes in SSAO activity are associated with cardiovascular pathologic states, this enzyme may play a protective or modulating role by regulating ECM production during pathologic insult.

Tricyclic antidepressants (TCA), such as imipramine, are well-accepted for the treatment of urinary incontinence and enuresis, but their mechanism of action remains undefined due to their multiple pharmacological actions. To explore only the contribution imparted by sympathomimetic effects on the urethra by norepinephrine (NE) reuptake inhibition, two selective NE reuptake inhibitors (nisoxetine and tomoxetine) that possess no antimuscarinic or serotonergic properties were examined for their effects on sympathetic hypogastric nerve (HgN) evoked urethral contractions in chloralose anesthetized cats. Under control conditions, HgN stimulation produced a biphasic response composed of a consistent initial contraction that was prazosin- (alpha adrenergic antagonist) sensitive, followed by a more variable relaxation that was propranolol- (beta adrenergic antagonist) sensitive. Unexpectedly, nisoxetine (0.03 to 1.0 mg./kg. intravenously, n = 6) and tomoxetine (0.3 to 3 mg./kg. intravenously, n = 3) produced decreases (about 50% to 60% of control) in HgN-evoked contractions. These inhibitory effects of the reuptake inhibitors were reversed by propranolol. In cats that were pretreated with propranolol, nisoxetine produced a significant increase in HgN-evoked contractions. In conclusion, these results indicate that inhibition of NE reuptake into the sympathetic nerve terminal produces a relative increase in the activation of beta adrenergic receptors compared with alpha adrenergic receptors in the urethra. This increased beta receptor stimulation might be due to a greater diffusion of NE away from the neuro-effector junction to extrajunctional sites following blockade of junctional reuptake. These findings should highlight the importance of urethral beta adrenergic receptors, which is not well-recognized in the literature.

The activity of the nitropropane analog of baclofen, 3-amino-2-(4-chlorophenyl)-nitropropane (N-BAC), has been examined at central and peripheral GABAB receptors. N-BAC was less potent than baclofen as a GABAB receptor agonist in depressing repetitive twitch contractions in the guinea-pig isolated ileum (IC50s for baclofen = 4.1 +/- 1.3 microM; N-BAC = 9.2 +/- 0.3 microM) and vas deferens (IC50s for baclofen = 30 microM; N-BAC = 100 microM), competitively antagonised by phaclofen, 2-hydroxysaclofen and CGP 35348 (3-aminopropyl-P-di-ethoxymethylphosphinic acid). In the ileum, the pA2 values for CGP 35348 with baclofen (4.7 +/- 0.2) and N-BAC (4.6 +/- 0.3) were not significantly different (P > 0.05), indicating that both agonists activate the same receptor type. By contrast, in rat neocortical slices, N-BAC was 20 times weaker than baclofen in attenuating spontaneous discharges, sensitive to CGP 35348, whilst it was 100 times less potent than baclofen in depressing evoked CA1 population spikes in the hippocampus. This new GABAB receptor agonist, N-BAC, is thus more active at peripheral than central GABAB receptors.

A new hitherto unknown important property of D-amphetamine (but not L-isomer) and DL-alpha-N-methyltryptamine was discovered. These substances decrease the irreversible inhibition by clorgyline of tyramine deamination without affecting a sharply expressed inhibitory effect of clorgyline on serotonin oxidation. As a result of such a directed increase of selectivity, clorgyline became a still more highly specific inhibitor of serotonin oxidation without affecting, even at relatively high concentrations, tyramine deamination.

Rats treated with Lilly 110140, a specific inhibitor of serotonin re-uptake in brain, are less sensitive to electroshock. Lilly 110140 antagonizes the hyperalgesia following injections of p-chlorophenylalanine and potentiates morphine analgesia. Naloxone blocks the analgesia following morphine, but has no effect on Lilly 110140-induced analgesia. Brain serotonin neurons may, at least in part, mediate analgesia.

Methylthiopropylamine (MTPA), an inhibitor of spermidine synthase, markedly induced ornithine decarboxylase (ODC) activity (about 30-fold of the basal level) in human lymphoid leukemia Molt 4B cells. This induction was blocked by the addition of spermidine, spermine or putrescine simultaneously with MTPA. Inhibition by spermidine or spermine of the MTPA-induced ODC activity was larger than that by putrescine. The increase of ODC activity by MTPA led to the large increase of cellular putrescine content. This increase of putrescine content was abolished drastically by the simultaneous addition of spermidine or spermine. The increase of ODC activity was almost completely blocked by the addition of cycloheximide or actinomycin D. This finding suggested that the increase of ODC activity was not due to activation of ODC preformed in Molt 4B cells. The ODC induction by MTPA was dose-dependently blocked by adding the calcium channel blockers (verapamil and nifedipine) or protein kinase C inhibitors (1-(5-isoquinolinesulfonyl)-2-methylpiperazine and palmitoyl carnithine). These results suggested that calcium and protein kinase C (PKC) were involved in MTPA-associated induction of ODC.