Enhanced large conductance K+ channel activity contributes to the impaired myogenic response in the cerebral vasculature of Fawn Hooded Hypertensive rats.

Recent studies have indicated that the myogenic response (MR) in cerebral arteries is impaired in Fawn Hooded Hypertensive (FHH) rats and that transfer of a 2.4 megabase pair region of chromosome 1 (RNO1) containing 15 genes from the Brown Norway rat into the FHH genetic background restores MR in a FHH.1(BN) congenic strain.

Cardiac toxicity of some echinocandin antifungals.

Background: Unexplained cardiovascular decompensation has been observed during central venous administration of some echinocandins.

Objective: The purpose of this study was to assess cardiac toxicity associated with the echinocandins.

Methods: Isolated rat hearts (Langendorff model) were perfused with anidulafungin (ANID), caspofungin (CASP), or micafungin (MICA) at exposures of 1, 4, and 10 times therapeutic concentrations.

Allopregnanolone reinstates tyrosine hydroxylase immunoreactive neurons and motor performance in an MPTP-lesioned mouse model of Parkinson's disease.

Restorative/protective therapies to restore dopamine neurons in the substantia nigra pars compacta (SNpc) are greatly needed to effectively change the debilitating course of Parkinson's disease. In this study, we tested the therapeutic potential of a neurogenic neurosteroid, allopregnanolone, in the restoration of the components of the nigrostriatal pathway in MPTP-lesioned mice by measuring striatal dopamine levels, total and tyrosine hydroxylase immunoreactive neuron numbers and BrdU-positive cells in the SNpc. An acute treatment (once/week for two weeks) with allopregnanolone restored the number of tyrosine hydroxylase-positive and total cell numbers in the SNpc of MPTP-lesioned mice, even though this did not increase striatal dopamine.

Allopregnanolone increases the number of dopaminergic neurons in substantia nigra of a triple transgenic mouse model of Alzheimer's disease.

More than a third of Alzheimer's disease (AD) patients show nigrostriatal pathway disturbances, resulting in akinesia (inability to initiate movement) and bradykinesia (slowness of movement). The high prevalence of this dysfunction of dopaminergic neuron in the nigrostriatal pathway in AD suggests that the risk factors for AD appear also significant risk factors for substantia nigra pars compacta (SNpc) lesions. Previously, we have demonstrated that allopregnanolone (APα) promotes neurogenesis and improves the cognitive function in a triple transgenic mouse model of AD (3xTgAD).

ASIC-like currents in freshly isolated cerebral artery smooth muscle cells are inhibited by endogenous oxidase activity.

Background/aims: The aim of this study was to determine if VSMC ASIC-like currents are regulated by oxidative state.

Methods: We used whole-cell patch clamp of isolated mouse cerebral VSMCs to determine if 1) reducing agents, such as DTT and GSH, and 2) inhibition of endogenous oxidase activity from NADPH and Xanthine oxidases potentiate active currents and activate electrically silent currents.

Results: Pretreatment with 2 mM DTT or GSH, increased the mean peak amplitude of ASIC-like currents evoked by pH 6.

Extracellular acidosis activates ASIC-like channels in freshly isolated cerebral artery smooth muscle cells.

Recent studies suggest that certain acid-sensing ion channels (ASIC) are expressed in vascular smooth muscle cells (VSMCs) and are required for VSMC functions. However, electrophysiological evidence of ASIC channels in VSMCs is lacking. The purpose of this study was to test the hypothesis that isolated cerebral artery VSMCs express ASIC-like channels.

Prostaglandin E2 enhances acetylcholine-induced, Ca2+-dependent ionic currents in swine tracheal mucous gland cells.

Airway submucosal gland cell (SMGC) secretions are under the control of various neurotransmitters and hormones. Interactions between different pathways, such as those mediated by cAMP and Ca(2+), in controlling mucus or electrolyte secretions are not well understood. Prostaglandin E(2) (PGE(2)) or forskolin has been shown to enhance acetylcholine (ACh)-induced short circuit current (I(SC)) in SMGC mucous cell monolayers.

Tachyphylaxis to the inhibitory effect of L-type channel blockers on ACh-induced [Ca2+]i oscillations in porcine tracheal myocytes.

Discrepancies about the role of L-type voltage-gated calcium channels (VGCC) in acetylcholine (ACh)-induced [Ca(2+)](i) oscillations in tracheal smooth muscle cells (TSMCs) have been seen in recent reports. We demonstrate here that ACh-induced [Ca(2+)](i) oscillations in TMCS were reversibly inhibited by three VGCC blockers, nicardipine, nifedipine and verapamil. Prolonged (several minutes) application of VGCC blockers, led to tachyphylaxis; that is, [Ca(2+)](i) oscillations resumed, but at a lower frequency.

Antimuscarinic actions of antihistamines on the heart.

Antimuscarinic side-effects, which include dry mouth, tachycardia, thickening of mucus possibly sedation, of the antihistamines limited the usefulness of these drugs. The advent of newer agents has reduced the sedative effect of the antihistamine. The data presented here show that one of the newest antihistamines, desloratadine, and a first generation drug, diphenhydramine, are both competitive inhibitors of muscarinic receptor mediated slowing of the heart as measured using a Langendorff preparation.

Prostanoids secreted by alveolar macrophages enhance ionic currents in swine tracheal submucosal gland cells.

We examined the effect of substances released by swine alveolar macrophages (AMs) on ionic currents in airway submucosal gland cells (SGCs). AMs obtained by lavage were activated by 24-h zymosan exposure (0.1 mg/ml).

Cardiodepressant and neurologic actions of Solenopsis invicta (imported fire ant) venom alkaloids.

Background: We hypothesized that the alkaloid compounds that are the majority components of fire ant (Solenopsis invicta) venom are capable of producing cardiovascular and central nervous system toxic effects in mammals.

Objective: To evaluate toxic effects of synthetic S. invicta alkaloids in rodent models.

Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transport.

Background: The first generation antihistamines, such as diphenhydramine, are fairly potent muscarinic antagonists in addition to being H1 selective antihistamines. The antimuscarinic action is often not desirable since it is in part responsible for the drying of secretions in the airways and the sedative effect. We therefore examined a number of antihistamines for antimuscarinic effects on ion transport by mucus gland cells isolated from the airways of swine.

Regulation of acetylcholine-induced phosphorylation of PLD1 in porcine tracheal smooth muscle.

The muscarinic agonist, acetylcholine (ACh), stimulates phospholipase D (PLD) activity in tracheal smooth muscle cells. Direct activation of protein kinase C (PKC) by phorbol-12-myristate-13-acetate (PMA) also stimulates PLD in this tissue. Activation of ACh-induced PLD was inhibited by the tyrosine kinase inhibitor genistein in a concentration-dependent manner.

Characterization of contractile function and expression of muscarinic receptors, G proteins and adenylate cyclase in cultured tracheal smooth muscle of Swine.

Smooth muscle cells lose their contractile function and phenotype very rapidly when placed in culture. During organ culture of smooth muscle strips, phenotype is lost more slowly. In the present studies, we established an organ culture model to study contractile function and expression of muscarinic receptors, G proteins and adenylyl cyclase in different serum concentrations in tracheal smooth muscle from swine.