HIF-1 regulation of miR-29c impairs SERCA2 expression and cardiac contractility.

The principal regulator of cellular response to low oxygen is hypoxia-inducible factor (HIF)-1, which is stabilized in several forms of heart failure. Our laboratory developed a mouse strain in which a stable form of HIF-1 can be inducibly expressed in cardiomyocytes. Strikingly, these mice show a rapid decrease in cardiac contractility and a rapid loss of SERCA2 protein, which is also seen in heart failure.

Implications of Dynamic Occupancy, Binding Kinetics, and Channel Gating Kinetics for hERG Blocker Safety Assessment and Mitigation.

Blockade of the hERG potassium channel prolongs the ventricular action potential (AP) and QT interval, and triggers early after depolarizations (EADs) and torsade de pointes (TdP) arrhythmia. Opinions differ as to the causal relationship between hERG blockade and TdP, the relative weighting of other contributing factors, definitive metrics of preclinical proarrhythmicity, and the true safety margin in humans. Here, we have used in silico techniques to characterize the effects of channel gating and binding kinetics on hERG occupancy, and of blockade on the human ventricular AP.

Conditional HIF-1alpha expression produces a reversible cardiomyopathy.

Background: The response to hypoxia in tissues is regulated by the heterodimeric transcription factor Hypoxia Inducible Factor-1 (HIF-1).

Methodology/principal Findings: We have created a strain of mice with inducible cardiomyocyte-specific expression of a mutated, oxygen-stable, form of HIF-1alpha. Cardiac function steadily decreased with transgene expression, but recovered after the transgene was turned off.

A mathematical model of electrotonic interactions between ventricular myocytes and fibroblasts.

Functional intercellular coupling has been demonstrated among networks of cardiac fibroblasts, as well as between fibroblasts and atrial or ventricular myocytes. In this study, the consequences of these interactions were examined by implementing the ten Tusscher model of the human ventricular action potential, and coupling it to our electrophysiological models for mammalian ventricular fibroblasts. Our simulations reveal significant electrophysiological consequences of coupling between 1 and 4 fibroblasts to a single ventricular myocyte.

K+ currents activated by depolarization in cardiac fibroblasts.

K(+) currents expressed in freshly dispersed rat ventricular fibroblasts have been studied using whole-cell patch-clamp recordings. Depolarizing voltage steps from a holding potential of -90 mV activated time- and voltage-dependent outward currents at membrane potentials positive to approximately -30 mV. The relatively slow activation kinetics exhibited strong dependence on the membrane potential.

K+ currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts.

Despite the important roles played by ventricular fibroblasts and myofibroblasts in the formation and maintenance of the extracellular matrix, neither the ionic basis for membrane potential nor the effect of modulating membrane potential on function has been analyzed in detail. In this study, whole cell patch-clamp experiments were done using ventricular fibroblasts and myofibroblasts. Time- and voltage-dependent outward K(+) currents were recorded at depolarized potentials, and an inwardly rectifying K(+) (Kir) current was recorded near the resting membrane potential (RMP) and at more hyperpolarized potentials.

A double-blind randomized study of cisapride in the treatment of nonulcer dyspepsia. The Canadian Cisapride Nud Study Group.

Cisapride is a substituted benzamide with gastrointestinal prokinetic effects presumed to be due to the enhancement of the physiological release of acetylcholine at the myenteric plexus. In a multicentre study, 189 patients with nonulcer dyspepsia (NUD) received single-blind placebo treatment for two weeks. A total of 123 patients with no or minimal response to placebo and epigastric pain of at least moderate severity and frequency were randomly assigned to one of the three parallel double-blind treatments for six weeks: cisapride 10 mg tid, cisapride 20 mg tid or placebo.

Reevaluation of the balloon in gastrointestinal manometry.

Although the flow-through catheter (FTC) system has been useful and satisfactorily accurate for gastrointestinal manometry, we hypothesized that a cylindrical, liquid-filled balloon would also accurately reflect stress imposed by a sphincter. Latex balloons were fitted over the side ports of a closed-end catheter. The responses of the balloon and FTC system were compared in a cylindrical chamber commonly identified as a Starling resistor.

Gastrointestinal inflammation: focus on the vascular endothelium.

Ischemia of the intestine predominantly affects the small bowel and colon, and may ensue from a variety of causes, ranging from radiation enteritis to the use of drugs that affect the intestinal vasculature. Gut ischemia has historically been thought of as "large-vessel" disease, but microcirculatory pathology and ischemia-reperfusion injury is increasingly being implicated in gut infections and even in chronic idiopathic inflammatory processes involving the gut, such as ulcerative colitis and Crohn's disease.

Isolation, Amino-Acid Sequence, Synthesis and Biological Properties of Urotensin I from Hippoglossoides elassodon.

Abstract A 41-residue urotensin I neuropeptide (H-UI) was isolated from urophyses of the marine teleost Hippoglossoides elassodon (the flathead sole). The peptide was recognized by its partial cross-reactivity in a radioimmunoassay developed for Catostomus (sucker) Ul (S-UI), and was purified by reversed-phase high-performance liquid chromatography. The amino-acid sequence was shown to be H-Ser-Glu-Glu-Pro-Pro-Met-Ser-lle-Asp-Leu-Thr-Phe-His-Met-Leu-Arg-Asn-Met-lle-His-Arg-Ala-Lys-Met-Glu-Gly-Glu-Arg-Glu-Gln-Ala-Leu-lle-Asn-Arg-Asn-Leu-Leu-Asp-Glu-Val-NH(2).

Treatment of acute colonic pseudoobstruction (Ogilvie's syndrome) with cisapride.

A 73-yr-old white woman admitted with lobar pneumonia and congestive heart failure developed progressive colonic pseudoobstruction (Ogilvie's syndrome) 2 days after admission which was unrelieved by diatrizoate meglumine (Gastrografin, Squibb Canada, Montreal) enema and rectal tube. Cisapride, a new gastrointestinal prokinetic agent, was administered intravenously with full resolution of the syndrome. To the authors' knowledge, this is the first reported case of successful treatment of acute colonic pseudoobstruction with cisapride.

Differential antagonism of alpha-1 and alpha-2 adrenoceptor-mediated vasoconstrictor responses by a vasodilator peptide, urotensin I: comparison with nifedipine.

We showed previously that in the dog, but not in the rat, Urotensin I, (UI), a neuropeptide with corticotropin releasing factor activity, selectively dilated the mesenteric circulation. Even in the rat, mesenteric arteries tested in vitro exhibited greater vasodilator responsiveness to UI than arterial preparations from elsewhere. In the rat in vivo, UI caused a preferential inhibition of alpha-1 adrenoceptor-mediated vasoconstriction, but it was unclear whether this provided an explanation for selective vasodilatation.

Midazolam in upper gastrointestinal endoscopy: a single-blind dose-finding study.

Midazolam is a water soluble benzodiazepine with potent sedative and amnestic properties. Sixty unpremedicated patients who were to undergo upper endoscopy for diagnostic purposes were enrolled in an open, non-randomized study to assess the efficacy of 4 increasing dosages of midazolam (0.05, 0.

Is the hypotension of cirrhosis a GABA-mediated process?

Systolic and diastolic blood pressures were recorded in 176 ambulant patients with chronic liver disease, including 36 patients with compensated cirrhosis (Group I), 119 patients with noncirrhotic chronic liver disease (Group II) and 21 patients with benign structural or functional liver disease (Group III). Group I patients had significantly lower systolic (113.0 +/- 2.

Distinct vascular actions of epidermal growth factor-urogastrone and transforming growth factor-alpha.

We compared the effects of epidermal growth factor-urogastrone (EGF-URO) with those of transforming growth factor-alpha (TGF-alpha) on regional blood flow in the anesthetized dog in vivo, and on isolated canine helical coronary artery strips in vitro. Like EGF-URO, TGF-alpha was a potent stimulator of femoral arterial blood flow in vivo; and, when added to the tissue bath in vitro before an agonist, TGF-alpha like EGF-URO was a potent inhibitor of the contractile responses of helical coronary arterial strips to various smooth muscle agonists: norepinephrine (NE), prostaglandin F2 alpha (PGF alpha) and potassium chloride (KCl). Nonetheless, there were marked differences between EGF-URO and TGF-alpha in terms of the two biological responses measured.

Epidermal growth factor-urogastrone causes vasodilatation in the anesthetized dog.

Epidermal growth factor-urogastrone (EGF-URO) administered intraarterially was a potent dilator in dog femoral (FEM), superior (cephalic) mesenteric (SMA), celiac (CAC), coronary (COR), carotid (CAR), and renal (REN) vascular beds. The effects of EGF-URO, which exhibited tachyphylaxis, could not be attributed either to recirculating EGF-URO or to the secondary release of other agonists or products of the cyclooxygenase pathway. Two vascular beds (FEM, SMA) showed a high maximum responsiveness to EGF-URO (maximum effect [Emax] approximately equal to 70% increase in flow) whereas another group (CAC, COR, CAR, and REN) exhibited lower responsiveness (Emax approximately equal to 20%).

Differential antagonism of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses by urotensin I, a selective mesenteric vasodilator peptide.

In order to characterize the hemodynamic actions of urotensin I, a vasodilator peptide with selectivity for the mesenteric vascular bed, we studied its hypotensive effects and interference with alpha-1 and alpha-2 adrenergic vasoconstrictor responses in the rat. After i.v.

Residual stalks of pedunculated adenomas. An underrecognized type of colonic polyp.

Variable lengths of stalk of colonic pedunculated adenomas may be left behind at polypectomy. At follow-up endoscopy, a residual stalk is a smooth-surfaced, sessile polyp, without a distinct head, and may be difficult to remove. It may be mistaken endoscopically for either a recurrent adenoma or a polyp missed at the original procedure.

Comparison of an intravenous selective mesenteric vasodilator with intraarterial papaverine in experimental nonocclusive mesenteric ischemia.

Acute nonocclusive mesenteric ischemia was produced in dogs anesthetized with pentobarbital by reversible pericardial tamponade, which reduced cardiac output and mesenteric blood flow by approximately 42% and 53%, respectively. Papaverine, infused into the cephalic (superior) mesenteric artery at an average dose of 100 micrograms/kg X min, was completely effective in restoring mesenteric blood flow and correcting altered intestinal oxygen kinetics. However, the same dose of papaverine given intravenously to other dogs was ineffective in correcting the deranged hemodynamics and oxygen kinetics.

Use of selective mesenteric vasodilator peptides in experimental nonocclusive mesenteric ischemia in the dog.

Three structurally related peptides, ovine corticotropin-releasing factor, sauvagine, and urotensin I are selective mesenteric vasodilators in dogs. To assess the possible benefit of these peptides in nonocclusive mesenteric ischemia, they were compared with a nonselective vasodilator, sodium nitroprusside, in the anesthetized dog. Mesenteric blood flow was reduced by approximately 30%, without lowering of systemic arterial pressure, by either digoxin or pericardial tamponade.

Reticuloendothelial system Fc receptor-mediated clearance of IgG-tagged erythrocytes from the circulation of patients with idiopathic ulcerative colitis and chronic liver disease.

Immune complexes may be important in the pathogenesis of the liver disease associated with idiopathic ulcerative colitis. In the present study, we documented Fc receptor-mediated clearance by the reticuloendothelial system of immune complex-like material from the systemic circulation of 25 healthy control subjects, 19 patients with ulcerative colitis alone, 9 patients with ulcerative colitis and elevated liver enzyme tests and 8 patients with various other forms of chronic liver disease. Following an intravenous infusion of IgG-tagged 51Cr-labeled autologous erythrocytes, serial blood samples were drawn over a 2-hr period of time, and computer-generated clearance curves were obtained.

Use of selective mesenteric dilator peptides to examine the role of the intestine in experimental hemorrhagic shock.

If mesenteric vasoconstriction sets in motion the chain of events that leads to shock, then the administration of a selective mesenteric vasodilator (which has no other known cardiovascular actions) should prevent, or at least modify, the hemodynamic events in a standardized shock preparation. We used the Wiggers model of experimental hemorrhagic shock in 20 pentobarbital-anesthetized dogs, giving half the dogs a selective mesenteric dilator peptide, sauvagine, to produce selective dilatation of the superior (cephalic) and inferior (caudal) mesenteric circulations. (Sauvagine does not dilate the coeliac vascular bed.