D5 dopamine receptor knockout mice and hypertension.

Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. All of the five dopamine receptor genes (D1, D2, D3, D4, and D5) expressed in mammals and some of their regulators are in loci linked to hypertension in humans and in rodents. Under normal conditions, D1-like receptors (D1 and D5) inhibit sodium transport in the kidney and the intestine.

Anomalous viscoelasticity near the isotropic-nematic phase transition in liquid crystals.

Recent optical Kerr effect experiments have shown that orientational relaxation of nematogens shows a pronounced slow down of the response function at intermediate times and also a power law decay near the isotropic-nematic (I-N) transition. In many aspects, this behavior appears to be rather similar to the ones observed in the supercooled liquid near-glass transition. We have performed molecular dynamics simulations of model nematogens (Gay-Berne with aspect ratio 3) to explore the viscoelasticity near the I-N transition and also investigated the correlation of viscoelasticity (if any) with orientational relaxation.

Differential release of MIP-1alpha and eotaxin during infection of mice by Histoplasma capsulatum or inoculation of beta-glucan.

Objective: In the present study, we evaluated the levels of MIP-1alpha and eotaxin and in vivo migration in the peritoneal cavity model, in mice inoculated with live yeast forms of Histoplasma capsulatum or the beta-glucan cell wall component of this fungus, and the influence of a leukotriene biosynthesis inhibitor, MK886, on the release of these chemokines in relation to cell recruitment.

Materials: Female outbred Swiss mice (N = 4-5 per group, 3-4 wk, were used. Mice were injected i.

In search of temporal power laws in the orientational relaxation near isotropic-nematic phase transition in model nematogens.

Recent Kerr relaxation experiments by Gottke et al. have revealed the existence of a pronounced temporal power law decay in the orientational relaxation near the isotropic-nematic phase transition (INPT) of nematogens of rather small aspect ratio, kappa (kappa approximately 3-4). We have carried out very long (50 ns) molecular dynamics simulations of model (Gay-Berne) prolate ellipsoids with aspect ratio 3 in order to investigate the origin of this power law.

Density and energy relaxation in an open one-dimensional system.

A new master equation to mimic the dynamics of a collection of interacting random walkers in an open system is proposed and solved numerically. In this model, the random walkers interact through excluded volume interaction (single-file system); and the total number of walkers in the lattice can fluctuate because of exchange with a bath. In addition, the movement of the random walkers is biased by an external perturbation.

Dopamine D3 receptor-mediated inhibition of Na+/H+ exchanger activity in normotensive and spontaneously hypertensive rat proximal tubular epithelial cells.

This study evaluated the response of the Na(+)/H(+) exchanger (NHE) to dopamine D(1)- and D(2)-like receptor stimulation in immortalized renal proximal tubular epithelial cells and freshly isolated renal proximal tubules from the spontaneously hypertensive rat (SHR) and their normotensive controls (Wistar Kyoto rats; WKY). Stimulation of D(1)-like receptors with SKF 38393 attenuated NHE activity in WKY cells (IC(50)=151 nM), but not in SHR cells. Stimulation of D(2)-like receptors with quinerolane (IC(50)=120 nM) attenuated NHE activity in SHR cells, but not in WKY cells.

Gialpha3 protein-coupled dopamine D3 receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event.

This study evaluated the transduction pathway associated with type 3 Na(+)/H(+) exchanger (NHE3) activity-induced inhibition during dopamine D(3) receptor activation in immortalized renal proximal tubular epithelial cells from the spontaneously hypertensive rat. The dopamine D(3) receptor agonist 7-OH-DPAT decreased NHE3 activity, which was prevented by the D(2)-like receptor antagonist S-sulpiride, pertussis toxin (PTX; overnight treatment), and the PKC inhibitor chelerythrine, but not by cholera toxin (overnight treatment), the MAPK inhibitor PD-098059, or the p38 inhibitor SB-203580. The PKA inhibitor H-89 abolished the inhibitory effects of forskolin on NHE3 activity, but not that of 7-OH-DPAT.

Over-expression of renal LAT1 and LAT2 and enhanced L-DOPA uptake in SHR immortalized renal proximal tubular cells.

Background: Spontaneously hypertensive rats (SHR) may have an increased renal production of dopamine. LAT2 promotes L-DOPA renal uptake, and this may determine the rate of dopamine synthesis. The present study evaluated L-DOPA inward and outward transfer in immortalized renal proximal tubular epithelial cells of SHR and Wistar-Kyoto rats (WKY).

Neonatal blood pressure regulation.

Hypertension is often viewed solely as a disease of the adult. However, early indicators of hypertension are frequently observed in young children and neonates. Having an adequate appreciation of the normal range of infant blood pressure is critical for the appropriate management of the conditions associated with elevated or abnormally low blood pressure.

Involvement of G protein-coupled receptor kinase 4 and 6 in rapid desensitization of dopamine D1 receptor in rat IEC-6 intestinal epithelial cells.

Dopamine-induced inhibition of Na(+)-K(+)-ATPase has been suggested to play a role in the regulation of Na(+) absorption at the intestinal level, and these effects were mediated by dopamine D(1)-like receptors. The aim of this work was to evaluate the effect of the activation of the D(1)-like receptors on the activity of the Na(+)/H(+) exchanger (NHE) in the rat intestinal epithelial cell line IEC-6. The presence of D(1) receptors was confirmed by immunoblotting.

Multilocus analysis of hypertension: a hierarchical approach.

While hypertension is a complex disease with a well-documented genetic component, genetic studies often fail to replicate findings. One possibility for such inconsistency is that the underlying genetics of hypertension is not based on single genes of major effect, but on interactions among genes. To test this hypothesis, we studied both single locus and multilocus effects, using a case-control design of subjects from Ghana.

Protein phosphatase 2A B56alpha during development in the spontaneously hypertensive rat.

Mistargeting of the regulatory subunit of protein phosphatase 2A (PP2A), B56alpha is involved in the hyperphosphorylation and desensitization of the D1 dopamine receptor in renal proximal tubules of spontaneously hypertensive rats (SHRs). However, the renal expression of B56alpha before hypertension develops is not known. Therefore, we studied the expression of B56alpha and PP2A activity in the kidney during development in the SHR and its normotensive control, the Wistar-Kyoto (WKY) rat.

The developing kidney and environmental toxins.

The effects of environmental chemicals, drugs, and physical agents on the developing kidney are influenced by the state of renal development and maturation. The development of the kidney, the major excretory organ after birth, consists of 3 stages: the pronephros, or cervical kidney; mesonephros, or thoracic kidney; and metanephros, or abdominal kidney, the definitive kidney. In humans, nephrogenesis and organogenesis occur from the 6th to the 36th weeks of gestational age.

Heme oxygenase attenuates allergen-induced airway inflammation and hyperreactivity in guinea pigs.

Heme oxygenase (HO), the heme-degrading enzyme, has shown anti-inflammatory effects in several models of pulmonary diseases. HO is induced in airways during asthma; however, its functional role is unclear. Therefore, we evaluated the role of HO on airway inflammation [evaluated by bronchoalveolar lavage (BAL) cellularity and BAL levels of eotaxin, PGE(2), and proteins], mucus secretion (evaluated by analysis of MUC5AC gene expression and periodic acid-Schiff staining), oxidative stress (evaluated by quantification of 4-hydroxynonenal adducts and carbonylated protein levels in lung homogenates), and airway responsiveness to histamine in ovalbumin (OVA)-sensitized and multiple aerosol OVA or saline-challenged guinea pigs (6 challenges, once daily, OVA group and control group, respectively).

Defective D1-like receptor-mediated inhibition of the Cl-/HCO3- exchanger in immortalized SHR proximal tubular epithelial cells.

The sensitivity of the Cl(-)/HCO(3)(-) exchanger to dopamine D(1)- and D(2)-like receptor stimulation in immortalized renal proximal tubular epithelial cells from the spontaneous hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) was examined. The activity of the Cl(-)/HCO(3)(-) exchanger (in pH U/s) in SHR cells (0.00191) was greater than in WKY cells (0.

Dopamine D1 receptor augmentation of D3 receptor action in rat aortic or mesenteric vascular smooth muscles.

Dopamine is an important modulator of blood pressure, in part, by regulating vascular resistance. To test the hypothesis that D(1) and D(3) receptors interact in vascular smooth muscle cells, we studied A10 cells, a rat aortic smooth muscle cell line, and rat mesenteric arteries that express both dopamine receptor subtypes. Fenoldopam, a D(1)-like receptor agonist, increased both D(1) and D(3) receptor protein in a time-dependent and a concentration-dependent manner in A10 cells.

Inhibition of IL-10 receptor function in alveolar macrophages by Toll-like receptor agonists.

Despite an immunosuppressive lung environment, alveolar macrophages (AM) retain the capacity to respond to microorganisms. This report demonstrates that IL-10, constitutively produced by normal alveolar epithelium, stimulates signal transduction through the IL-10R on AM and that IL-10R function can be inhibited by stimulation of Toll-like receptor (TLR) on AM. IL-10 mRNA and protein were constitutively expressed in normal alveolar epithelium of mice, and IL-10R were constitutively expressed on normal murine AM.

Aberrant D1 and D3 dopamine receptor transregulation in hypertension.

Dopamine plays a role in the regulation of blood pressure by inhibition of sodium transport in renal proximal tubules (RPTs) and relaxation of vascular smooth muscles. Because dopamine receptors can regulate and interact with each other, we studied the interaction of D(1) and D(3) receptors in immortalized RPT cells and mesenteric arteries from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs), and in human coronary artery smooth muscle cells (CASMCs). In WKY rats, the D(1)-like agonist, fenoldopam, increased D(3) receptor protein in a time-dependent and concentration-dependent manner (EC(50)=4.

Regulation of blood pressure by dopamine receptors.

Dopamine is an important regulator of blood pressure. Its actions on renal hemodynamics, epithelial transport and humoral agents such as aldosterone, catecholamines, endothelin, prolactin, pro-opiomelanocortin, renin and vasopressin place it in central homeostatic position for regulation of extracellular fluid volume and blood pressure. Dopamine also modulates fluid and sodium intake via actions in the central nervous system and gastrointestinal tract, and by regulation of cardiovascular centers that control the functions of the heart, arteries and veins.

Lack of association between the G protein beta3 subunit gene and essential hypertension in Chinese: a case-control and a family-based study.

A C825T polymorphism of the gene encoding the G protein beta3 subunit (GNB3) is associated with enhanced G protein activity and increased intracellular signal transduction. The 825T allele has been implicated in the development of hypertension in some ethnic groups, especially in whites. Studies in Asians and blacks are more controversial, and little information is available on this polymorphism in the susceptibility to hypertension in the Chinese population.

Perturbation of D1 dopamine and AT1 receptor interaction in spontaneously hypertensive rats.

The dopaminergic and renin-angiotensin systems interact to regulate blood pressure. Because this interaction may be perturbed in genetic hypertension, we studied D1 dopamine and AT1 angiotensin receptors in immortalized renal proximal tubule (RPT) and A10 aortic vascular smooth muscle cells. In normotensive Wistar-Kyoto (WKY) rats, the D1-like agonist fenoldopam increased D1 receptors but decreased AT1 receptors.

Proteoglycans are potent modulators of the biological responses of eosinophils to chemokines.

Chemokines play critical roles in governing the recruitment and activation of eosinophils at sites of allergic inflammation, particularly the asthmatic lung. However, we know little of how chemokine function is regulated post-translationally. Proteoglycans, consisting of a core protein and glycosaminoglycan (GAG) side chains, are cell surface molecules and components of the extracellular matrix that are able to bind chemokines, whilst heparin is a GAG with therapeutic value in asthma.

Diagnosis of CAD in patients with diabetes: who to evaluate.

Effective diagnosis and treatment of coronary artery disease (CAD) are key to the management of patients with diabetes. Although the use of specialized cardiac testing for CAD screening in asymptomatic patients varies widely and is the source of current controversy, evidence is emerging on the prevalence and predictors of asymptomatic ischemia in diabetic patients. Accurate diagnosis and risk stratification are essential in symptomatic patients with known or suspected CAD.