Biomedical subjects
S Setty
Publications and source records attributed to S Setty.
Right ventricular oxygen supply/demand balance in exercising dogs.
This is the first investigation of right ventricular (RV) myocardial oxygen supply/demand balance in a conscious animal. A novel technique developed in our laboratory was used to collect right coronary (RC) venous blood samples from seven instrumented, conscious dogs at rest and during graded treadmill exercise. Contributions of the RV oxygen extraction reserve and the RC flow reserve to exercise-induced increases in RV oxygen demand were measured. Strenuous exercise caused a 269% increase in RV oxygen consumption. Expanded arteriovenous oxygen content difference (A-V(Delta)O2) provided 58% of this increase in oxygen demand, and increased RC blood flow (RCBF) provided 42%. At less strenuous exercise, expanded A-V(Delta)O2 provided 60-80% of the required oxygen, and increases in RCBF were small and driven by increased aortic pressure. RC resistance fell only at strenuous exercise after the extraction reserve had been mobilized. Thus RC resistance was unaffected by large decreases in RC venous PO2 until an apparent threshold at 20 mmHg was reached. Comparisons of RV findings with published left ventricular data from exercising dogs demonstrated that increased O2 demand of the left ventricle is met primarily by increasing coronary flow, whereas increased O2 extraction makes a greater contribution to RV O2 supply.
Endogenous nitric oxide modulates myocardial oxygen consumption in canine right ventricle.
The role of endogenous nitric oxide (NO) in modulating myocardial oxygen consumption (MVO2) is unclear, in part because of systemic and coronary hemodynamic effects of blocking NO release. This study evaluated the effect of NO on right ventricular MVO2 under controlled hemodynamic conditions. In 12 open-chest dogs, N(omega)-nitro-L-arginine methyl ester (L-NAME, 150 microg/min), a NO synthase (NOS) blocker, was infused into the right coronary artery. Heart rate and mean aortic pressure were constant. Right coronary blood flow and right ventricular MVO2 were measured at normal and elevated right coronary perfusion pressures (RCP) before and after L-NAME. To avoid effects of NO synthesis blockade on right coronary blood flow, which might have altered right ventricular MVO2, experiments, were conducted during adenosine-induced maximal coronary vasodilation. L-NAME did not affect right coronary blood flow (P = 0.51). However, L-NAME significantly increased right ventricular MVO2 (6% at RCP 100 mmHg, and 21% at RCP 180 mmHg). Right coronary blood flow varied with perfusion pressure (P < 0.02), and the elevation of MVO2 produced by L-NAME increased at higher flows (P < 0.04), consistent with the greater shear stress-mediated release of NO. These findings indicate that endogenous NO limits right ventricular MVO2.
Antiphospholipid antibody syndrome. A literature review.
Antiphospholipid syndrome (APS) occurs as a primary or secondary syndrome and has various manifestations, including arterial and venous thrombosis, thrombocytopenia, fetal loss, livedo reticularis, and cardiac and neurological sequelae. APS is linked with autoantibodies that were originally thought to have specificity for negatively charged phospholipids. Recent data suggest specificity for different phospholipid-binding plasma proteins, including 2-glycoprotein I, prothrombin, protein C, and protein S. The most well-known antiphospholipid antibodies are lupus anticoagulant and anticardiolipin antibody. These antibodies are detected through lupus anticoagulant assays, anticardiolipin assays, and certain serologic tests for syphilis. This article describes 2 cases encountered in our clinical work and reviews the literature on APS.
Interactions of type IV collagen and its domains with human mesangial cells.
Type IV collagen (COL-IV) interacts with a variety of cell types. We present evidence that human mesangial cells (HMC) bind directly to COL-IV, its major triple helical domain, and the main non-collagenous, NC1 domain. A synthetic peptide, HEP-III, and its triple helical counterpart (THP-III), previously reported to be a heparin-binding domain, also promoted approximately 15% adhesion of HMC. HMC bound to solid-phase-immobilized, intact COL-IV (approximately 75%), isolated NC1 domain (approximately 15%), and a pepsin-derived triple helical fragment,which lacks Hep-III (approximately 65%). We further examined inhibition of HMC adhesion to COL-IV and its domains by using anti-integrin antibodies. Blocking monoclonal antibodies against the alpha2 integrin resulted in 70% inhibition of adhesion to COL-IV and 80% inhibition to HEP-III. Moderate inhibition was observed on the NC1 and triple helical fragments. Anti-alpha1 antibodies inhibited the binding of HMC to COL-IV, the NC1, and triple helical domains, but not to peptide HEP-III. Anti-beta1 antibodies inhibited almost completely (>95%) the adhesion to COL-IV, the NC1, and triple helical fragments; inhibition on HEP-III was approximately 30%. Affinity chromatography studies with solid-phase HEP-III and mesangial cell lysate also demonstrated the presence of integrin alpha2 beta1 along with alpha3 beta1. We conclude that alpha2 beta1 and alpha1 beta1 integrins mediate HMC adhesion to COL-IV. Peptide HEP-III is a major, specific site for alpha2 integrin-mediated binding of mesangial cells to COL-IV. Both the alpha1 beta1 and alpha2 beta1 integrins interact with the NC1 and triple helical fragments of COL-IV. Therefore, we demonstrate that several sites for integrin-mediated interactions exist on several collagenous and non-collagenous domains of COL-IV.
Altered kidney matrix gene expression in early stages of experimental diabetes.
The expression of mRNA and distribution of alpha 1(IV), alpha 3(IV) chains of type IV collagen, matrix metalloproteinase 2 (MMP-2), and tissue inhibitor of metalloproteinase 1 (TIMP-1) were examined in kidneys from streptozotocin-diabetic rats, 2.5 months after administration of the drug, an early time point when specific diabetic glomerular changes were still minimal. Ten age-matched Sprague-Dawley rats were assigned to control and diabetic groups. Compared to the controls, the diabetic rats had a significantly lower body weight, higher kidney weight and serum glucose levels, but no significant changes of glomerular surface area and urine albumin were observed. Northern blot analysis, using whole kidney mRNA, revealed that diabetic rat kidneys expressed 113.5% more alpha 1(IV), 46.5% more alpha 3(IV), 54.8% less MMP-2 and 246% more TIMP-1 (in all instances: p < 0.05). These results were corroborated by in situ hybridization for RNA expression. A quantitative analysis of the data indicated the following changes in glomeruli: (1) 74.6% more alpha 1(IV), (2) 103.8% more alpha 3(IV), (3) 40.7% less MMP-2 and (4) 80.9% more TIMP-1. Similar changes were observed in tubular (proximal and distal) cells. We conclude that an increased synthesis and decreased degradation of renal extracellular matrix components occur early after induction of experimental diabetes, before the onset of typical structural changes in the kidneys, and represent changes of specific gene expression at the transcriptional level. All the cell types in the glomerulus as well as the proximal and distal tubules appear to be involved in this alteration of expression, and this is a novel finding.
Distribution of integrin subunits in human diabetic kidneys.
Integrins are cell-surface protein receptors that participate in cell adhesion to multiple extracellular matrix ligands, and consist of alpha and beta chain heterodimers. This study examined altered integrin distribution in diabetic nephropathy by investigating 12 human diabetic kidney biopsies, which were compared with normal human kidney. Diabetic nephropathy is characterized by mesangial expansion and progressive thickening of the glomerular basement membrane. Based on morphometric studies of mesangial expansion, diabetic nephropathy was determined to be moderate or severe. Three different patterns (P) of altered intensity of integrin staining were observed. In the mesangial integrin P, the intensity of integrin subunit staining of mesangial cells (alpha 1, alpha 2, alpha 3, beta 1, alpha V, alpha V beta 5) was increased in moderate diabetic nephropathy and further increased in severe diabetic nephropathy. In the epithelial integrin P, integrin subunits localized to epithelial cells (alpha V, beta 3, alpha V beta 3, alpha V beta 5) were increased to the same extent in moderate and severe diabetic nephropathy. In the endothelial integrin P, integrin subunits localized to endothelial cells (alpha 3, alpha 5, alpha 6, beta 1) were increased in moderate diabetic nephropathy but returned to normal kidney staining intensity in severe diabetic nephropathy. From these observations, it was concluded that there is significant alteration in the expression of integrin subunits in diabetic nephropathy that is related to the severity of diabetic mesangial expansion. Additionally, the spectrum of integrin subunit alteration appears to be unique to individual glomerular cell types. Given the role of integrins in cell-surface interactions with extracellular matrix components, abnormalities in the expression of these molecules may be important in the pathogenesis of diabetic nephropathy.
Glucose-induced alteration of integrin expression and function in cultured human mesangial cells.
Alteration in mesangial volume, due to an increase of the matrix surrounding mesangial cells, is a hallmark indicator of nephropathy in diabetes. Mesangial cells may also play a significant role in the development of nephropathy. Therefore, we examined the effect of glucose on the expression of integrins by cultured human mesangial cells and their ability to interact with collagen IV, a major component of the mesangial matrix. Human mesangial cells were grown in 5 and 25 mM glucose and their integrin profile was examined by immunoprecipitation and flow cytometry in each experimental condition. The results indicate that when mesangial cells were grown in 25 mM glucose, the expression of integrin subunit alpha 2, was increased, while the alpha 1 subunit was considerably decreased, as compared to cells grown in 5 mM glucose. Additionally, mesangial cells were tested for their ability to adhere to collagen IV in a solid-phase assay in the presence of neutralizing antibodies to integrin subunits. The results of these experiments indicate that both alpha 1 and alpha 2 complexed to beta 1 (alpha 2 beta 1 and alpha 1 beta 1) are major mesangial cell receptors for adhesion to collagen IV both in 5 and 25 mM glucose. The two receptors act in concert to mediate adhesion of mesangial cells to type IV collagen. When cell surface expression of the alpha 1 subunit in 25 mM glucose was reduced, the alpha 2 subunit was involved in adhesion to a greater extent than it was in 5 mM glucose. Immunoperoxidase histochemical studies localized both alpha 1 and alpha 2 integrin subunits in the mesangium of normal adult kidneys, suggesting that in vivo interaction with collagen IV could involve both of these receptors. These observations suggest that glucose-induced alterations in integrin expression may modify the ability of mesangial cells to interact with collagen IV.
Respiratory syncytial virus in lower respiratory tract infections.
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The effects of porcine follicular fluid inhibin on gonadotropin secretion in the rabbit.
Porcine follicular fluid (pff), treated with charcoal to remove steroids, was used to determine whether inhibin is active in the laboratory rabbit. When pff (5 ml/4 kg body weight) was injected (ip) into does that had been castrated 2 weeks earlier, there was a significant decline in blood follicle-stimulating hormone (FSH) levels; the decline lasted for 8-12 h. Blood levels of luteinizing hormone (LH) were suppressed, but only briefly at 3 h after injection. In other experiments, intact does which had been injected with pff 9 h and 10 min before receiving a single, i.v. injection of luteinizing hormone-releasing hormone (LHRH) (10 micrograms/kg body weight) showed a sharp reduction in the concentration of LH in the blood samples collected 15, 30 and 60 min after LHRH administration. Secretion of FSH responded poorly to LHRH stimulation, and pff had little suppressive action on blood levels. Having established that the pff preparation had inhibin activity, its action on the postovulatory surge of FSH secretion was next examined. This release of FSH, which occurs 6 to 36 h after ovulation, has been hypothesized to be required for the establishment of pregnancy by stimulating the growth of the ovarian follicles supplying the luteotropic estradiol. To test this hypothesis, pff was injected into rabbits every 8 h for the first 5 days of pregnancy and found to block the postovulatory FSH surge. The patterns of secretion of LH and progesterone in the same pff-injected animals were, however, not altered from normal pregnancy patterns by pff.(ABSTRACT TRUNCATED AT 250 WORDS)