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Biomedical subjects

P Narayan

Publications and source records attributed to P Narayan.

At least 55 records · Page 3Linked to original sources
PubMed1999

Species-dependent hemodynamic effects of adenosine A3-receptor agonists IB-MECA and Cl-IB-MECA.

The purpose of this study was to compare the hemodynamic effects of the adenosine A3-receptor agonists N6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-beta-D-ribofuranosyl]aden ine (IB-MECA) and 2-chloro-N6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-beta-D-ribofu ranosy l]adenine (Cl-IB-MECA) in isolated rat and rabbit hearts and in the intact, open-chest pig. Isolated hearts perfused with Krebs-Henseleit buffer at a constant pressure (70 mmHg) were treated with 50 nM of either IB-MECA or Cl-IB-MECA. Neither IB-MECA nor Cl-IB-MECA altered ventricular function or heart rate in the isolated rat and rabbit hearts, and neither agent altered coronary flow in the rabbit. However, 2 min of IB-MECA treatment in the isolated rat heart increased coronary flow by 25%, an effect that did not exhibit tachyphylaxis. The IB-MECA-induced coronary dilation was only partially attenuated by the adenosine A3-receptor antagonist MRS-1191 (50 nM). IB-MECA-induced coronary dilation was completely blocked by the adenosine A2a-receptor antagonist 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine (Sch-58261, 50 nM). Cl-IB-MECA (50 nM) did not increase coronary flow in the rat, but 100 nM did increase flow by 18%. In pentobarbital sodium-anesthetized pigs IB-MECA (5 micrograms/kg iv) decreased systemic blood pressure and increased pulmonary artery pressure, effects that did exhibit tachyphylaxis. These results illustrate that adenosine A3-receptor agonists produce species-dependent effects, which in the rat heart appear to be caused by adenosine A2a-receptor activation.

Adenosine↗
PubMed1999

Identification of ionizable amino acid residues on the extracellular domain of the lutropin receptor involved in ligand binding.

The LH receptor (LHR) is a G protein-coupled receptor characterized by a relatively large N-terminal extracellular domain responsible for high affinity ligand binding. Based on a model proposed for a major portion of the extracellular domain that contains a number of leucine-rich repeats, nine ionizable amino acid residues (Glu57, Glu80, Lys158, Glu181, Lys183, Glu184, Glu188, Lys190, and Asp206) were selected for charge reversal mutagenesis based on their locations in the proposed model and their potential to serve as ligand contact sites. Mutant LHR complementary DNAs were transiently transfected into COS-7 cells, and the expressed receptors were characterized by Western blot analysis, competitive ligand (hCG) binding, and ligand-mediated cAMP production. The most interesting mutants were K158E, K183E, E184K, and D206K, which were present on the plasma membrane fraction, as judged by Western blots, but were incapable of binding hCG and, of course, were deficient in hCG-mediated cAMP production. Other replacements at these positions, K158R,Q,G; K183R,Q,G; E184N; and D206E,Q, led to cell surface binding and signaling. The mutants E57K, E189K, and K190E behaved similarly to wild-type LHR; E80K was trapped intracellularly, but bound ligand in solubilized cells; and E181K was not expressed or was rapidly degraded. These results, based on 18 point mutants of LHR, indicate that Lys158, Lys183, Glu184, and Asp206 are involved, either directly or indirectly, in gonadotropin binding and support the general nature of the proposed model.

Amino Acid Sequence↗
PubMed1999

Characterization of a region of the lutropin receptor extracellular domain near transmembrane helix 1 that is important in ligand-mediated signaling.

The lutropin receptor (LHR), a member of the G protein-coupled receptor family, contains a relatively large N-terminal extracellular domain, accounting for about half of the receptor and responsible for high affinity ligand binding, and a standard heptahelical portion with connecting loops and a C-terminal tail. LHR and the other two glycoprotein hormone receptors, i.e. the follitropin and TSH receptors, contain an invariant 10-amino acid residue sequence, FNPCEDIMGY (residues 328-337 in rat LHR), in the extracellular domain separated by only a few amino acid residues from the beginning of transmembrane helix 1. In view of the invariant nature of this region in the three glycoprotein hormone receptors and preliminary data in the literature on the importance of Glu332 and Asp333 in signal transduction, we undertook a systematic investigation of all 10 amino acid residues because this region may function as a switch or trigger for communicating ligand binding to the extracellular domain with a conformational change of the membrane-embedded C-terminal half of the receptor to activate G proteins, particularly Gs. A total of 36 single, double, and multiple replacements, as well as two deletions, of LHR were prepared and characterized in transiently transfected COS-7 cells. Of these mutants LHRs, 26 expressed on the cell surface in sufficient numbers that quantitative assessments could be made of human choriogonadotropin binding and ligand-mediated cAMP production. Replacements of Cys331 abolished ligand binding to intact cells, although binding could be detected after solubilization of the cells. Replacements of the other nine amino acid residues that did not interfere with receptor folding or trafficking had no significant effect on ligand binding affinity; however, replacements of Pro330, Glu332, and Asp333 resulted in diminished signaling, especially for the two acidic residues. An interesting observation was made in which replacement of Tyr337 with Ala or Asp, while having no profound change on receptor function, could overcome to some extent limited expression of replacements at positions 332 and/or 333, thus permitting a more definitive analysis of signaling. Replacement of the decapeptide sequence with Gly10 prevents expression, whereas deletion of all 10 residues and deletion of Glu332-Asp333 prevents functional expression at the cell surface. Thus, this invariant sequence in the glycoprotein hormones is required for proper folding, trafficking, and ligand-mediated signaling, but not ligand binding, in LHR. Amino acid residues, Glu332, Asp333, and to a limited extent, Pro330, are important in ligand-mediated signaling but not ligand binding.

Amino Acid Sequence↗
PubMed1998

Effects of moderate intensity exercise on serum lipids in African-American men with severe systemic hypertension.

The prevalence of systemic hypertension and its cardiovascular consequences is higher in African-Americans than in whites. Low to moderate intensity aerobic exercise lowers blood pressure (BP) in African-American patients with severe hypertension. It is not known whether such exercise can improve lipid metabolism in these patients. Thirty-six African-American men with established essential hypertension, aged 35 to 76 years, were randomly assigned to an exercise (n = 17) or no exercise (n = 19) group. The exercise group exercised for 16 weeks, 3 times/week, at 60% to 80% of maximum heart rate. After 16 weeks, peak oxygen uptake in the exercise group improved (21+/-4 vs 23+/-3 ml/kg/min; p <0.001). Body weight did not change. Exercise intensity correlated with high-density lipoprotein (HDL) cholesterol changes from baseline to 16 weeks (r = 0.65; p <0.01) and was the strongest predictor of these changes (R2 = 0.4; p = 0.009). Lipoprotein-lipid changes in the 2 randomized groups did not differ significantly. A 10% increase in HDL cholesterol--42+/-19 versus 46+/-19 mg/dl; p = 0.003--noted in 10 patients who exercised > or = 75% of maximal heart rate suggested the existence of an exercise intensity threshold. Thus low to moderate intensity aerobic exercise may not be adequate to modify lipid profiles favorably in patients with severe hypertension. However, substantial changes in HDL cholesterol were noted in patients exercising at intensities > or = 75% of age-predicted maximum heart rate, suggesting an exercise-intensity threshold.

Adult↗
PubMed1998

31P-NMR analysis of congestive heart failure in the SHHF/Mcc-facp rat heart.

31P-NMR was used to monitor myocardial bioenergetics in compensated and failing SHHF/MCC-fa(cp) (SHF) rat hearts. The SHHF/Mcc-fa(cp) (spontaneous hypertension and heart failure) rat is a relatively new genetic model in which all individuals spontaneously develop congestive heart failure, most during the second year of life. Failing SHF rat hearts displayed a pronounced decrease in resting PCr:ATP ratios (P<0.001), which was explained by a significant (P<0. 0001) drop in total creatine (47.2+/-3.1 nmol/mg protein) v age matched controls (106+/-3 nmol/mg protein). In end stage failure, NMR determined PCr was 2.9+/-0.1 micro mol/g wet weight under basal conditions. In contrast, 6- and 20-month-old controls and compensated SHFs had PCr values of 5.3+/-0.1, and 5.1+/-0.5 and 5. 1+/-0.2 micro mol/g wet weight. Both compensated and failing SHF hearts were metabolically compromised when the rate pressure product (RPP) was increased, as evidenced by an increase in Pi and a drop in PCr. Compensated SHF hearts, however, were able to increase rate pressure products (RRP, mmHg X beats/min) from 44.5+/-1.4 to 66.6+/-3. 4 K with dobutamine infusion, whereas hearts in end-stage failure were able to increase their RPP from baseline values of 27+/-4 K to only 37+/-7 K. The data indicate that a pronounced decline in PCr and total creatine signals the transition from compensatory hypertrophy to decompensation and failure in the SHF rat model of hypertensive cardiomyopathy.

Adenine Nucleotides↗
PubMed1998

Adenosine A1 receptor stimulation antagonizes the negative inotropic effects of the PKC activator dioctanoylglycerol.

It has been suggested that adenosine cardioprotection occurs via adenosine A1 receptor-mediated activation of protein kinase C (PKC). However, adenosine has well-known vasodilatory effects in the myocardium, whereas PKC is a vasoconstrictor. This study examined whether adenosine A1 receptor activation alters the effects of the PKC activator. 1,2-dioctanoyl-s,n-glycerol (DOG) in isolated perfused rat hearts (left-ventricular developed pressure) and rat ventricular myocytes ([Ca2+]i and cell shortening). Exposure to DOG decreased left-ventricular developed pressure by 30%, an effect that was completely reversible. Pretreatment of isolated hearts with either the PKC inhibitor chelerythrine or the adenosine A1 agonist 2-chloro-N6-cyclo-cyclo-isolated pentlyadenosine (CCPA) attenuated the negative inotropic effects of DOG. In the isolated myocytes, DOG decreased [Ca2+]i and cell shortening by 25 and 28%, respectively, effects that were attenuated by both chelerythrine and CCPA. The CCPA attenuation of the DOG-induced decrease in [Ca2+]i and cell shortening was blocked by pretreating the myocytes with the adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). These results indicate that in rat ventricular myocardium, adenosine A1 receptor activation attenuates the apparent PKC-dependent negative inotropic effects of DOG via preservation of [Ca2+]i levels.

Adenosine↗
PubMed1998

Influence of risk factors on peripheral and cerebrovascular disease in men with coronary artery disease, low high-density lipoprotein cholesterol levels, and desirable low-density lipoprotein cholesterol levels. HIT Investigators. Department of Veterans Affairs HDL Intervention Trial.

BACKGROUND: The Veterans Administration-HDL Intervention Trial is an ongoing, 20-center, randomized, double-blind, placebo-controlled study aiming to assess the effect of gemfibrozil-improved low high-density lipoprotein cholesterol levels on cardiovascular morbidity and mortality rates. METHODS AND RESULTS: Eligible patients were men with low high-density lipoprotein cholesterol levels and demonstrable coronary heart disease. A total of 2531 patients (average age 63.5 years) were randomly assigned in this study, with a mean high-density lipoprotein cholesterol level of 0.83 mmol/L (32 mg/dL) and low-density lipoprotein cholesterol level of 2.87 mmol/L (111 mg/dL). Baseline data provided the opportunity to assess the interaction of several coronary heart disease risk factors and comorbid vascular diseases. Of these patients, 206 had diabetes mellitus (DM) alone, 1021 had hypertension (HTN) alone, 421 had both DM and HTN, and 883 had neither ("others"). Considering the influence of these risk factors on comorbidities independent of smoking status, patients with DM alone had a 2-fold increase in the prevalence of peripheral vascular disease and a 1.5-fold increase in congestive heart failure. Patients with HTN had a significant increase in the prevalence of cerebrovascular disease, stroke, and congestive heart failure. Patients with HTN and DM had a significant increase in all comorbidities. Smoking resulted in substantial increase of both peripheral vascular disease and cerebrovascular disease. Compared with nonsmoking patients with no DM or HTN, patients with DM and HTN and smoking had a 3-fold increase in the prevalence of peripheral vascular disease and a 3.5-fold increase in cerebrovascular disease (P < .001). CONCLUSIONS: We conclude that DM is a strong correlate of peripheral vascular disease, hypertension of cerebrovascular disease, and that there is a strong additive effect between DM, HTN, and smoking on both.

Aged↗
PubMed1998

Novel staging tool for localized prostate cancer: a pilot study using genetic adaptive neural networks.

PURPOSE: An estimated $1.5 billion is spent annually for direct medical expenses and an additional $2.5 billion for indirect costs for the management of prostate cancer. Today there are several procedures for staging prostate cancer, including lymph node dissection. Despite these procedures, the accuracy of predicting extracapsular disease remains low (range 37 to 63, mean 45%). Use of multiple staging procedures adds significantly to the costs of managing prostate cancer. Recently artificial intelligence based neural networks have become available for medical applications. Unlike traditional statistical methods, these networks do not assume linearity or homogeneity of variance and, thus, they are more accurate for clinical data. We applied this concept to staging localized prostate cancer and devised an algorithm that can be used for prostate cancer staging. MATERIALS AND METHODS: Our study comprised 1,200 men with clinically organ confined prostate cancer who underwent preoperative staging using serum prostate specific antigen, systematic biopsy and Gleason scoring before radical prostatectomy and lymphadenectomy. The performance of the neural network was validated for a subset of patients and network predictions were compared with actual pathological stage. Mean patient age was 62.9 years, mean serum prostate specific antigen 8.1 ng./ml. and mean biopsy Gleason 6. Of the patients 55% had organ confined disease, 27% positive margins, 8% seminal vesicle involvement and 7% lymph node disease. Of margin positive patients 30% also had seminal vesicle involvement, while of seminal vesicle positive patients 50% also had positive margins. RESULTS: The sensitivity of the network was 81 to 100%, and specificity was 72 to 75% for various predictions of margin, seminal vesicle and lymph node involvement. The negative predictive values tended to be relatively high for all 3 features (range 92 to 100%). The neural network missed only 8% of patients with margin positive disease, and 2% with lymph node and 0% with seminal vesicle involvement. CONCLUSIONS: Our study suggests that neural networks may be useful as an initial staging tool for detection of extracapsular extension in patients with clinically organ confined prostate cancer. These networks preclude unnecessary staging tests for 63% of patients with clinically organ confined prostate cancer.

Algorithms↗
PubMed1998

Transurethral needle ablation for benign prostatic hyperplasia: 12-month results of a prospective, multicenter U.S. study.

OBJECTIVES: To report the safety and efficacy of the transurethral needle ablation (TUNA) procedure for the treatment of clinical benign prostatic hyperplasia (BPH). METHODS: One hundred thirty patients with BPH were enrolled in two identical protocols and treated by the TUNA procedure. Entry criteria included an American Urological Association symptom index (AUA SI) of 13 points or higher and a peak flow rate of 12 mL/s or less. Patients were followed up for 12 months. Efficacy parameters included the AUA SI, AUA problem index, BPH impact index (BPH II), quality of life (QOL) score, and peak flow rate. At each visit, side effects were elicited. Follow-up data are available for 93 patients at 12 months. All patients were given intraurethral lidocaine augmented by oral and/or parenteral sedation. No patient received spinal or general anesthesia. RESULTS: All patients tolerated the procedure well, and there were no deaths. Forty-one percent of patients (n = 53) had a catheter placed immediately after the procedure. At 12 months, the AUA SI had decreased from 23.7 to 11.9 (P < 0.0001) and the BPH II from 7.5 to 2.5 (P < 0.0001), whereas the peak flow rate had increased from 8.7 to 14.6 mL/s (P < 0.0001). Irritative voiding symptoms were noted in 20 patients (16%) at some point during follow-up. Two patients reported erectile dysfunction, and 1 reported retrograde ejaculation. CONCLUSIONS: In this prospective study of 130 patients with clinical BPH and lower urinary tract symptoms, TUNA provided substantive and lasting improvement according to AUA SI, BPH II, and QOL scores as well as peak flow rate over 1 year. The TUNA procedure was well tolerated, with few major side effects and complications noted. Longer follow-up is needed to document the maintenance of clinical benefit beyond 12 months.

Aged↗
PubMed1998

Overview of alpha-blocker therapy for benign prostatic hyperplasia.

Management of benign prostatic hyperplasia (BPH) is rapidly changing. Established surgical procedures are being replaced by minimally invasive modalities such as electrovaporization and transurethral needle ablation. Improved understanding of pathophysiology and developments in molecular biology has provided drugs for alleviating the symptoms of prostatic enlargement. Currently, medical therapy is the first-line treatment modality in the management of BPH. There are two types of medical treatment available: alpha-adrenoceptor-blockers and 5-alpha-reductase inhibitors. Alpha-blockers relieve the dynamic component of obstruction whereas 5-alpha-reductase inhibitors relieve the mechanical component of obstruction. At present, alpha-blockers are used most frequently. However, they do have significant cardiovascular side effects. More uroselective alpha-blockers have recently become available and may reduce the risk of cardiovascular side effects. This review summarizes relevant literature on the use of alpha-blockers in the treatment of BPH.

Adrenergic alpha-Antagonists↗
PubMed1998

Surface retention of an inactivating lutropin receptor mutant in exoloop 3.

The heptahelical lutropin receptor (LHR) signals primarily via the Gs-adenylyl cyclase pathway and undergoes ligand-mediated receptor desensitization and internalization. A loss-of-function rat LHR mutant was recently described in which a single amino acid residue replacement in exoloop 3, K583E, had no effect on human choriogonadotropin (hCG) binding but essentially abolished signaling. This LHR mutant is a prime candidate for which to study hCG-mediated receptor internalization since it is highly unlikely that an amino acid residue in exoloop 3 , i.e. an extracellular portion of LHR connecting transmembrane helices 6 and 7, could have any direct interaction with Galpha(s), which is located on the cytoplasmic face of the plasma membrane. A method to study endocytosis was adapted that involves concanavalin A binding to the glycoproteins on the cell surface, thus facilitating separation of the plasma membrane fraction from other cellular membrane fractions by sucrose gradient centrifugation. Conditions were used such that a single round of endocytosis could be determined with [125I]hCG. Endocytic rate constants of 0.03 and O min(-1) were obtained for LHR and the mutant, respectively, in transfected human embryonic kidney 293 cells; moreover, internalization of the mutant could not be restored by the addition of 8-Br-cAMP. Thus, the presence of the second messenger cAMP is not sufficient for internalization of ligand-occupied LHR. Rather, it appears that ligand-mediated activation and subsequent internalization of LHR results from an altered conformational state or a conformation-dependent post-ligand binding modification such as phosphorylation.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1998

Minimally invasive therapies for the treatment of symptomatic benign prostatic hyperplasia: the University of Florida experience.

OBJECTIVE: To describe the University of Florida experience with minimally invasive therapies in the surgical treatment of benign prostatic hyperplasia (BPH). BACKGROUND DATA: Typically, the standard surgical treatment for symptomatic benign prostatic hyperplasia (BPH) has been transurethral resection of the prostate (TURP). Due to the morbidity associated with TURP, several minimally invasive therapies, such as laser, microwaves, high intensity focused ultrasound, and radiofrequency needle ablation, have been utilized to treat BPH. METHODS: The authors review their experience, along with that of others, with various forms of heat therapy in the treatment of BPH. RESULTS AND CONCLUSIONS: Although high intensity focused ultrasound (HIFU), interstitial laser, and microwaves procedures have been shown to be effective in the treatment of BPH, our experience has been with laser, VaporTrode, and TUNA. We found that VaporTrode and TUNA currently offer several advantages over many of the other modalities.

Electrosurgery↗
PubMed1998

Prostatectomy tissue for research: balancing patient care and discovery.

The application of modern technology in basic research often requires fresh tissue from human organs. The acquisition of this tissue challenges the anatomic pathologist to balance the needs of the basic scientist with the requirements of quality patient care. Our experience indicates that fresh tissue adequate for research can be obtained from neoplastic prostate glands without compromising patient care. The process requires dedicated, knowledgeable individuals and extensive documentation. Potential problems include low yield for research studies, loss of all residual carcinoma, compromise of the specimen margin, and unforeseen costs. Best collaborations occur in situations in which basic scientists and anatomic pathologists establish a working relationship and develop a mutually supportive means of funding.

Antineoplastic Agents, Hormonal↗
PubMed1998

The endothelin subtype A receptor undergoes agonist- and antagonist-mediated internalization in the absence of signaling.

The potent vasoconstrictor and mitogen to smooth muscle cells, endothelin-1 (ET-1), acts via two distinct G protein-coupled receptors, subtype A (ETAR) and subtype B, that are coupled primarily to the Gq-phospholipase C signaling pathway. It is known that ET-1 binding to ETAR promotes internalization, with subsequent degradation of at least a portion of the bound ligand. To investigate whether signaling is required for endocytosis, we developed stably transfected lines of human embryonic kidney 293 cells expressing wild-type ETAR and a receptor chimera (ETARC) in which the C-terminal cytoplasmic tail to ETAR was replaced with that of the lutropin receptor, another G protein-coupled receptor, but one which signals through the Gs-adenylyl cyclase pathway. ETARC binds ET-1 like ETAR, but is deficient in signaling. Using a combined concanavalin A/sucrose gradient centrifugation technique to separate plasma membranes from other cellular membranes, we found that [125I]ET-1 is rapidly internalized into ETAR-expressing cells at 37 C (t1/2 for internalization = 5 min; endocytic rate constant = 0.1 min(-1); ETARC-expressing cells also internalize [125I]ET-1, albeit at a somewhat slower rate than wild-type receptor (t1/2 for internalization = 15 min; endocytic rate constant = 0.03 min(-1). Using immunofluorescence confocal microscopy and an antibody developed to the N-terminal region of ETAR, qualitatively similar results were obtained. In addition, it was found using confocal microscopy that the ETAR-selective antagonist, BQ123, also promoted rapid internalization in cells expressing ETAR. These results establish that inositol 1,4,5-trisphosphate signaling is not required for ligand-mediated internalization of ETAR and suggest that a receptor conformational change is necessary. Moreover, the finding that BQ123 promotes ETAR internalization is novel and has potentially important implications in its clinical use.

Biological Transport↗
PubMed1998

Systematic biopsy-based staging of prostate cancer: scientific background, individual variables, combination of parameters, and current integrative models.

Staging of the prostate cancer remains the mainstay of treatment decisions and prognostication. Multiple staging tests, which are currently available, fail to provide optimal staging accuracy in the management of prostate cancer. Systemic biopsy can provide useful data regarding bilaterality, Gleason grade, cancer map, perineural infiltration, tumor volume, percentage cancer and microvessel density. We have reviewed existing literature on systematic biopsy in this review. We have further discussed the role of neural network technology in integrating this information.

Biopsy↗