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Biomedical subjects

R D Feldman

Publications and source records attributed to R D Feldman.

At least 37 records · Page 2Linked to original sources
PubMed1999

Clinical problem solving based on the 1999 Canadian recommendations for the management of hypertension.

The 1999 Canadian Recommendations for the Management of Hypertension are notable for the trends that they represent with regard to the evolution of the management of hypertension. Diagnostically, the Recommendations endorse the greater use of non-office-based measures of blood pressure control and greater emphasis on the assessment of other atherosclerotic risk factors, both when considering prognosis in hypertension and in the choice of therapy. On the treatment side of the equation, lower targets for blood pressure control have been advocated in subgroups of hypertensive patients, particularly in those with diabetes and renal disease. In conjunction with the recently published recommendations on lifestyle management, there is a greater emphasis on lifestyle modification, both as initial and adjunctive therapy in hypertension. Implicit in the recommendations for therapy is the principle that for the vast majority of hypertensive patients treated pharmacologically, practitioners should not follow a stepped-care approach. Instead, therapy should be individualized, primarily based on consideration of concurrent diseases, both cardiovascular and noncardiovascular (Tables 1 and 2). Through the consensus process, there was a general appreciation of how far we have come in the development of evidence-based recommendations for hypertension management. However, there was also an increasing appreciation of how far we have to go in effectively translating these recommendations into better blood pressure control.

Adult↗
PubMed1998

CXCR1 and CXCR2 are rapidly down-modulated by bacterial endotoxin through a unique agonist-independent, tyrosine kinase-dependent mechanism.

The expression of the seven-transmembrane domain chemokine receptors CXCR1 and CXCR2 modulates neutrophil responsiveness to the chemoattractant IL-8 and a number of closely related CXC chemokines. In the present study, we investigated the mechanism by which bacterial LPS induces the down-modulation of IL-8 responsiveness and CXCR1 and CXCR2 expression on human neutrophils. Treating neutrophils with LPS reduced IL-8R expression to 55 +/- 5% of the control within 30 min and to 23 +/- 2% within 1 h of stimulation. Furthermore, this down-modulation could not be attributed to increased concentrations of IL-8, TNF-alpha, or IL-1beta, since ELISA studies indicated that LPS-stimulated neutrophils did not release detectable amounts of these proteins before 2 h poststimulation. The tyrosine kinase (TK) inhibitors genistein and herbimycin A attenuated the LPS-mediated down-modulation of CXCR1 and CXCR2, indicating that the activation of a TK is required for LPS to mediate its effect. The effect of LPS on receptor expression paralleled the hyperphosphorylation of the protein TK p72syk. Although IL-8 induced a comparable down-modulation of CXCR1 and CXCR2, TK inhibitors did not attenuate this effect. These studies provide the first evidence of an agonist-independent, TK-dependent pathway of chemokine receptor regulation by endotoxin.

Antigens, CD↗
PubMed1998

Secretoneurin and chemoattractant receptor interactions.

Secretoneurin (SN) is a 33-amino acid peptide derived from secretogranin II (chromogranin C) which induces chemotaxis of monocytes but not neutrophils. In this study, we found that SN interacted with specific cell surface binding sites on human monocytes. The chemoattractants MCP-1, MCP-2 or fMLP could not compete for SN binding sites suggesting SN may bind to a novel chemotactic receptor. Additional studies showed that neither SN nor MCP-2 induced a rise in cytosolic Ca2+, and chemotaxis to SN was inhibited by cholera toxin (CT) and pertussis toxin (PT). Chemotactic desensitization studies demonstrated that fMLP, MCP-1, SN, and MCP-2 could all desensitize monocytes to subsequent SN stimulation. Our results indicate that SN binds to a cell surface receptor expressed on monocytes and activates signaling pathways which are sensitive to CT and PT.

Binding Sites↗
PubMed1998

Impaired vasodilator function in hypertension: the role of alterations in receptor-G protein coupling.

Defects in vascular relaxation mechanisms may have an important role in the pathogenesis and maintenance of the elevation in peripheral vascular resistance characteristic of the hypertensive state. Receptor systems that mediate vasorelaxation via elevation of vascular smooth muscle intracellular cAMP concentrations appear to be globally impaired. Recent studies have indicated that this defect may be due to alterations in the transmembrane signaling processes that link receptor activation with the stimulation of adenylyl cyclase. Reduced G-protein function has been reported. However, increased activity of a member of a family of enzymes, the G protein-receptor kinases (GRK), which reduces the efficiency of coupling between the receptor and G protein, may be the key factor accounting for impaired receptor-mediated adenylyl cyclase activation and impaired vasodilator function in the hypertensive state.

Journal Article↗
PubMed1997

G-protein-coupled receptor kinase activity is increased in hypertension.

Impaired vascular beta-adrenergic responsiveness may play an important role in the development and/or maintenance of hypertension. This defect has been associated with an alteration in receptor/guanine nucleotide regulatory protein (G-protein) interactions. However, the locus of this defect remains unclear. G-Protein-coupled receptor kinases (GRKs) phosphorylate serine/threonine residues on G-protein-linked receptors in an agonist-dependent manner. GRK activation mediates reduced receptor responsiveness and impaired receptor/G-protein coupling. To determine whether the impairment in beta-adrenergic response in human hypertension might be associated with altered GRK activity, we studied lymphocytes from younger hypertensive subjects as compared with older and younger normotensive subjects. We assessed GRK activity by rhodopsin phosphorylation and GRK expression by immunoblot. GRK activity was significantly increased in lymphocytes from younger hypertensive subjects and paralleled an increase in GRK-2 (beta ARK-1) protein expression. In contrast, no alterations in cAMP-dependent kinase (A-kinase) activity or GRK-5/6 expression were noted. GRK activity was not increased in lymphocytes from older normotensive subjects who demonstrated a similar impairment in beta-adrenergic-mediated adenylyl cyclase activation. These studies indicate that GRK activity is selectively increased in lymphocytes from hypertensive subjects. The increase in GRK activity may underlie the reduction in beta-adrenergic responsiveness characteristic of the hypertensive state.

Adenylyl Cyclases↗
PubMed1997

Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination.

BACKGROUND: It is widely presumed that the development of postoperative hyponatremia (which may be severe) results from administration of hypotonic fluids while antidiuretic hormone is acting. OBJECTIVE: To show that hyponatremia would occur in patients 24 hours after surgery if only near-isotonic solutions are given and to evaluate the mechanisms responsible for hyponatremia in this setting. DESIGN: Prospective cohort study. SETTING: University medical center. PATIENTS: 22 women who were having uncomplicated gynecologic surgery with infusion of near-isotonic solutions only (sodium chloride, 154 mmol/L, or Ringer lactate [sodium, 130 mmol/L, and potassium, 4 mmol/L]). MEASUREMENTS: Plasma electrolyte levels were measured at the time of induction of anesthesia and 24 hours later. Data on the balance of water and electrolytes were obtained for the same 24-hours period. RESULTS: At the time of induction of anesthesia, the plasma sodium concentration was 140 +/- 1 mmol/L; 24 hours later, it decreased in 21 of 22 patients (mean decrease, 4.2 +/- 0.4 mmol/L [P < 0.001]; lowest level, 131 mmol/L in 2 patients). The urine remained hypertonic (peak sodium plus potassium concentration in urine, 294 +/- 9 mmol/L) in all patients for the first 16 hours after induction of anesthesia. CONCLUSIONS: Postoperative hyponatremia occurred within 24 hours of induction of anesthesia when only near-isotonic fluids were infused. Hyponatremia was generally caused by generation of electrolyte-free water during excretion of hypertonic urine-a desalination process. This electrolyte-free water was retained in the body because of the actions of antidiuretic hormone. If the pathophysiology of this hyponatremic state is understood, recommendations for its prevention and treatment can be deduced.

Adult↗
PubMed1997

A randomized study comparing a patient-directed hypertension management strategy with usual office-based care.

This study aimed to compare the efficacy of a patient-directed management strategy with office-based management in maintaining blood pressure control in patients with chronic stable hypertension using a randomized trial of two months duration. The subjects had chronic stable essential hypertension without secondary causes or unstable cardiovascular disease and were selected through the offices of 11 family physicians and a tertiary care hypertension research unit. Patients were randomly assigned (2:1 ratio) to either a patient-directed management strategy using home blood pressure monitoring to adjust drug therapy if readings consistently exceeded defined limits, or office-based management through physician visits. The primary endpoint was the change from baseline in mean arterial pressure as determined by automatic ambulatory blood pressure monitoring. Secondary endpoints were changes in compliance, quality of life, and health care resource use. Ninety-one potential subjects were screened and 31 were randomized. Subjects in the patient-directed management group employed the drug adjustment protocols appropriately without complications. A significant difference in change in mean blood pressure was observed, favoring the patient-directed management (-0.95 mm Hg and +1.90 mm Hg, respectively, for patient-directed management and office-based management, P = .039). Compliance rates and quality of life scores were not significantly different between groups. Physician visits were more frequent in the patient-directed management group (1.05 v 0.20 visits/8 weeks, respectively, for patient-directed management and office-based management groups, P = .045). A patient-directed hypertensive management strategy may be feasible for patients with chronic stable hypertension. Such a strategy may improve blood pressure control compared with usual office-based care. However, physician visits may be increased using this strategy, at least in the short term.

Adult↗
PubMed1997

Review article: Drug development in inflammatory bowel disease: budesonide--a model of targeted therapy.

The use of non-specific anti-inflammatory drugs such as the glucocorticoids is the foundation of medical therapy for inflammatory bowel disease. Although conventional steroid drugs are highly effective, their use is associated with the adverse effects of Cushing's syndrome. However, the therapeutic index of these drugs can be improved by chemical modification of the steroid nucleus and the use of new drug delivery systems that target the bowel wall as the pharmacokinetic compartment of interest. Budesonide is a novel glucocorticoid compound that illustrates the potential of this approach to identify effective and safe new treatments. Regional therapy for inflammatory bowel disease is an important pharmacological concept for the future development of the new glucocorticoids and other classes of drugs.

Administration, Oral↗
PubMed1997

G-protein function is reduced in hypertension.

A functional impairment in vasodilator tone may be important in the pathogenesis and/or maintenance of elevated peripheral vascular resistance in hypertension. Previous studies of hypertensive subjects have demonstrated impaired beta-adrenergic-mediated vasodilation paralleling a reduction in lymphocyte beta-adrenergic-stimulated adenylyl cyclase activity. We have suggested that this impairment is related to a defect in G-protein function. To determine whether this defect alters the coupling between the G-protein complex and adenylyl cyclase, we performed [3H]forskolin binding studies in lymphocytes from hypertensive subjects, older normotensive subjects, and younger normotensive control subjects. Maximal specific [3H]forskolin binding was used as an index of adenylyl cyclase binding sites. Gpp(NH)p-, NaF/AlCl3-, and isoproterenol-stimulated binding were used as indices of G-protein/adenylyl cyclase coupling. In the absence of other stimulators, maximal [3H]forskolin binding was not significantly different among groups. However, both Gpp(NH)p- and isoproterenol-stimulated [3H]forskolin binding were significantly decreased in lymphocytes from hypertensive subjects. Overall, Gpp(NH)p- and isoproterenol-stimulated [3H]forskolin binding were significantly inversely correlated with blood pressure. No differences in NaF/AlCl3-stimulated [3H]forskolin binding were detected between groups. These studies indicate that G-protein/adenylyl cyclase coupling is impaired in lymphocytes from younger hypertensive subjects and may contribute to the blood pressure-related defect in beta-adrenoceptor-stimulated adenylyl cyclase activity.

Adenylyl Cyclases↗
PubMed1996

Direct angiotensin converting enzyme inhibitor-mediated venodilation.

BACKGROUND: The vasodilator effects of angiotensin converting enzyme inhibitors have been ascribed to systemic inhibition of the angiotensin II generation. However, local mechanisms of vasodilation also have been suggested. We tested whether the angiotensin converting enzyme inhibitor enalaprilat mediated local vasodilation in human dorsal hand veins. METHODS: We infused enalaprilat and assessed changes in dorsal hand vein compliance using the linear variable differential transducer technique. Enalaprilat-mediated effects were assessed in small and large veins and in the presence and absence of one of two vasoconstrictors: exogenous norepinephrine or physiologic vasoconstriction by cooling. RESULTS: We infused locally in small dorsal hand veins at skin temperatures of less than 29.0 degrees C (baseline distention < 0.35 mm) in the absence of exogenous vasoconstrictors, enalaprilat mediated dose-dependent vasodilation (median effective dose [ED50], 12 ng/min to a maximal effect of 162% +/- 15% of baseline, p < 0.01). Maximal enalaprilat-mediated vasodilation was comparable to dilation mediated by insulin (175% +/-17% of baseline; p = 0.21) and less than dilation mediated by nitroglycerin (221% +/- 20% of baseline; p = 0.011). At skin temperatures > 31 degrees C, enalaprilat mediated dose-dependent vasodilation in small vessels only when vessels were preconstricted with norepinephrine (ED50 = 5.1 ng/min, maximal enalaprilat-mediated effect of 164% +/- 21% of baseline; p < 0.05). CONCLUSIONS: These data suggest enalaprilat mediates local vasodilation in dorsal hand veins, with an ED50 comparable to plasma enalaprilat concentrations achieved with oral enalapril therapy. This effect is dependent on vessel size and on the presence of preconstruction. Local vasodilator effects may be important in the clinical hemodynamic effects of angiotensin converting enzyme inhibitors.

Adult↗
PubMed1996

Dietary salt restriction increases vascular insulin resistance.

BACKGROUND: Recent studies have shown that insulin has a direct vasodilator effect and that vascular sensitivity to insulin is impaired in hypertension. How the vasodilator effect of insulin is regulated physiologically is unknown. It has been appreciated that salt restriction may have adverse effects on glucose and lipid metabolism--processes regulated by insulin. To determine whether dietary salt restriction might affect vascular sensitivity to insulin, we studied 13 subjects (including eight borderline hypertensive subjects and five normotensive subjects) after 1 week of a normal sodium diet (240 mEq/day) and after 1 week of a low-sodium diet (20 mEq/day) with a randomized, double-blind crossover design. METHODS AND RESULTS: Vascular sensitivity to insulin was assessed with the dorsal hand vein linear variable differential transformer technique. When the "normal" salt diet was given, vascular sensitivity for insulin was significantly less (i.e., dose that produced the half-maximal response [ED50] insulin was higher) in hypertensive subjects (ED50 insulin for hypertensive subjects, 5.75 milliunits (mU)/min; ED50 insulin for normotensive subjects, 0.23 mU/min; p < 0.05). Vascular sensitivity to insulin was inversely correlated with mean arterial pressure and plasma norepinephrine concentration. When the low salt diet was given, vascular sensitivity to insulin decreased in both the normotensive and hypertensive groups, paralleling an increase in plasma norepinephrine. Blood pressure was not significantly decreased by reducing salt intake. CONCLUSION: In these younger normotensive and hypertensive subjects, dietary salt restriction increases resistance to the vasodilating effects of insulin.

Adult↗
PubMed1995

G protein alterations in hypertension and aging.

Defective vasodilator function could be important in the pathogenesis and/or maintenance of the hypertensive state and the predisposition of the elderly to hypertension. Impaired beta-adrenergic-mediated vasodilation and reduced lymphocyte beta-adrenergic activation of adenyl cyclase have been demonstrated both in aging and with hypertension. The cellular mechanisms responsible for these alterations remain unclear. To determine if these defects may be due to alterations in guanine nucleotide regulatory proteins (G proteins) that link receptor activation with effector function, we assessed (1) human lymphocyte adenyl cyclase activity, (2) stimulatory G proteins by cholera toxin-mediated [32P]ADP ribosylation and, in hypertensive subjects, with alpha s-specific and beta-subunit antisera, and (3) inhibitory G proteins by pertussis toxin-mediated [32P]ADP ribosylation and, in older subjects, with alpha i,1,2- and beta-subunit-specific antisera. Lymphocytes from older subjects and from hypertensive subjects demonstrated a comparable reduction in isoproterenol-stimulated adenyl cyclase. However, aluminum fluoride-stimulated activity was reduced only in lymphocytes from hypertensive subjects. Furthermore, aluminum fluoride-stimulated activity was inversely correlated with mean arterial pressure. In lymphocytes from younger hypertensive subjects, cholera toxin-mediated labeling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. In lymphocytes from older subjects, cholera toxin-mediated labeling was not altered; however, pertussis toxin-mediated labelling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. Overall, the study suggests alterations of G protein function of adenyl cyclase is impaired. However, these defects are associated with divergent alterations in stimulatory and inhibitory G proteins.

Adenylate Cyclase Toxin↗
PubMed1995

Oxidant stress enhances adenylyl cyclase activation.

The generation of oxygen-derived free radicals has been implicated in the disordered vascular regulation of inflammation and reperfusion. In the vasculature, oxygen-derived free radicals are vasodilatory. The mechanisms underlying this effect remain unclear. To examine the cellular processes involved, we studied the effects of hydrogen peroxide (H2O2) on adenylyl cyclase activity in A10 cells, a murine vascular smooth muscle cell line. Pretreatment with H2O2 caused a dose-dependent enhancement of forskolin-stimulated adenylyl cyclase activity (ED50, 44 mumol/L to a maximum of 166% of control activity; n = 4). This enhancement was attenuated by iron chelation with deferoxamine and by the intracellular hydroxyl scavenger dimethylthiourea and mimicked by preincubation with purine/xanthine oxidase either alone or in the presence of superoxide dismutase. The effects of H2O2 were completely blocked by the tyrosine kinase inhibitors genistein and tyrphostin A9 but not by its inactive analogue tyrphostin A1 (H2O2 alone, 149 +/- 13%; H2O2 + tyrphostin A9, 100 +/- 9%; H2O2 + tyrphostin A1, 171 +/- 21%; n = 4). H2O2 comparably enhanced adenylyl cyclase activity stimulated by isoproterenol (166 +/- 17% of control, n = 5) and sodium fluoride (177 +/- 18% of control, n = 5). Thus oxygen-derived free radicals enhance adenylyl cyclase activation, probably via tyrosine kinase-mediated effects on the catalytic subunit of adenylyl cyclase. Sensitization of adenylyl cyclase activation may be an important mechanism by which free radicals modulate hormone-mediated vasodilation.

Adenylyl Cyclases↗
PubMed1995

Extracellular nucleotides potentiate the cytosolic Ca2+, but not cyclic adenosine 3', 5'-monophosphate response to parathyroid hormone in rat osteoblastic cells.

Binding to PTH to its cell surface receptor activates both adenylyl cyclase and phospholipase-C, leading to elevation of cytosolic cAMP and free Ca2+. We have shown previously that extracellular nucleotides interact with P2U and P2Y subtypes of purinoceptor on osteoblastic cells, both linked to Ca2+ mobilization. In the present study, we investigated possible interactions between nucleotide and PTH signaling pathways in osteoblastic cells. The cytosolic free Ca2+ concentration ([Ca2+]i) of UMR-106 osteoblastic cells was monitored by fluorescence spectrophotometry. PTH (0.01-1 microM; bovine 1-84 or human 1-34) induced a small transient elevation of [Ca2+]i, lasting less than 1 min. A number of nucleotides, including ATP, UTP, and UDP, induced transient elevation of [Ca2+]i and potentiated the subsequent Ca2+ response to PTH. Of the nucleotides tested, UDP was the most effective at potentiating the PTH-induced Ca2+ transient. Treatment of cells with UDP (100 microM for 2.5 min), but not inorganic phosphate or uridine, reversibly potentiated the Ca2+ response to PTH (0.1 microM) by 11 +/- 2-fold (mean +/- SEM; n = 39). In contrast, UDP did not affect the cAMP response to PTH, indicating a selective action on Ca2+ signaling. Potentiation of the Ca2+ signal was still observed in the absence of extracellular Ca2+, establishing that nucleotides enhance PTH-induced release of Ca2+ from intracellular stores. Studies using selective purinoceptor agonists suggest that potentiation of PTH signaling is mediated by the P2U receptor subtype. In vivo, nucleotides released during trauma or inflammation may modulate PTH-induced Ca2+ signaling in osteoblasts.

Adenosine Triphosphate↗
PubMed1995

Parallel regulation of the local vascular and systemic metabolic effects of insulin.

Recent studies have focused on the link between the development of disordered vascular regulation (e.g. hypertension) and alteration in the effects of insulin to mediate glucose uptake. We and others have recently demonstrated that insulin is a potent vasodilator. Further, it has been suggested that impairment of insulin-mediated vasodilation may be an important contributing factor in the development of increased peripheral resistance. However, whether the local vascular effects of insulin correlate with its systemic glucose regulatory effects remains unclear. Therefore, we assessed both vascular sensitivity to insulin (using dorsal hand vein linear variable differential transformer techniques) and glucoregulatory sensitivity to insulin (using the minimal model technique applied to a frequently sampled iv glucose tolerance test) in 12 normotensive nondiabetic volunteers. In these subjects, metabolic sensitivity to insulin and venous sensitivity to insulin were highly correlated (r2 = 0.42; P = 0.02). Additionally, vascular sensitivity to insulin was inversely correlated with fasting C-peptide levels (r2 = 0.49; P = 0.02). Both systemic and vascular sensitivities to insulin were also highly correlated with body mass index. These studies demonstrate that the glucoregulatory effects of insulin are paralleled by its local vasodilating effects and continue to support this linkage as an important factor in the correlation between alterations in systemic sensitivity to insulin and the development of elevated peripheral resistance in hypertension and obesity.

Adult↗