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Biomedical subjects

R D Feldman

Publications and source records attributed to R D Feldman.

At least 55 records · Page 3Linked to original sources
PubMed1994

Vascular alpha-adrenergic responsiveness is reduced in cirrhosis.

Cirrhosis of the liver is associated with altered cardiovascular regulation. Patients with cirrhosis often have decreased total peripheral vascular resistance despite increased sympathetic activity. To determine whether this reduction in effective sympathetic activity may be caused by an alteration in vascular adrenergic responsiveness, we studied nine patients with biopsy-proven cirrhosis and 12 age-matched control subjects. To assess human vascular adrenergic responsiveness, we used dorsal hand vein linear variable differential transformer techniques. Sensitivity for phenylephrine-mediated vasoconstriction was significantly reduced in patients with cirrhosis (median effective dose [ED50] for phenylephrine: cirrhosis, 1514 ng/min; control subjects, 282 ng/min; p = 0.026). In contrast, the effect of isoproterenol did not differ (cirrhosis: 89% +/- 15% of maximal nitroglycerin effect; control subjects 79% +/- 6%; ED50 for isoproterenol: cirrhosis, 38 ng/min; control subjects, 20 ng/min). These studies indicate that vascular alpha-adrenergic responsiveness in patients with cirrhosis is decreased, whereas beta-adrenergic responsiveness remains intact. A selective decrease in vascular alpha-adrenergic responsiveness may contribute to the decreased peripheral vascular resistance in cirrhosis.

Adult↗
PubMed1994

Human insulin-mediated enhancement of vascular beta-adrenergic responsiveness.

Insulin may play an important role in the physiological and/or pathophysiological regulation of the cardiovascular system. Defects in insulin secretion and insulin receptor responsiveness have been associated with increased peripheral resistance and hypertension. The mechanisms linking these events remain unclear. To assess the effect of insulin on beta-adrenergic-mediated vasodilation, we examined aortic ring segments obtained from normotensive male Wistar and spontaneously hypertensive rats. Vessels were maximally preconstricted with phenylephrine (3 mumol/L). Relaxation was induced by either isoproterenol (10 mumol/L) or sodium nitroprusside (10 nmol/L), and the relaxant response was followed for 20 minutes. Insulin exposure did not alter phenylephrine-mediated constriction. However, insulin mediated a dose-dependent increase in isoproterenol-induced relaxation, to a maximum of 120 +/- 4% of baseline isoproterenol-mediated relaxation, with an EC50 for insulin of 32 pmol/L in aortic rings from Wistar rats. Insulin exposure also did not alter nitroprusside-mediated relaxation. In contrast to the results obtained in rings from Wistar rats, insulin did not enhance isoproterenol-mediated responses in rings from spontaneously hypertensive rats. Thus, insulin mediates a selective enhancement of vascular beta-adrenergic responsiveness in aortas from normotensive but not hypertensive animals.

Animals↗
PubMed1994

How will we use clinical guidelines? The experience of Medicare carriers.

While support for the development of clinical guidelines is widespread, there is little agreement about how they should be used. Because cost control is the force behind the medical effectiveness movement, the payers' preference, to link clinical guidelines to reimbursement, will likely prevail. We examine the utilization review programs of Medicare Part B carriers and the carriers' attempts to use clinical guidelines to determine medical necessity for the purpose of payment. We find that because the utilization review programs are driven by concerns about cost control, the carriers' actual review process relies on aggregate utilization and spending targets that have little to do with clinical guidelines. The carriers' medical review rhetoric--using the terms medically unnecessary and fraud and abuse as synonyms--also highlights their focus on cost control and the lack of concern about why services are used inappropriately.

Attitude of Health Personnel↗
PubMed1993

Insulin-mediated vasodilation: impairment with increased blood pressure and body mass.

Insulin resistance is associated with hypertension although it is not known if this relationship is casual. Studies have shown that insulin increases skeletal-muscle blood flow despite also increasing sympathetic activity. To determine whether insulin may act as a direct vasodilator and whether insulin-mediated vascular effects are altered in hypertension, we studied insulin-mediated alterations in dorsal-hand-vein compliance in normotensive and mild and borderline hypertensive subjects. In phenylephrine pre-constricted vessels, insulin caused a dose-dependent increase in venous distensibility. Insulin-mediated venodilation was significantly impaired in hypertensive subjects. The vasodilator potency of insulin was significantly correlated with both blood pressure and body mass index. Insulin may be an endogenous vasodilator. Further, in hypertensive and obese subjects, impairment of insulin-mediated vasodilation may contribute to the increase in peripheral resistance characteristic of hypertension.

Adult↗
PubMed1993

Beta-adrenergic responsiveness is regulated selectively in hypertension.

beta-Adrenergic receptor responsiveness is impaired in hypertension. A low-sodium diet both corrects this defect and lowers blood pressure. To determine whether upregulation of beta-adrenergic receptor function in hypertension might be related nonspecifically to lowering of blood pressure, vascular beta-adrenergic response was assessed after pharmacologic antihypertensive treatment by use of dorsal hand vein linear differential transformer techniques in patients with hypertension. Subjects were studied after randomized treatments with placebo and verapamil and after randomized treatments with verapamil and hydrochlorothiazide. After 2 weeks of treatment, verapamil lowered blood pressure in the subjects with hypertension but did not significantly upregulate vascular beta-adrenergic response (58% +/- 8% to 68% +/- 8%; p > 0.2 versus placebo). Further vascular beta-adrenergic responsiveness after treatment with hydrochlorothiazide did not significantly differ from that with verapamil (hydrochlorothiazide, 68% +/- 9%; verapamil, 53% +/- 7%; n = 8, p > 0.3). Thus, reduction of blood pressure with either verapamil or hydrochlorothiazide did not correct the defect in beta-adrenergic responsiveness in hypertension. Vascular beta-adrenergic response appears to be regulated selectively in hypertension, not simply by lowering of blood pressure.

Adult↗
PubMed1993

Insulin-mediated sensitization of adenylyl cyclase activation.

1. Insulin may be an important regulator of vascular function. We have previously studied lymphocyte beta-adrenoceptors as a model for the human vascular beta-adrenoceptor. To examine the effects of insulin on human beta-adrenoceptor responsiveness, adenylyl cyclase activity, cyclic AMP-dependent protein kinase activity and beta-adrenoceptor radioligand binding assays were performed on permeabilized mononuclear leukocytes. 2. With acute exposure to insulin in vitro, followed by washing and permeabilization there was a dose-dependent increase in both lymphocyte NaF-stimulated activity and beta-adrenoceptor-stimulated adenylyl cyclase activity paralleling an increase in beta-adrenoceptor-stimulated protein kinase A activity. Manganese-, forskolin- and forskolin plus guanylimidodiphosphate-stimulated adenylyl cyclase activities were not altered by insulin pretreatment. Additionally, mononuclear leukocyte beta-adrenoceptor density, proportion of externalized receptors and receptor affinity for agonist were not altered. 3. The data indicate that acute exposure to insulin sensitizes G-protein-stimulated adenylyl cyclase activity. These findings suggest a potential role for insulin in the regulation of beta-adrenoceptor responsiveness in man.

Adenylyl Cyclases↗
PubMed1993

Inhibition of Na-K-Cl cotransport by amiloride analogues is associated with stimulation of cyclic AMP-dependent protein kinase.

Analogues of amiloride are widely used as pharmacological probes for inhibition of sodium-hydrogen counter-transport. In Jurkat cells, a leukemic T lymphocyte cell line, analogues of amiloride are also potent inhibitors of Na-K-Cl cotransport. The effects of these agents are not additive with those of beta-adrenoceptor agonists (which inhibit Na-K-Cl cotransport presumably by stimulation of adenylyl cyclase). Further, analogues of amiloride potently stimulate cAMP-dependent protein kinase activity. The present studies indicate that beta-adrenoceptor agonists and analogues of amiloride both act to inhibit Na-K-Cl cotransport and both stimulate cAMP-dependent protein kinase activity. Furthermore, these studies demonstrate a novel mechanism by which amiloride analogues may mediate effects separately from inhibition of sodium-hydrogen exchange.

Adenylyl Cyclases↗
PubMed1992

Differential effect of intravenous procainamide on anterograde and retrograde accessory pathway refractoriness.

Although procainamide may markedly impair or abolish anterograde conduction over an accessory atrioventricular (AV) pathway, orthodromic AV reentry may remain inducible. This difference may be related to a systemic differential effect of procainamide on anterograde and retrograde accessory pathway refractoriness. To examine this phenomenon, an infusion of procainamide producing five incremental blood levels over 75 min was administered to 15 patients with the Wolff-Parkinson-White syndrome. At each procainamide level, accessory pathway effective refractory period and accessory pathway block cycle length were determined in the anterograde and retrograde directions. At baseline, there were no significant differences between anterograde and retrograde accessory pathway effective refractory periods (282 +/- 7 vs. 266 +/- 9 ms, p = 0.08) and block cycle lengths (288 +/- 15 vs. 283 +/- 9 ms, p = 0.66). The concentration of procainamide resulting in 50% prolongation of accessory pathway refractoriness was less in the anterograde direction than in the retrograde direction (27.5 [log concentration -4.56 +/- SE 0.13] vs. 64.6 [-4.19 +/- 0.11] mumol/liter, p = 0.02). Similarly, the concentration of procainamide resulting in 50% prolongation of accessory pathway block cycle length in the anterograde direction (25.1 [-4.60 +/- 0.13] mumol/liter) was less than in the retrograde direction (52.5 [-4.28 +/- 0.07] mumol/liter, p = 0.01). The probability of persistence of accessory pathway conduction in the anterograde direction was less than in the retrograde direction by Kaplan-Meier analysis (p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Beta-adrenergic inhibition of Na-K-Cl cotransport in lymphocytes.

Lymphocytes contain a homogeneous population of beta 2-adrenoceptors. However, their physiological role in the regulation of lymphocyte function, especially early in the activation/proliferation process, remains unclear. To study the role of beta-adrenergic activation on the regulation of membrane transport, we examined 86Rb uptake in the Jurkat human lymphoma cell line. 86Rb uptake was predominantly accounted for by bumetanide-sensitive uptake (74 +/- 2% total 86Rb uptake) and ouabain-sensitive uptake (20 +/- 2%). Bumetanide potently inhibited 86Rb uptake (50% inhibitory concentration = 210 +/- 40 nM), and bumetanide-sensitive uptake was dependent on extracellular sodium and chloride, consistent with uptake via Na-K-Cl cotransport. The beta-adrenergic agonist isoproterenol (10 microM) mediated a 50 +/- 11% reduction in bumetanide-sensitive uptake without a significant alteration in ouabain-sensitive uptake. The effect of isoproterenol was potent (50% effective concentration = 4.42 +/- 1.70 nM), stereoselective, and was inhibited by the beta-adrenergic antagonist nadolol. The effect of isoproterenol was mimicked by permeant adenosine 3',5'-cyclic monophosphate analogues but not by pindolol. These data indicate that beta-adrenoceptor activation decreases 86Rb uptake in lymphocytes via inhibition of Na-K-Cl cotransport. Modulation of this transporter could be one mechanism by which beta-adrenergic agonists regulate lymphocyte function.

Adenylyl Cyclases↗
PubMed1992

A low-sodium diet corrects the defect in beta-adrenergic response in older subjects.

BACKGROUND: One of the prominent cardiovascular abnormalities in the elderly is reduced beta-adrenoceptor responsiveness. Because dietary sodium restriction corrects the defect in vascular and lymphocyte beta-adrenoceptor responsiveness in hypertensive subjects, we postulated an analogous effect in the elderly. Thus, vascular and lymphocyte beta-adrenergic responsiveness were studied in 10 older normotensive subjects (age, 56 +/- 2 years) on either a 400- or 10-meq/day sodium diet. METHODS AND RESULTS: In older subjects fed a high-sodium diet, maximal isoproterenol-mediated vasodilation was depressed compared with a group of normotensive younger subjects studied previously. When they were fed a low-sodium diet, however, maximal isoproterenol-mediated vasodilation in the elderly was increased significantly. Lymphocyte adenylyl cyclase sensitivity to isoproterenol was comparably increased. Blood pressure was significantly reduced on a low-sodium diet, and mean arterial pressure was significantly inversely correlated with the extent of isoproterenol-mediated vasodilation. CONCLUSIONS: These studies indicate that a low-sodium diet corrects the defect in both vascular and lymphocyte beta-adrenergic responsiveness with aging. This suggests an important role for dietary modification in the adrenergic regulation of vascular tone in the elderly.

Adenylyl Cyclases↗
PubMed1990

Beta-adrenoceptor responsiveness in hypertension: effects of dietary NaCl intake.

1. Adrenergic responsiveness may be an important determinant of peripheral resistance in man. We have demonstrated that vascular beta-adrenergic responsiveness is reduced in young borderline hypertensive subjects. A parallel defect in beta-adrenergic mediated adenylyl cyclase activity and beta-adrenoceptor affinity for agonists also has been identified in lymphocytes from borderline hypertensive subjects. In contrast, it is unclear whether cardiac beta-adrenergic responsiveness is altered. 2. The reduction in lymphocyte and vascular beta-adrenergic responsiveness is corrected when hypertensive subjects are fed a low sodium chloride diet. This pattern of regulation differs from that seen in young normotensive subjects fed a low NaCl diet where either reduced or unchanged beta-adrenergic responsiveness has been reported. 3. These studies suggest a generalized defect in beta 2-adrenergic responsiveness in borderline hypertensive subjects and demonstrate important differences between normotensive and hypertensive subjects in the pattern of beta-adrenoceptor regulation mediated by dietary sodium intake. The mechanism by which dietary sodium modulates beta-adrenergic responsiveness is yet to be determined.

Animals↗
PubMed1990

Beta-adrenergic-mediated Cl secretion: evidence for additional non-cAMP-dependent pathway of effect.

It has been suggested that beta-adrenergic receptor antagonists with intrinsic sympathomimetic activity, like pindolol, are weak partial agonists for beta-adrenergic-stimulated adenylyl cyclase activation. To evaluate this possibility, beta-adrenergic-mediated chloride secretion was studied in tracheal epithelial cells maintained in primary culture. Pindolol caused a dose-dependent increase in chloride secretion with a half-maximal effective concentration of 91 pM to a maximum that was 30 +/- 3% that of isoproterenol. Pindolol-induced chloride secretion was antagonized by the beta-adrenergic antagonist nadolol. However, in contrast to isoproterenol, pindolol did not stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation, adenylyl cyclase activity, or protein kinase A activation. Further studies examined the coupling of beta-adrenergic stimulation of cAMP accumulation to beta-adrenergic stimulation of chloride secretion. Coincubation of cells with the phosphodiesterase inhibitor RA233 increased maximal isoproterenol-stimulated cAMP accumulation eightfold but did not significantly increase the potency or maximal effect of isoproterenol for chloride secretion. It is clear that beta-adrenergic-stimulated elevations in cAMP mediate chloride secretion. These studies also demonstrate that pindolol, a drug with intrinsic sympathomimetic activity, mediates a beta-adrenergic receptor-specific increase in chloride secretion without increasing adenylyl cyclase nor protein kinase A activities. Thus intrinsic sympathomimetic activity may represent a non-cAMP-dependent mechanism of beta-adrenergic effect.

Adenylyl Cyclases↗
PubMed1990

Defective venous beta-adrenergic response in borderline hypertensive subjects is corrected by a low sodium diet.

Hypertensive patients have reduced lymphocyte beta-adrenergic responsiveness which is corrected by a low sodium (Na) diet. To determine if this represents a more generalized abnormality in beta adrenoceptor response, we studied beta adrenergic-mediated vasodilation in hand veins of borderline hypertensive subjects and controls. Subjects received a 5-d diet containing high Na/low potassium (K), high Na/high K, or low Na/high K. Venous distension, as evaluated by a linear variable differential transformer, was measured in relation to infusion of phenylephrine followed by isoproterenol and nitroglycerin. On both the high Na/high K and high Na/low K diets, hypertensive subjects had significantly decreased isoproterenol-mediated vasodilation (47% decrease, P less than 0.01 and 36% decrease, P less than 0.01, respectively). On the low Na/high K diet, isoproterenol-mediated vasodilation in hypertensive subjects increased 41% (P less than 0.01) to a level not different from controls. Nitroglycerin-mediated vasodilation was not different in normotensive and hypertensive subjects, nor was it altered with Na intake. Phenylephrine-mediated vasoconstriction did not differ between normotensive and hypertensive groups. Venous beta-adrenergic response correlated with lymphocyte beta adrenoceptor density in normotensive (r = 0.53, P less than 0.005) but not hypertensive subjects. This study demonstrates that beta-adrenergic responsiveness is selectively reduced in peripheral veins of borderline hypertensive subjects, and this is corrected by a low Na diet. In view of our previous findings of reduced lymphocyte beta-adrenergic responsiveness in borderline hypertension, these studies suggest a generalized defect of beta adrenoceptor responsiveness in human hypertension. Further, dietary Na may play an important role in regulating this abnormality.

Adult↗
PubMed1989

Development of a computer-based instructional system in pharmacokinetics: efficacy in clinical pharmacology teaching for senior medical students.

The teaching of pharmacokinetics is acknowledged to be a key aspect of the core curriculum in clinical pharmacology and therapeutics, but is also widely acknowledged to be a very difficult part of the curriculum to teach. In order to assess the potential efficacy of interactive computer instruction in clinical pharmacokinetics we have developed a prototype computer-based instructional package. The courseware contains a comprehensive learning system including tutorial, simulation, and problem solving components. To determine the efficacy of this approach we randomly assigned senior medical student volunteers enrolled in the fourth year clinical pharmacology and therapeutics course to receive conventional teaching in clinical pharmacokinetics and/or adjuctive teaching using the computer-based instructional system. There was a high degree of acceptance of the program and over the short term of the trial those students using the computer program scored significantly higher [35%, P less than 0.05] on the mid-term pharmacokinetics quiz. The data suggests that a computerized instructional system in pharmacokinetics may significantly improve the teaching of clinical pharmacokinetics to medical students.

Computer-Assisted Instruction↗
PubMed1989

Beta-adrenergic receptors on canine coronary collateral vessels: characterization and function.

The present studies were performed to examine the role of beta-adrenergic receptors in modulating smooth muscle tone in mature coronary collaterals. To examine the beta-adrenergic receptor population present, radioligand binding-cover slip autoradiographic studies were performed on sections of native canine coronary vessels and sections of coronary collaterals developed after placement of Ameroid constrictors. Specific binding of the nonselective beta-adrenergic antagonist [125I]iodopindolol to vascular smooth muscle in segments of both collaterals and native coronary arteries was saturable and stereospecific. Maximal binding and the potency of beta-adrenergic subtype-selective antagonists were similar in all segments. Beta-adrenergic relaxation of native coronary vessels and collateral vessels were studied in isolated organ chambers after preconstriction with prostaglandin F2 alpha. Both native coronary arteries and collateral segments demonstrated beta-adrenergic-mediated relaxation with affinities for both agonists and antagonists compatible with a mixed population of beta 1- and beta 2-adrenergic receptors. These studies indicate that during development, the new collateral vascular smooth muscle expresses a functional population of beta-adrenergic receptors, comparable to that in native vessels.

Adrenergic beta-Antagonists↗
PubMed1989

Adrenergic stimulation of inositol phosphate accumulation in tracheal epithelium.

To determine whether inositol phosphates are important second messengers in the regulation of Cl- secretion by airway epithelia, we examined the relationship between inositol phosphate accumulation and Cl- secretion in response to adrenergic agonists. We found that epinephrine stimulated Cl- secretion and inositol phosphate accumulation with similar concentration dependence. Although isoproterenol stimulated Cl- secretion, there was no effect of beta-adrenergic receptor activation on inositol phosphate accumulation. In contrast, alpha 1-adrenergic receptor activation stimulated inositol phosphate accumulation but failed to induce Cl- secretion. Another Cl- secretagogue, prostaglandin E1, also failed to stimulate inositol phosphate accumulation. These data suggest that inositol phosphate accumulation is neither sufficient nor required for stimulation of Cl- secretion in cultured canine tracheal epithelial cells.

Adrenergic alpha-Agonists↗