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Biomedical subjects

M B Zimmerman

Publications and source records attributed to M B Zimmerman.

53 records · Page 3Linked to original sources
PubMed1988

Correlation between binding affinities for brain A1 and A2 receptors of adenosine agonists and antagonists and their effects on heart rate and coronary vascular tone.

The activities of a series of A1 and A2 adenosine receptor agonists and antagonists were determined using radioligand binding techniques in rat brain tissues. The potencies of these agonists on heart rate and coronary vascular tone were also assessed in the perfused working rat heart preparation. The order of potency of these agonists in producing negative chronotropic effects was similar to the rank order for their A1 receptor binding activities [6-N-cyclohexyladenosine (CHA) = 6-N-(R-phenylisopropyl)-adenosine greater than 5'-N-ethylcarboxamideadenosine (NECA) = 2-chloroadenosine greater than 2-phenylaminoadenosine] with a correlation coefficient of 0.97. Their order of potency in reducing coronary vascular tone followed the same rank order as their A2 receptor binding activities with a correlation coefficient of 0.97 (NECA greater than 2-chloroadenosine = 6-N-(R-phenylisopropyl)-adenosine = 2-phenylaminoadenosine greater than CHA). In addition, the antagonists 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]ox]phenyl-1,3- dipropylxanthine (XAC), 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine (PACPX) and 8-phenyltheophylline (8-PT) blocked the negative chronotropic effect of CHA and the vasodilatory effect of NECA in a concentration-dependent manner. The same order of potency of the antagonists was noted in blocking CHA-induced bradycardia and A1 receptor binding activities (XAC = PACPX greater than 8-PT). A similar correlation was observed for their effects in blocking NECA-induced vasodilation and A2 receptor binding activity (XAC greater than PACPX greater than 8-PT).(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Evidence for A1 and A2 adenosine receptors in guinea pig trachea.

The adenosine analogs [5'-N-ethylcarboxamideadenosine (NECA), 2-Chloro-adenosine (2-ClA), R-phenylisopropyladenosine (R-PIA), N6-cyclohexyl adenosine (CHA), and N6-cyclopentyladenosine (CPA)] produced both relaxation and contraction responses in isolated guinea-pig trachea. A concentration-related relaxation response was observed in trachea which were precontracted with either histamine or KC1. This response followed an order of analog potency that was indicative of the A2 receptor subtype (NECA greater than 2-ClA greater than R-PIA greater than CPA greater than CHA). Theophylline, an adenosine-receptor antagonist, blocked this relaxation response. In addition, a concentration-related contractile response was produced with adenosine analogs in those trachea that were not previously contracted. In contrast, the contractile response followed an analog potency indicative of the A1 receptor subtype (R-PIA greater than 2-ClA = CPA = CHA). This contractile response was not mediated by cholinergic, adrenergic or histaminergic receptors. 2-ClA induced a biphasic response, while NECA only relaxed these tissue under basal tone. Unlike the relaxation response, these contractile responses were not attenuated by theophylline, but were blocked by 1,3 dipropyl-8-(2 amino-4-chlorophenyl)xanthine (PACPX). These findings confirm the existence of two subpopulations of adenosine receptors in guinea pig trachealis muscle.

Adenosine↗
PubMed1987

Central and peripheral inhibition of angiotensin converting enzyme (ACE) in the SHR: correlation with the antihypertensive activity of ACE inhibitors.

A series of five structurally distinct ACE inhibitors were evaluated for their ability to inhibit tissue ACE activity in the SHR after oral administration. In the first series of experiments, the ACE inhibitors captopril, enalapril, pentopril, CGS 14824A and CGS 16617 were given to groups of SHR at doses that produced a 15 to 20 mm Hg reduction in blood pressure within 1 hour. Under these conditions of dose and time, only captopril significantly inhibited brain ACE activity (43%), whereas inhibition of serum ACE activity ranged from 72% to 99% with these agents. Inhibition of aortic ACE activity ranged from 54% to 87%, and lung ACE inhibition varied from 50% to 83%. In the second series of experiments, SHR were administered higher doses of each ACE inhibitor such that these compounds produced peak reductions in blood pressure (-25 mm Hg to -33 mm Hg) within a range of 2 to 6 hours. When tissue ACE activity was measured at the time corresponding to peak reduction in blood pressure, all five ACE inhibitors produced a significant inhibition of brain ACE activity ranging from 21% to 76%. Serum ACE activity was almost completely inhibited by these agents, with the exception of captopril (62% inhibition). The inhibition of aortic ACE activity ranged from 79% to 99%, while the inhibition of lung ACE activity did not increase under these conditions. These data suggest that ACE inhibitors may exert their maximal antihypertensive effects by inhibiting ACE in vascular tissues and brain.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Pharmacological characterization of CGS 15943A: a novel nonxanthine adenosine antagonist.

CGS 15943A is a potent adenosine receptor antagonist with a novel nonxanthine heterocyclic ring structure. In vitro, CGS 15943A competitively inhibited the 2-chloroadenosine-induced A2 receptor-mediated relaxation of dog coronary artery strips contracted with KCl (25 mM). Similarly, CGS 15943A blocked 2-chloroadenosine- and N-ethylcarboxamideadenosine-induced A2 receptor-mediated relaxation of histamine-contracted guinea pig tracheal strips. Schild analysis of these results yielded pA2 values of 10.8 and 10.1 for the coronary arteries and the tracheal smooth muscle strips, respectively. In comparison, 8-phenyltheophylline blocked 2-chloroadenosine-induced tracheal response with a pA2 value of 7.0. CGS 15943A was devoid of intrinsic activity, and did not affect either histamine- or KCl-induced contractions of the smooth muscle strips. In the electrically stimulated guinea pig left atrial preparation, CGS 15943A antagonized the A1 receptor-mediated negative inotropic effects of R-phenylisopropyladenosine with a pA2 value of 7.4. In vivo, i.v. administration of CGS 15943A blocked the vasodepressor response to 2-chloradenosine in anesthetized normotensive rats with an ID50 of 0.024 mg/kg. In addition, p.o. administration of CGS 15943A (4.0 mg/kg) to conscious rats inhibited 2-chloroadenosine-induced decreases in diastolic blood pressure; maximal effects were observed 30 min after dosing, with a T1/2 of approximately 103 min. Therefore suggesting that CGS 15943A is an orally active antagonist of adenosine receptors. These results indicate that CGS 15943A antagonized both A1 and A2 receptor-mediated responses with a greater affinity toward the A2 than the A1 receptor subtype.

2-Chloroadenosine↗
PubMed1986

Dopaminergic mediation of the diuretic and natriuretic effects of ANF in the rat.

Atrial natriuretic factor (ANF) increases sodium (Na+) and water excretion 8-10 fold on repeated administration to anesthetized rats. SCH-23390 (80 micrograms/kg i.v.) and R-sulpiride (80 micrograms/kg i.v.), selective antagonists of dopamine receptors in the renal vasculature, inhibited diuresis and natriuresis induced by AP III and dopamine. These findings suggest that ANF exerts its effects on renal Na+ and water handling via a dopaminergic mechanism; however, changes in intrarenal hemodynamics secondary to dopamine receptor blockade may attenuate the actions of ANF.

Animals↗
PubMed1986

Synthesis and renal vasodilator activity of 2-chlorodopamine and N-substituted derivatives.

A four-step synthesis of 2-chlorodopamine (2b) is presented as well as methods for the syntheses of the N-methyl, ethyl, and n-propyl analogues (2c-e). Compounds 2b and 2c were essentially equipotent to dopamine for increasing renal blood flow in anesthetized dogs that had been treated with the alpha-adrenergic antagonist phenoxybenzamine. The increases in renal blood flow were blocked by the DA1 antagonist (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine. Compounds 2d and 2e were significantly less potent than dopamine in the same model; the increases in renal blood flow were attenuated by propranolol and blocked by a combination of propranolol and (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine. The significance of an o-chloro substituent on dopamine analogues for the activation of the DA1 receptor is briefly discussed.

Animals↗
PubMed1981

Water intake in hypovolemic sheep: effects of crushing the left atrial appendage.

Sheep increased their water intake in proportion to the amount of protein-free, isosmotic fluid that was removed from their blood by ultrafiltration. This behavioral response to hypovolemia was eliminated by crushing the left atrial appendage of the heart. The surgical maneuver had no effect on basal water intake or on the drinking response to a salt load. These findings suggest that left atrial stretch receptors, which influence secretion of antidiuretic hormone when stimulated, may also play an important role in mediating thirst during hypovolemia.

Animals↗
PubMed1979

Renin secretion during dynamic changes in renal perfusion pressure.

Uninephrectomized ewes were prepared with a renal artery flow probe and catheters were implanted into the renal artery, vein, and ureter. The renal perfusion pressure (RPP) of conscious animals was decreased externally by 13 +/- 3, 21 +/- 3, 31 +/- 3 mmHg over 5 min and returned to control levels over 5 min. Reduction of RPP by 13 and 21 mmHg resulted in prompt increases in renin secretion (RS) which were maximal coincident with the nadir of the downward ramp (delta RS 195 +/- 43 P less than 0.05, and 1,077 +/- 208 ng AI/min, P less than 0.01, respectively). Directly measured renal blood flow (RBF) was not decreased and no measurable change occured in GFR. When RPP was reduced by 31 mmHg, RBF and GFR were decreased and renin secretion rose further (delta RS 1,480 +/- 384 AI/min, P less than 0.05). On the upward pressure ramp, RS fell promptly and was nearly at control levels upon restoration of RPP. It was concluded that renin secretion responds rapidly to alterations in RPP in the autoregulatory range and these changes in renin secretion are unlikely to be mediated by a tubular receptor.

Animals↗
PubMed1978

Water and NaCl intake after furosemide treatment in sheep (Ovis aires).

Intravenous infusion of the natriuretic drug furosemide in sheep led to the excretion of large quantitites of hypotonic urine. The sheep consumed more water than was needed simply to restore osmotic equilibrium. The stimulus for the additional intake was presumably hypovolemia resulting from the loss of sodium in urine. Despite the natriuresis, in only 2 of 15 experiments did sheep drink significant amounts of .5 M NaCl solution during the first 10 hr after the onset of furosemide treatment, and hemoconcentration and arterial hypotension were evident during this time. By 24 hr, however, the saline consumption in all but three experiments had increased and compensated adequately (together with the water intakes) for the furosemide-induced loss of sodium-rich fluid in urine. These results provide evidence that following acute hypovolemia in sheep, as in rats, the onset of sodium appetite is delayed relative to the appearance of thirst.

Animals↗
PubMed1978

Renal function and renin secretion after administration of ouabain and ouabain plus furosemide in conscious sheep.

The effects of ouabain or ouabain and furosemide on renal function and renin secretion were studied in conscious isovolemic sheep. The sheep received a continuous renal arterial infusion of papaverine, 7 mg/min, throughout the experiment. Ouabain alone (7 X 10(-7) M in the renal plasma) produced significant decreases in glomerular filtration rate (GFR) and renal plasma flow (RPF) but not in renal perfusion pressure. Plasma [K+] rose after ouabain administration. Fractional (FENa) and absolute (UNaV) Na+ excretion were 2.9 +/- 1.0% (mean +/- SE) and 78 +/- 54 muEq/min, respectively, during the papaverine infusion and rose to 19 +/- 5.1% (P less than 0.05) and 528 +/- 116 muEq/min (P less than 0.01) after ouabain administration. Despite the large changes in Na+ reabsorption, renin secretion was not stimulated. During the control period, renin secretion was 281 +/- 131 ng/min and the average renin secretion after ouabain administration was 310 +/- 78 ng/min (not significant). A smaller dose of ouabain (2 X 10(-7) M) infused into the renal artery with 40 mg of furosemide, iv, did not decrease GFR but RPF was suppressed. FENa and UNaV averaged 4.4 +/- 1.6% and 121 +/- 44 muEq/min, respectively, while papaverine was infused into the renal artery and increased to 18 +/- 4.8% (P less than 0.05) and 636 +/- 209 muEq/min (P less than 0.05) after ouabain and furosemide were infused. Renin secretion was 118 +/- 62 ng/min during the control period and averaged 240 +/- 67 ng/min after ouabain plus furosemide. The difference was not statistically significant. Thus ouabain alone does not stimulate renin secretion in the conscious, isovolemic sheep despite a presumed increase in [NaCl] at the macula densa and inhibition of NaCl transport by the loop of Henle. Ouabain also blocks the normal stimulatory effects of furosemide on renin secretion.

Animals↗
PubMed1977

Caffeine restores feeding response to 2-deoxy-D-glucose in 6-hydroxydopamine-treated rats.

A large portion of the central catecholaminergic nerve terminals of the rat are destroyed by administering 6-hydroxydopamine (6-HDA) via the cerebrospinal fluid. Animals lesioned in this way often appear normal, yet show many subtle behavioural abnormalities. We have been examining one example of this phenomenon, the failure of 6-HDA-lesioned rats to increase food intake when given a systemic injection of 2-deoxy-D-glucose (2-DG) (refs 5, 6). This glucose analogue seems to elicit feeding in intact rats due to its inhibition of glycolysis in cerebral chemoreceptor cells. We have proposed that lesioned animals do not eat because of an insufficient central catecholaminergic response to the severe decrease in glucose utilisation induced by 2-DG (ref. 10). If so, then pretreatments which serve to augment this neurochemical response might be expected to reinstate behavioural function. Consistent with this hypothesis, very large increases in telencephalic tyrosine hydroxylase activity in 6-HDA-lesioned animals, which occur following chronic insulin treatment, are associated with the restoration of 2-DG-induced feeding. Many of the physiological effects of catecholamines in the sympathetic nervous system seem to be mediated by an increase in the cyclic AMP concentration of the target cells. Methylxanthenes, such as caffeine and theophylline, inhibit phosphodiesterase, prevent cyclic AMP degradation, and thereby potentiate the catecholamine-stimulated rise in cyclic nucleotide. They also enhance many of the behavioural and physiological effects of catecholamines, presumably by the same mechanism. We therefore sought to determine whether the acute administration of those sympathomimetic agents, in intact and 6-HDA-lesioned rats, also would potentiate 2-DG-induced feeding, a behaviour that seems to be mediated, in part, by central catecholaminergic neurons. We report that caffeine restores the 2-DG-induced feeding response.

Animals↗
PubMedDate not supplied

Comparison of appropriateness ratings for cataract surgery between convened and mail-only multidisciplinary panels.

BACKGROUND: In this article, the authors determine the reproducibility of appropriateness ratings for cataract surgery between a multidisciplinary physician panel that convened and a multidisciplinary physician panel that completed ratings by mail. METHODS: Eighteen panelists, who constituted 2 distinct multidisciplinary panels, rated 2894 clinical scenarios as an appropriate, inappropriate, or uncertain indication to perform cataract surgery. Each panel's summary score for each scenario was calculated. Weighted kappa values were determined to assess the level of agreement between the ratings of the 2 panels. RESULTS: The panels had a substantial level of agreement overall, with a weighted kappa statistic of 0.64. There was agreement on about 68% of the scenarios, and serious disagreement, in which one panel rated an indication appropriate and the other rated it inappropriate, occurred in only 1% of the ratings. CONCLUSION: There was substantial agreement about the ratings by the 2 panels. The panel that convened rated fewer scenarios uncertain and more appropriate, suggesting the impact of group dynamics and face-to-face discussion on resolution of uncertainty.

Cataract Extraction↗
PubMedDate not supplied

Role of thrombocytosis in diagnosis of giant cell arteritis and differentiation of arteritic from non-arteritic anterior ischemic optic neuropathy.

PURPOSE: To investigate the role of thrombocytosis in the diagnosis of giant cell arteritis (GCA), and differentiation of arteritic (A-AION) from non-arteritic (NA-AION) anterior ischemic optic neuropathy; and comparison of the sensitivity and specificity of platelet count to that of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and some other hematologic variables in the diagnosis of GCA. METHODS: This retrospective study is based on 121 temporal artery biopsy confirmed GCA patients and 287 patients with NA-AION seen in our clinic. For inclusion in this study, all GCA patients, at their initial visit, prior to the initiation of corticosteroid therapy, must have had ESR (Westergren), platelet count and complete blood count, and temporal artery biopsy. From 1985 onwards CRP estimation was done. For inclusion in this study, all NA-AION patients at the initial visit must have undergone evaluation similar to that described above for GCA, except for temporal artery biopsy. Wilcoxon rank-sum test and the two-sample t-test were used to compare hematologic variables between GCA patients with and without visual loss, between those with and without systemic symptoms, and also between GCA and NA-AION patients. Pearson correlation coefficient was computed to measure the association of platelet counts and the other hematologic variables with ESR. Receiver operating characteristic (ROC) curves were constructed for ESR, CRP, platelet count, combinations of ESR and platelet count, and CRP and platelet count, hemoglobin, hematocrit, and white blood cell (WBC) count and the area under the curve (AUC) were compared. RESULTS: Comparison of ESR, CRP, and hematologic variables of GCA patients and of A-AION with the NA-AION group, showed significantly (p <0.0001) higher median levels of ESR, CRP, platelet count, and WBC count and lower levels of hemoglobin and hematocrit in the GCA patients and A-AION than in NA-AION. Comparing AUC of the ROC curve between ESR and platelet count, ESR was a better predictor of GCA compared to platelet count (AUC of 0.946 vs. 0.834). There was a slight improvement in prediction of GCA using the combination of ESR and platelet count (AUC=0.953). The other hematologic variables had an AUC that was smaller than platelet count (0.854 for hemoglobin; 0.841 for hematocrit), with WBC being the least predictive of GCA (AUC=0.666). The AUC of the ROC curve for CRP was 0.978. There was no improvement in prediction of GCA using platelet count in combination with CRP (AUC=0.976). CONCLUSIONS: Patients with GCA had significantly (p <0.0001) higher values of platelet count, ESR, CRP and WBC but lower values for hemoglobin and hematocrit compared to the NA-AION group. Predictive ability of an elevated platelet count did not surpass elevated ESR or CRP as a diagnostic marker for GCA. Thrombocytosis may complement ESR. Hemoglobin, hematocrit and WBC were much less predictive of GCA. Elevated CRP had a greater predictive ability for GCA compared to ESR or the other hematologic parameters; thrombocytosis in combination with CRP did not yield an improvement in prediction of GCA.

Aged↗
PubMedDate not supplied

Physician use of and attitudes regarding the minimum data set.

OBJECTIVE: To determine physician use of the Minimum Data Set (MDS), part of the Resident Assessment Instrument (RAI). DESIGN: A population-based survey. SETTING: The United States. PARTICIPANTS: A total of 2223 physicians listing geriatrics as their primary specialty, 1921 of whom are internists and 302 family physicians. MEASUREMENTS: A 34-item questionnaire asking nine physician-specific demographic questions; nursing home caseload; percent time spent reviewing MDS and care plan; how the information on the MDS was used. Physicians were also asked to describe their attitudes about the MDS. RESULTS: Among the 472 physicians who completed the survey and cared for nursing home patients, 357 were internists and 107 were family physicians. Ninety-one percent of the physicians were board certified, 76% had certificate of added qualifications in geriatrics,65% oversaw 20 nursing home patients. Only 11% of physicians reported reviewing the entire MDS, and 21% part of the MDS for all of their patients. Nineteen percent of physicians did not review the care plan for any of their patients. Fifty-six percent of 461 comments made by physicians regarding the MDS were negative or derogatory. CONCLUSIONS: Many practicing geriatricians are not using MDS to facilitate medical decisions. If this physician population is not using the MDS, there is a need to improve the information transfer from the MDS form to the busy clinician.

Journal Article↗