Search PubMed⌕ Search

Biomedical subjects

R Schulz

Publications and source records attributed to R Schulz.

At least 181 records · Page 10Linked to original sources
PubMed1999

Attenuation of myocardial stunning by the AT1 receptor antagonist candesartan.

The effect of AT1 receptor blockade on myocardial stunning is still somewhat ambiguous. In some prior studies, coronary occlusion was of too long duration such that the effects of infarction and stunning on the recovery of contractile function could not be distinguished. In others, blood pressure was decreased such that the improved wall excursion could be the consequence of reduced afterload and/or of attenuated stunning. The present study, therefore, investigated the effect of the AT1 receptor antagonist candesartan in a pure model of myocardial stunning with controlled systemic hemodynamics. Fourteen anesthetized open-chest dogs were subjected to 15 minutes occlusion of the left circumflex coronary artery (LCx) and 4 hours subsequent reperfusion. Systemic hemodynamics (micromanometer), regional myocardial blood flow (colored microspheres), and posterior wall thickening (PWT, sonomicrometry) were measured, and data were compared between 7 placebo controls (group 1) and 7 dogs receiving 1 mg/kg candesartan i.v. before LCx occlusion (group 2). Left ventricular peak pressure was kept constant by an intra-aortic balloon, and heart rate did not change throughout the protocol. Regional myocardial blood flow was not different between the groups under control conditions, increased in response to candesartan in group 2 (posterior subendocardial blood flow from 0.99 +/- 0.18 to 1.57 +/- 0.45; p < 0.05 vs. control conditions), but was not different during myocardial ischemia and at 4 hours of reperfusion between the groups. Under control conditions and during myocardial ischemia, PWT was also not different between the groups. At 4 hours of reperfusion, PWT was still depressed in group 1 (-1.5 +/- 3.4% vs. 17.7 +/- 5.6% during control conditions, p < 0.05), whereas PWT had recovered in group 2 (11.4 +/- 3.7% at 4 hours reperfusion vs. 18.3 +/- 2.7 during control conditions, NS, p < 0.05 vs. group 1). In conclusion, pretreatment with the AT1 receptor antagonist candesartan improved the functional recovery of reperfused myocardium. This attenuation of myocardial stunning was not based on more favorable systemic hemodynamics or regional myocardial blood flow.

Angiotensin Receptor Antagonists↗
PubMed1999

Mu-opioid receptor expression in High Five insect cells is regulated by 5' untranslated region (5'UTR).

There is increasing evidence that the 5'UTR of mRNAs affects regulation of gene expression in eukaryotic cells. We examined the overexpression of the mu-opioid receptor in High Five insect cells, employing rat mu-receptor cDNA linked to variable lenghts of their native 5'UTR. The sequences employed consist of either 209 nucleotides (termed ,,long") upstream the translation initiation site of the mu-receptor mRNA, or a truncated 5'UTR comprising only 11 nucleotides (,,short"). These constructs served to generate recombinant baculovirus for the expression of mu-receptor protein in High Five insect cells. 48 hours after baculovirus infection cells were harvested for mu-receptor characterization or RNA analysis. Scatchard analysis of radioligand binding consistently revealed three to four fold higher concentrations of the mu-opioid receptors expressed with the ,,long" over the ,,short" UTR containing baculovirus. The distinct expression rates of mu-receptors paralleled the amounts of mRNAs determined by RNase protection assay. Regardless of the distinct 5'UTR regions, the expressed opioid receptors displayed identical high affinity binding characteristics for the opioid antagonist diprenorphine and similar EC50 values to inhibit forskolin (10(-5) M) stimulated cAMP synthesis. Our results demonstrate that the native 5'UTR of the mu-opioid receptor has an enhancing effect on expression in the baculovirus/insect cell system.

5' Untranslated Regions↗
PubMed1999

Effect of technical and functional quality on patient perceptions of pharmaceutical service quality.

PURPOSE: To evaluate the relative importance of functional quality (how services were provided) and technical quality (what was received for those services) on patient perceptions of pharmaceutical service quality. METHODS: A scenario-based experimental design was chosen to manipulate functional (FQ) and technical quality (TQ). Subjects were asked to read one of four scenarios describing a pharmacy service experience and imagine that he or she were in the situation described. High and low TQ were manipulated by describing the presence or absence of a prescription medication dispensing error made by the pharmacist in the scenario. Each subject completed a survey about their evaluations of the service provided in the scenario. An ANOVA using a 2 x 2 completely randomized factorial design was conducted to compare the effects of TQ, FQ, and their interaction on perceptions of service quality and behavioral intention. Effect sizes were measured with the calculation of omega-square. RESULTS: FQ had the greatest impact on patient perceptions of service quality and behavioral intentions. FQ explained 44% of the variance in service quality and 39% in intention to return. TQ and the interaction accounted for a significant but much lesser effect. The interaction showed that the effect of FQ was greatest under conditions of high TQ. There were no significant associations between any demographic characteristics and responses to service quality. CONCLUSIONS: The results suggest that FQ has the greatest impact on consumer perceptions of pharmaceutical service quality even under conditions of an obvious example of low TQ which respondents perceive as serious and possibly harmful. This study underscores the limitations of relying on patient perceptions in evaluating pharmaceutical services. Although patient evaluations are important, they can be inadequate for assessing the professional quality of services.

Adult↗
PubMed1999

The primacy of primary control is a human universal: a reply to Gould's (1999) critique of the life-span theory of control.

This reply to S. J. Gould's (1999) critique of J. Heckhausen and R. Schulz's (1995) life-span theory of control addresses four issues: (1) the universal claim that primary control holds functional primacy over secondary control, (2) the status of secondary control as a confederate to primary control, (3) empirical evidence and paradigms for investigating universality and cultural variations, and (4) the capacity of the human control system to manage both gains and losses in control throughout the life span and aging-related decline in particular. Theoretical perspectives and empirical evidence from evolutionary, comparative, developmental, and cultural psychology are presented to support the authors' view that primary control striving holds functional primacy throughout the life span and across cultural and historical settings. Recommendations for empirically investigating the variations in the way primary control striving is expressed in different cultures are outlined.

Adult↗
PubMed1999

The effect of bosentan on the pharmacokinetics of digoxin in healthy male subjects.

AIMS: To investigate the effect of multiple oral dose treatment with the endothelin receptor antagonist bosentan on the pharmacokinetics of digoxin in healthy subjects. METHODS: This was an open-label, randomized, two-way crossover study in 18 evaluable young male subjects. They received, on two occasions which were separated by at least 2 weeks washout period, 0.375 mg digoxin once daily for 13 days following a loading dose of 0.375 mg given twice on the day before the once daily dosing regimen started. On one occasion treatment with 500 mg bosentan twice daily was started on the eighth day of digoxin treatment and continued for 1 week. Serum concentrations of digoxin were determined up to 24 h postdose on day 8 (first day of bosentan treatment) and day 14 (last day of bosentan treatment) of the digoxin treatment period. Plasma concentrations of bosentan were measured at two time points after the first bosentan dose and up to 12 h after the last morning dose of bosentan. Safety was assessed by adverse events, clinical laboratory tests, blood pressure and pulse rate measurements and ECG recordings. RESULTS: Steady-state of digoxin was always achieved after 7 days of treatment. Serum concentrations of digoxin were within the usual therapeutic range. Average steady-state Cmax and Ctr were 2-2.1 microg l-1 and 0.65-0.69 microg l-1, respectively, when given alone. Bosentan did not lead to statistically significant changes in Cmax and Ctr of digoxin. AUC (0,24h) of digoxin, however, was slightly reduced after 1 week of treatment with bosentan. The reduction was 12% on average with a narrow 95% confidence interval of 0-23%. Bosentan pharmacokinetic parameters after 1 week of treatment were as expected with a mean Cmax of 3260 microg l-1 and a mean AUC (0, 12h) of 12 600 microg l-1 h. CONCLUSIONS: Treatment with bosentan 500 mg twice daily for 1 week did not show clinically relevant effects on the pharmacokinetics of digoxin in healthy human subjects

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Aging, culture and control: setting a new research agenda.

In the context of reviewing the current status of research on aging and control, we put forth five propositions: (1) Striving for primary control is a human universal invariant across historical time and diverse cultural settings; (2) the expression of control striving is in part shaped by culture; (3) the field needs to move away from the study of perceived control and its correlates to the study of motivational aspects of control; (4) control should be studied in a life span context and the focus should be on key transitions that redefine opportunities for control striving; and (5) inasmuch as primary control striving is such a central element of human functioning, research on its demise at the end of life should receive high priority.

Aged↗
PubMed1999

Stability and change in older adults' social contact and social support: the Cardiovascular Health Study.

OBJECTIVES: The aim of this study was to examine the degree of individual change in structural indicators of social support (family network contact and close friend network contact) and functional indicators of social support (belonging, appraisal, and tangible support) during late life. METHODS: Using a large population-based sample of older adults, hierarchical linear modeling was applied to examine the extent of change in social contact and support as well as sociodemographic characteristics (age, race, gender, and education) that might explain individual variability in contact and support at baseline and over time. RESULTS: Consistent with predictions, small yet significant increases were observed in belonging support and tangible support. Contrary to predictions, no evidence was found for significant individual change in family network contact, close friend network contact, or appraisal support. Sociodemographic characteristics were more consistent predictors of variability in contact and support at baseline than variability over time. DISCUSSION: The findings of this study add to a growing literature suggesting that late life is not typically characterized by a decline in important social resources.

Age Factors↗
PubMed1999

Prevalence and impact of caregiving: a detailed comparison between dementia and nondementia caregivers.

Analyzing data from more than 1,500 family caregivers from the 1996 National Caregiver Survey, this study documents the ways in which dementia care is different from other types of family caregiving. Not only do dementia caregivers spend significantly more hours per week providing care than nondementia caregivers, they also report greater impacts in terms of employment complications, caregiver strain, mental and physical health problems, time for leisure and other family members, and family conflict. Differential impacts remain even after controlling for intensity of caregiving involvement and sociodemographic factors. Study findings suggest the need to tailor programs and services to the unique challenges faced by dementia caregivers.

Activities of Daily Living↗
PubMed1999

Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts.

We examined the mechanism of the time- and protein synthesis-dependent decline in cardiac mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer for 120 min in the presence or absence of the protein synthesis inhibitor cycloheximide (CX; 10 microM). Cardiac work remained stable for 60 min and then spontaneously decreased during 60-120 min of perfusion. This was accompanied by an increase in myocardial inducible nitric oxide synthase (iNOS) and xanthine oxidase (XO) activities and enhanced dityrosine formation in the perfusate, an indicator of peroxynitrite generation. CX markedly attenuated the loss in contractile function and prevented the increase in iNOS and XO activities and dityrosine level. Despite the decline in cardiac work in control hearts, the coupling between tricarboxylic acid (TCA) cycle activity and oxygen consumption remained constant in both groups. ATP, creatine phosphate, and glycogen levels were not different between control and CX groups and did not differ over 120 min of perfusion. We concluded that the delayed and spontaneous loss in myocardial mechanical function in isolated working rat hearts is 1) attenuated by CX treatment, 2) accompanied by a concomitant increase in both iNOS and XO activities and peroxynitrite generation in the heart, and 3) not dependent on a direct impairment in myocardial ATP production, myocardial oxygen consumption, or TCA cycle acetyl-CoA production but may be due to an inefficiency of the heart to utilize ATP for contractile work.

Animals↗
PubMed1999

Endotoxin and ischemic preconditioning: TNF-alpha concentration and myocardial infarct development in rabbits.

Ischemic preconditioning (IP) and prior exposure to lipopolysaccharides (LPS) reduce infarct size (IS) and serum tumor necrosis factor-alpha (TNF-alpha) concentration resulting from myocardial ischemia-reperfusion in rabbits. The decrease in TNF-alpha might relate to an induced TNF-alpha inhibitory serum activity (TNF-alpha-ISA). We analyzed TNF-alpha and TNF-alpha-ISA during 30 and 180 min ischemia and reperfusion, respectively, in anesthetized rabbits either untreated (group 1, n = 7), preconditioned (5 and 10 min ischemia and reperfusion, respectively, group 2, n = 9), or exposed to LPS 72 h before ischemia (group 3, n = 9). TNF-alpha-ISA was assessed by coincubating LPS-stimulated rabbit blood with serum of groups 1-3 and measuring TNF-alpha (WEHI assay). With a comparable area at risk, IS in group 1 was 36.9 +/- 11.1 (SD)%, and it was reduced to 13.1 +/- 11.6% and 17.3 +/- 11.3% (both P < 0.05) in groups 2 and 3, respectively. TNF-alpha was increased during ischemia-reperfusion in group 1 but remained unchanged in rabbits subjected to IP or LPS. TNF-alpha-ISA was detected during ischemia-reperfusion in group 2 (29% and 38% of maximum inhibition, respectively) and during baseline, ischemia and reperfusion in group 3 (51%, 46%, 48% of maximum inhibition, respectively) but was absent in group 1. Cardioprotection by IP and LPS is associated with a reduced TNF-alpha and an induced TNF-alpha-ISA during ischemia-reperfusion.

Animals↗
PubMed1999

Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility.

Previous studies have demonstrated the existence of a circulating myocardial depressant substance during human septic shock. We have recently identified this substance as a synergistic combination of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). This study utilized an in vitro cardiac myocyte assay to evaluate the potential mechanistic role of nitric oxide (NO) and cGMP in depression of myocyte contractility induced by TNF-alpha, IL-1beta, TNF-alpha + IL-1beta (at low concentrations), and human septic shock serum (HSS). TNF-alpha, IL-1beta, TNF-alpha + IL-1beta, and each of 5 sera from patients with acute septic shock caused depression of both maximum extent and peak velocity of cardiac myocyte shortening and an increase in intracellular cGMP concentration during 30 min of exposure (minimum P < 0.01). NO synthetase (NOS) and guanylate cyclase inhibitors such as N-methyl-L-arginine (L-NMA) and methylene blue prevented these effects; an excess of L-arginine with L-NMA restored them (minimum P < 0.01). In contrast, D-arginine failed to reestablish cytokine-induced myocyte depression and cGMP accumulation prevented by L-NMA. Exposure of myocytes to TNF-alpha, IL-1beta, or TNF-alpha + IL-1beta produced a concentration-dependent increase in intracellular cGMP that paralleled the depression of cardiac myocyte contractility (minimum P < 0.001). In addition, TNF-alpha, IL-1beta, TNF-alpha + IL-1beta, or HSS application to cardiac myocytes resulted in increased NO gas generation, which was inhibited by L-NMA (minimum P < 0.01). Furthermore, unstimulated cardiac myocytes were shown to harbor constitutive but not inducible NOS activity. These data suggest that the sequential generation of NO by a constitutive NOS and cGMP by guanylate cyclase represents an important mechanism of cardiac myocyte depression by TNF-alpha, IL-1beta, TNF-alpha + IL-1beta, and the myocardial depressant substance(s) of septic shock.

Animals↗
PubMed1999

Effect of the endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin.

To investigate the effects of bosentan (Ro 47-0203), an endothelin receptor antagonist, on the pharmacokinetics and pharmacodynamics of warfarin, a double-blind, placebo-controlled, randomized, two-way crossover study was performed in 12 healthy male volunteers. All subjects received a single oral dose of 26 mg racemic warfarin twice, once in the morning of the 6th day of treatment with 500 mg bosentan twice daily for 10 days and once at the same time point during treatment with placebo twice daily for 10 days. Both treatments were separated by a 2- to 3-week washout period. Blood samples were collected at intervals up to 120 hours following the warfarin dose for the measurement of prothrombin time and factor VII activity and for determination of plasma concentrations of R- and S-warfarin. Bosentan treatment led to a statistically significant reduction of the maximal prothrombin time (PTmax) and the AUC0-120 h of PT and factor VII activity compared to placebo, on average, by 23% to 38%. This reduction could be explained by an increase in the elimination of the pharmacologically more active S-enantiomer whose mean AUC0-infinity was reduced by 29%. The mean AUC0-infinity of R-warfarin was also decreased by 38%. Cmax and tmax of both enantiomers did not change. Close monitoring in patients receiving warfarin is recommended at initiation or discontinuation of treatment with bosentan.

Adult↗
PubMed1999

Response of fetal rabbit ductus arteriosus to bradykinin: role of nitric oxide, prostaglandins, and bradykinin receptors.

Nitric oxide plays a major role in vascular tone control. Increased blood levels of bradykinin (BK), which stimulates nitric oxide biosynthesis, occur at birth. BK effects on ductus arteriosus (DA) tone were investigated in fetal rabbit under fetal (2.5% O2 "low PO2") and neonatal (30% O2 "high PO2") conditions using in vitro isometric tension studies. Intact and endothelium-denuded DA, contracted with norepinephrine (ED75-90), showed a biphasic response to BK, with relaxation at 10(-9) to 10(-7) M BK and contraction at 10(-6) to 10(-5) M BK. BK (10(-6) to 10(-5) M) contracted intact DA from baseline tension, with greater contraction under high PO2. The B2-receptor antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (Hoe-140, 10(-7) M) abolished relaxation, but not contraction, to BK in intact and denuded DA. The B1-receptor antagonist des-Arg9-[Leu5]-BK (10(-7) M) reduced BK-induced contraction but not relaxation in intact DA only. Nitric oxide synthase inhibitors, N(omega)-nitro-L-arginine methyl ester (10(-4) M) and N(omega)-monomethyl-L-arginine (10(-4) M) partially inhibited relaxation to BK in intact DA, with L-arginine (3 x 10(-4) M) reversing N(omega)-monomethyl-L-arginine inhibition. N(omega)-nitro-L-arginine methyl ester (10(-4) M) caused a small but significant inhibition of relaxation to BK in denuded DA. Indomethacin (2.8 x 10(-6) M), a cyclooxygenase inhibitor, abolished relaxation but not contraction to BK in intact and denuded DA. BK-induced relaxation of the DA acts through B2-receptors, releasing both nitric oxide and prostaglandins, whereas endothelial B1-receptors may mediate contraction. BK action on isolated DA changes from relaxation to contraction as its concentration increases, with greater contraction at neonatal PO2. Thus increased BK levels at birth may aid functional closure of the DA.

Animals↗
PubMed1999

Effect of phosducin on opioid receptor function.

Phosducin (Phd) regulates the function of G proteins by its ability to tightly bind Gbetagamma subunits. Because the internalization of opioid receptors as well as the activity of adenylyl cyclase (AC) activity depends on G proteins, we tested Phd on these parameters. NG 108-15 hybrid cells stably expressing the phosphoprotein were challenged with [D-penicillamine2,D-penicillamine5]enkephalin to inhibit cAMP generation, demonstrating an increased efficacy of the opioid on AC. Studying the binding of [35S]guanosine-5'-O-(gamma-thio)-triphosphate to membranes from Phd overexpressing cells, we found that [D-penicillamine2, D-penicillamine5 ]enkephalin failed, in the presence of Phd (0.1 nM), to elevate incorporation of the nucleotide. Phd also strongly inhibited opioid-stimulated GTPase activity. NG 108-15 cells were also employed to investigate the effect of Phd on opioid receptor internalization. Control cells and cells overexpressing Phd were transiently transfected to express mu-opioid receptors fused to green fluorescence protein. In controls and in Phd overexpressing cells confocal microscopy identified fluorescence associated with the membrane. Time-lapse series microscopy of living control cells challenged with etorphine (1 microM) revealed receptor internalization within 30 min. In contrast, Phd overexpressing cells largely failed to respond to the opioid. Thus, in Phd overexpressing cells, opioids exhibit an increased efficacy despite the inhibitory action of the phosphoprotein on opioid-stimulated incorporation of [35S]guanosine-5'-O-(gamma-thio)-triphosphate. We suggest that inhibition of GTPase stabilizes the opioid-induced G protein Gi-GTP complex, which is believed to enhance AC inhibition. Finally, scavenging of Gbetagamma by Phd attenuates internalization of opioid receptors, which may contribute to the efficacy of opioids.

Cyclic AMP↗
PubMed1999

AT1 receptor blockade in experimental myocardial ischemia/reperfusion.

The renin-angiotensin system is activated during myocardial ischemia, and local angiotensin II formation occurs in ischemic hearts. At least two angiotensin II receptor subtypes, the AT1 and the AT2 receptor, have been identified. The cardiovascular effects of angiotensin II have been attributed largely to activation of AT1 receptors. In ventricular preparations from normal rat and pig hearts, the density of AT1 receptors is higher than that of AT2 receptors, whereas data on the AT receptor subtype density and its distribution in human hearts remain controversial. AT1 receptor blockade increases coronary blood flow during ischemia in dogs and during reperfusion in rats, reduces the incidence of ischemia-related arrhythmias in rats and guinea pigs, limits infarct size in pigs, improves functional and metabolic recovery after myocardial ischemia, and attenuates ventricular remodeling post-myocardial infarction in rats. The potential mechanisms responsible for the cardioprotection by AT1 receptor blockade remain to be elucidated in detail, but appear to involve AT2 receptor activation and the subsequent action of bradykinin, prostaglandins, and/or nitric oxide. Patients under treatment with AT1 receptor blockers for indications such as hypertension and ventricular dilation after myocardial infarction are likely to have improved prognosis when suffering an acute myocardial infarction.

Angiotensin Receptor Antagonists↗
PubMed1998

Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs.

OBJECTIVE: We studied the effect of the angiotensin II type 1 (AT1)-receptor antagonist candesartan on infarct size resulting from regional myocardial ischemia in pigs. BACKGROUND: The effects of AT1-receptor blockade on infarct size in different species remain controversial and its potential cardioprotective mechanisms are still unclear. In pigs, infarct development closely resembles that observed in humans. METHODS: A total of 62 enflurane-anesthetized pigs underwent a protocol of 90-min low-flow ischemia and 120-min reperfusion. Systemic hemodynamics (micromanometer), regional myocardial function (sonomicrometry), regional myocardial blood flow (microspheres) and infarct size (TTC [triphenyl tetrazolium chloride]-staining) were determined. RESULTS: Left ventricular peak pressure decreased with candesartan (1 mg/kg i.v.) from 97+/-2 standard error of the mean (SEM) to 86+/-5 mm Hg and was then readjusted by aortic banding. In placebo pigs (n=9), infarct size was 21.8+/-4.8% of the area at risk. Candesartan (n=7) reduced infarct size to 9.7+/-2.5% (p < 0.05). Pretreatment with the AT2-receptor antagonist PD123319 (3 microg/kg/min intracoronarily [i.c.]; n=8), the bradykinin B2-receptor antagonist HOE140 (0.01 microg/kg/min i.c.; n=8) or the cyclooxygenase inhibitor indomethacin (10 mg/kg i.v.; n= 8) per se did not affect infarct size but did abolish the reduction of infarct size achieved by candesartan (PD123319 + candesartan (n=7): 23.2+/-4.7%; HOE140 + candesartan (n=7): 18.2+/-4.0%; indomethacin + candesartan (n=8): 21.1+/-5.2%). Hemodynamics, regional myocardial blood flow during ischemia and the area at risk were comparable among all groups of pigs. CONCLUSIONS: Reduction of infarct size by the AT1-receptor antagonist candesartan in pigs involves angiotensin II type 2 receptor (AT2) activation, bradykinin and prostaglandins.

Angiotensin Receptor Antagonists↗