published_or_final_version / Anaesthesiology / Master / Doctor of Medicine

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

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Katecholamine beeinflussen durch direkte Stimulation über adrenerge Rezeptoren die Funktion von Immunzellen. Ziel der Untersuchungen an Patienten mit Rheumatoider Arthritis war es, das Expressionsprofil unterschiedlicher adrenerger Rezeptorsubtypen in CD4(+)T-Lymphozyten dieser Patienten zu bestimmen. Zur Quantifizierung der Expression wurden semiquantitative RT-PCR-Analysen durchgeführt. Die Untersuchung zeigte, dass alpha1-adrenerge Rezeptoren in CD4(+)-T-Lymphozyten von RA-Patienten exprimiert werden. Es scheint eine Korrelation zwischen bestimmten extraartikulären Organmanifestationen (z.B. Sicca-Sydrom und Tenosynovitis) und der Expression alpha1-adrenerger Rezeptoren zu bestehen. Die gefundene differenzielle Expression der Rezeptoren in CD4(+)-T-Lymphozyten von RA-Patienten legen vertiefende Untersuchungen zur Relevanz des adrenergen Systems bei der Lymphozytenfunktionsmodulation nahe.

Previous studies have suggested that phosphodiesterase (PDE) hydrolysis of cyclic adenosine monophosphate (cAMP) is important in the generation of specific and segregated cAMP signals within cells. The purpose of this study was to determine if PDE compartmentation was important in cardiac ventricular myocytes. Therefore, we investigated the effects of β-adrenergic (β-AD) stimulation with isoproterenol in the presence of cilostamide, a PDE3 inhibitor, or Ro 20-1724, a PDE4 inhibitor, on unloaded cell shortening, L-type calcium currents and intracellular calcium levels in freshly dissociated adult rat ventricular myocytes. PDE3 inhibition resulted in a 216 ± 17 % (n=8) increase in unloaded cell shortening after ten minutes of isoproterenol exposure, whereas isoproterenol produced a statistically smaller increase of 155 ± 12 % (n=8) in the presence of PDE4 inhibition. There was a non-significant trend for PDE4 inhibition to produce larger increases in calcium currents (179 ± 17 % (n=4) of controls) than PDE3 inhibition (155 ± 10 % (n=6) of controls). Both PDE3 and PDE4 inhibitors had similar effects on isoproterenol-stimulated increases of calcium transient amplitude with values of 209 ± 14 % (n=8) and 185 ± 12 % (n=8), respectively. Determination of sarcoplasmic reticulum (SR) calcium load using caffeine pulse experiments demonstrated that PDE4 inhibition and isoproterenol superfusion produced a statistically larger increase in SR-calcium loading (139 ± 9 % (n=6)) than PDE3 inhibition and isoproterenol superfusion (113 ± 9 % (n=6)). These results suggest that PDE3 may be active in proximity to the contractile apparatus of cardiac myocytes, whereas PDE4 may be localized in a domain consisting of the L-type calcium channel and junctional SR. Consequently, our study provides functional evidence for differential localization of PDE isoforms in cardiac myocytes. / Thesis (Master, Physiology) -- Queen's University, 2008-01-18 10:14:29.671 / CIHR OGS OGSST

Objectives. beta-blockers can alter bone turnover and increase bone formation in animals. It is unknown whether beta-blockers have similar bone protective effects in humans. We aimed to estimate the effects of beta-blockers on bone mineral density (BMD) and fractures using data from the Canadian Multicentre Osteoporosis Study, a large prospective cohort study. / Methods. All medications, including beta-blockers, taken at baseline and after five years of follow-up were recorded. BMD was measured at baseline. During the five years of follow-up, incident minimal trauma fractures were documented by yearly questionnaires. To compare users of beta-blockers to non-users while controlling for possible confounders, multiple linear regression was utilized to estimate between group differences in BMD and multivariate logistic regression was employed to estimate differences in fracture risk. / Results. Of the 9423 participants, 236 of 2884 males (8.2%) and 600 of 6539 females (9.2%) used beta-blockers at some point during the study. In men, beta-blocker users had differences of +1.1% (95% confidence interval [CI] -0.9%, 3.0%) and +1.2% (95% CI -0.5%, 4.0%) in baseline BMD at the total hip and at the lumbar spine, respectively, compared to non-users. In women, beta-blocker users had differences of +0.05% (95% CI -1.2%, 1.3%) and +0.2% (95% CI -1.3%, 1.7%) for the BMD of the total hip and the lumbar spine, respectively, compared to non-users. For users of beta-blockers at baseline, the adjusted odds ratio (OR) for any minimal trauma fracture was 1.23 (95% CI 0.67--2.25) in men and 1.02 (95% CI 0.76--1.35) in women. Chronic use (user at baseline and year 5) in men had an OR for any minimal trauma fracture of 2.1 (95% CI 1.0--4.3). In women who used beta-blockers at baseline but not at year 5, the OR for hip fracture was 6.3 (95% CI 2.0--19.3). The risk of fractures for other sites was inconclusive owing to wide confidence intervals. / Conclusion. Despite relatively large numbers of subjects, wide confidence intervals do not permit strong conclusions with regards to the effect of beta-blockers on BMD in men. Using a 2% limit of clinical importance for BMD, there appears to be no effect of beta-blockers on BMD in women. There is some evidence from our study that beta-blockers may be associated with an increased risk of fractures in certain subsets of users.

Purpose. To examine the outcome of a 6-month treatment with carvedilol or metoprolol on peak and submaximal exercise performance and ventilatory efficiency in patients with heart failure (HF). / Methods. 27 patients with HF were randomized to receive either metoprolol or carvedilol for 6 months and compared with 12 healthy controls. Maximal exercise capacity was assessed at baseline and after 6 months with a symptom limited incremental treadmill protocol (RAMP). Submaximal exercise was determined to be the portion of exercise below a respiratory exchange ratio of 1.0. Peak heart rate (HR), oxygen uptake (VO2), and ventilatory equivalent for O2 and CO2 were recorded. The slopes of the VE vs. VCO2, VE vs. VO2 and VE/VCO2 vs. VO2 relationships were calculated for each subject from submaximal values. / Results. Resting HR decreased to similar extent in both treatment groups. There were no other significant changes in resting hemodynamics or ventricular function. Peak VO2 and HR decreased significantly in both treatment groups. Peak VE/VCO2 and submaximal VCO 2 vs. VE slope were not changed significantly after therapy. / Conclusion. beta-blocker treatment with either metoprolol or carvedilol does not decrease the slope of the VCO2 vs. VE relationship. The present observations may suggest that the exaggerated ventilatory response of patients with moderate HF is not mediated by beta-adrenergic receptors.

Background/Rationale: In addition to their established cardioprotective role, β-adrenergic antagonists also increase the risk of stroke and mortality. We propose that a vascular mechanism could contribute to cerebral tissue ischemia in β-blocked patients. Methods: Cardiac output (CO), mean arterial pressure (MAP) and microvascular brain oxygen tension (PBrmvO2) were measured in anesthesized mice treated with metoprolol (3mg•kg-1, i.v.). Dose-response curves (DRCs) for adrenergic-agonists were generated in mesenteric resistance arteries (MRAs; isoproterenol, clenbuterol) and posterior cerebral arteries (PCAs; phenylephrine, isoproterenol) before and after metoprolol treatment. Results: Metoprolol reduced CO, maintained MAP and increased systemic vascular resistance (SVR) resulting in a decreased PBrmvO2 in mice. Metoprolol attenuated β-adrenergic mediated vasodilation in both MRAs and PCAs. Conclusions: Metoprolol reduced brain perfusion in mice. A decrease in CO contributed however, metoprolol also inhibited β-adrenergic vasodilation of mesenteric and cerebral arteries. This provides evidence in support of a vascular mechanism for cerebral ischemia in β-blocked patients.

Background/Rationale: In addition to their established cardioprotective role, β-adrenergic antagonists also increase the risk of stroke and mortality. We propose that a vascular mechanism could contribute to cerebral tissue ischemia in β-blocked patients. Methods: Cardiac output (CO), mean arterial pressure (MAP) and microvascular brain oxygen tension (PBrmvO2) were measured in anesthesized mice treated with metoprolol (3mg•kg-1, i.v.). Dose-response curves (DRCs) for adrenergic-agonists were generated in mesenteric resistance arteries (MRAs; isoproterenol, clenbuterol) and posterior cerebral arteries (PCAs; phenylephrine, isoproterenol) before and after metoprolol treatment. Results: Metoprolol reduced CO, maintained MAP and increased systemic vascular resistance (SVR) resulting in a decreased PBrmvO2 in mice. Metoprolol attenuated β-adrenergic mediated vasodilation in both MRAs and PCAs. Conclusions: Metoprolol reduced brain perfusion in mice. A decrease in CO contributed however, metoprolol also inhibited β-adrenergic vasodilation of mesenteric and cerebral arteries. This provides evidence in support of a vascular mechanism for cerebral ischemia in β-blocked patients.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.