Biomedical subjects

Martin Laser

Publications and source records attributed to Martin Laser.

5 recordsLinked to original sources

PubMed2003

Increased myocardial oxygen consumption by TNF-alpha is mediated by a sphingosine signaling pathway.

The present study investigated the effect of tumor necrosis factor (TNF)-alpha on myocardial energy metabolism as estimated by myocardial oxygen consumption (MVo(2)). MVo(2) of electrically stimulated isolated trabeculae of right ventricular Wistar rat myocardium was analyzed using a Clark-type oxygen probe. After the initial data collection in the absence of TNF-alpha, measurements were repeated after TNF-alpha stimulation. In separate experiments, pretreatment with the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) or the ceramidase inhibitor n-oleoylethanolamine (NOE) was done to investigate NO/sphingosine-related effects. TNF-alpha impaired myocardial economy at increasing stimulation frequencies without altering baseline MVo(2). Incubation with TNF-alpha in the presence of l-NAME further impaired myocardial economy. NOE preincubation abrogated the TNF-alpha effect on myocardial economy. Moreover, the negative inotropic effect of TNF-alpha was observed in NOE-pretreated but not l-NAME-pretreated muscle fibers. Exogenous sphingosine mimicked the TNF-alpha effect on mechanics and energetics. We conclude that TNF-alpha impairs the economy of chemomechanical energy transduction primarily through a sphingosine-mediated pathway.

Amidohydrolases↗

PubMed2003

CB(1) cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction.

1. To study the long-term effects of altered cannabinoid receptor activity on myocardial and vascular function, Wistar rats were treated with the selective CB(1) antagonist AM-251 (0.5 mg kg(-1) d(-1)), the potent synthetic cannabinoid HU-210 (50 micro g kg(-1) d(-1)) or vehicle for 12 weeks after coronary artery ligation or sham operation. 2. AM-251 further reduced the pressure-generating capacity, shifted the pressure volume curve to the right (P<0.05) and increased the left-ventricular operating volume (AM-251: 930+/-40 micro l vs control: 820+/-40 micro l vs HU-210: 790+/-50 micro l; P<0.05) in rats with large myocardial infarction (MI). 3. Left-ventricular CB(1) immunoactivity in rats 12 weeks after large MI was unaltered as compared with noninfarcted hearts. 4. Cannabinoid receptor activation through HU-210, a cannabinoid that alters cardiovascular parameters via CB(1) receptors, increased the left-ventricular end-diastolic pressure (LVEDP, P<0.05). However, it prevented the drop in left-ventricular systolic pressure (HU-210: 142+/-5 mm Hg; P<0.05 vs control: 124+/-3 mm Hg; and P<0.001 vs AM-251: 114+/-3 mm Hg) and prevented endothelial dysfunction (ED) in aortic rings of rats with large MI (P<0.05). 5. Compared with AM-251, HU-210 prevented the decline in the maximal rate of rise of left-ventricular pressure and the maximum pressure-generating ability (P<0.05). In rats with small MI, HU-210 increased cardiac index (P<0.01) and lowered the total peripheral resistance (P<0.05). 6. The study shows that during the development of congestive heart failure post-large MI, cannabinoid treatment increases LVEDP and prevents hypotension and ED. Presumed CB(1) antagonism promotes remodeling despite unchanged myocardial CB(1) expression.

Animals↗

PubMed2003

Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle.

Cannabinoids elicit hypotension mainly via activated CB(1) receptors and show complex cardiovascular actions. Effects on human heart muscle have not been studied yet. Isolated human atrial heart muscle preparations were stimulated by electrical field with 1 Hz to contract isometrically at optimal length and were challenged with the endogenous cannabinoid arachidonyl ethanolamide (anandamide), the metabolically stable analogue R-methanandamide, and the potent synthetic CB(1) receptor agonist HU-210. Anandamide dose-dependently decreased systolic force (82.2 +/- 4.8% and 60.8 +/- 6.8% of maximal systolic force for 0.1 and 1 microM, respectively, P < 0.05). The selective CB(1) receptor antagonist AM-251 (1 microM, P < 0.05), but not the CB(2) receptor antagonist, AM-630 (1 microM), the nitric oxide synthase inhibitor N omega-nitro-l-arginine methyl ester (l-NAME) (500 microM), or the cyclooxygenase inhibitor indomethacin (100 microM), prevented the effect. Contrary to indomethacin, l-NAME alone showed negative inotropic effects (72.1 +/- 3.54%, P < 0.001). The R-methanandamide (1 microM: 50.4 +/- 3.5%, P < 0.001) and HU-210 (1 microM: 60.1 +/- 3.8%, P < 0.001) had similar negative inotropic effects. The existence of CB(1) receptors on heart muscle was verified using Western blot analysis and immunofluorescence staining. The conclusion is that anandamide, R-methanandamide, and HU-210 decrease contractile performance in human atrial muscle via CB(1) receptors.

Atrial Function↗

PubMed2003

Retinal preconditioning and the induction of heat-shock protein 27.

PURPOSE: Brief periods of ischemia have been shown to protect the retina from potentially damaging periods of ischemia. This phenomenon has been termed ischemic preconditioning or ischemic tolerance. In the present study the cellular changes in levels of heat shock protein (Hsp)27, -70, and -90 mRNA and expression of Hsp in the rat retina associated with ischemic preconditioning were evaluated. METHODS: Unilateral retinal ischemia was created in Long-Evans and Sprague-Dawley rats for 5 minutes. Rats were then left for 1 hour to 7 days, to allow the retina to reperfuse. Retinas were dissected, the mRNA and protein isolated, and Northern and Western blot analyses conducted to detect changes in expression of Hsp27, -70, and -90. Immunohistochemical studies were used to identify retinal regions where Hsp changes occurred. Selected animals were subjected to a second ischemic event, 60 minutes in duration, to correlate the changes in expression of Hsp with functional protection of the retina from ischemic injury. RESULTS: In control and sham-treated animals retinal Hsp27, -70, and -90 mRNAs were detectable. Five hours after retinal preconditioning, levels of Hsp27 mRNA were elevated above control levels, and 24 hours later, mRNA levels increased 200% over basal levels. Hsp27 expression remained elevated for up to 72 hours and then began to return to control levels. Hsp27 protein levels were increased by 200% over basal levels 24 hours after retinal preconditioning, remained at this level for 72 hours, and then returned to control levels. In contrast, no consistent change in Hsp70 or -90 mRNA or protein levels was observed during the course of the study. Immunohistochemical studies demonstrated that the increase in expression of Hsp27 was localized to neuronal and non-neuronal cells in the inner layers of the retina. Electroretinography studies demonstrated a strong correlation between the protection of retinal function from ischemic injury and the expression of Hsp27. CONCLUSIONS: These results provide evidence that the induction of Hsp27 is a gene-specific event associated with ischemic preconditioning in the retina. This increase in expression of Hsp27 occurs in both neuronal and non-neuronal retinal cells, and appears to be one component of the neuroprotective events induced by ischemic preconditioning in the retina.

Animals↗

PubMed2002

c-Raf/MEK/ERK pathway controls protein kinase C-mediated p70S6K activation in adult cardiac muscle cells.

p70S6 kinase (S6K1) plays a pivotal role in hypertrophic cardiac growth via ribosomal biogenesis. In pressure-overloaded myocardium, we show S6K1 activation accompanied by activation of protein kinase C (PKC), c-Raf, and mitogen-activated protein kinases (MAPKs). To explore the importance of the c-Raf/MAPK kinase (MEK)/MAPK pathway, we stimulated adult feline cardiomyocytes with 12-O-tetradecanoylphorbol-13-acetate (TPA), insulin, or forskolin to activate PKC, phosphatidylinositol-3-OH kinase, or protein kinase A (PKA), respectively. These treatments resulted in S6K1 activation with Thr-389 phosphorylation as well as mammalian target of rapamycin (mTOR) and S6 protein phosphorylation. Thr-421/Ser-424 phosphorylation of S6K1 was observed predominantly in TPA-treated cells. Dominant negative c-Raf expression or a MEK1/2 inhibitor (U0126) treatment showed a profound blocking effect only on the TPA-stimulated phosphorylation of S6K1 and mTOR. Whereas p38 MAPK inhibitors exhibited only partial effect, MAPK-phosphatase-3 expression significantly blocked the TPA-stimulated S6K1 and mTOR phosphorylation. Inhibition of mTOR with rapamycin blocked the Thr-389 but not the Thr-421/Ser-424 phosphorylation of S6K1. Therefore, during PKC activation, the c-Raf/MEK/extracellular signal-regulated kinase-1/2 (ERK1/2) pathway mediates both the Thr-421/Ser-424 and the Thr-389 phosphorylation in an mTOR-independent and -dependent manner, respectively. Together, our in vivo and in vitro studies indicate that the PKC/c-Raf/MEK/ERK pathway plays a major role in the S6K1 activation in hypertrophic cardiac growth.

Adenoviridae↗