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Biomedical subjects

A Koller

Publications and source records attributed to A Koller.

At least 55 records · Page 3Linked to original sources
PubMed2001

Selected contribution: NO released to flow reduces myogenic tone of skeletal muscle arterioles by decreasing smooth muscle Ca(2+) sensitivity.

To clarify the contribution of intracellular Ca(2+) concentration ([Ca(2+)](i))-dependent and -independent signaling mechanisms in arteriolar smooth muscle (aSM) to modulation of arteriolar myogenic tone by nitric oxide (NO), released in response to increases in intraluminal flow from the endothelium, changes in aSM [Ca(2+)](i) and diameter of isolated rat gracilis muscle arterioles (pretreated with indomethacin) were studied by fluorescent videomicroscopy. At an intraluminal pressure of 80 mmHg, [Ca(2+)](i) significantly increased and myogenic tone developed in response to elevations of extracellular Ca(2+) concentration. The Ca(2+) channel inhibitor nimodipine substantially decreased [Ca(2+)](i) and completely inhibited myogenic tone. Dilations to intraluminal flow (that were inhibited by N(omega)-nitro-L-arginine methyl ester) or dilations to the NO donor S-nitroso-N-acetyl-DL-penicillamine (that were inhibited by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) were not accompanied by substantial decreases in aSM [Ca(2+)](i). 8-Bromoguanosine cGMP and the cGMP-specific phosphodiesterase inhibitor zaprinast significantly dilated arterioles yet elicited only minimal decreases in [Ca(2+)](i). Thus flow-induced endothelial release of NO elicits relaxation of arteriolar smooth muscle by a cGMP-dependent decrease of the Ca(2+) sensitivity of the contractile apparatus without substantial changes in the pressure-induced level of [Ca(2+)](i).

Animals↗
PubMed2001

Effect of estrogen on flow-induced dilation in NO deficiency: role of prostaglandins and EDHF.

To investigate the role of estrogen in flow-induced dilation (FiD) in nitric oxide (NO) deficiency, FiD was examined in isolated gracilis arterioles of ovariectomized (OVX) and OVX rats with estrogen replacement (OVE). Both groups of rats were treated chronically with N(omega)-nitro-L-arginine methyl ester. Plasma concentration of NO(2)/NO(3) was reduced in both groups. Plasma concentration of estradiol was lower in OVX than in OVE rats. FiD was similar in vessels of the two groups; calculated wall shear stress and basal tone were significantly greater in OVX vs. OVE rats. Indomethacin did not affect FiD in vessels from OVE rats but abolished dilation in vessels from OVX rats. Valeryl salicylate or NS-398 inhibited FiD by approximately 50%, whereas their simultaneous administration eliminated the response in arterioles from OVX rats. In vessels from OVE rats, miconazole or charybdotoxin eliminated FiD. Thus, in NO deficiency, prostaglandins derived from both cyclooxygenase isoforms mediate FiD in gracilis arterioles of OVX rats. Estrogen replacement switches the mediation, showing dependence on endothelium-derived hyperpolarizing factor in the arterioles of OVE rats.

Animals↗
PubMed2001

Flow-induced constriction in arterioles of hyperhomocysteinemic rats is due to impaired nitric oxide and enhanced thromboxane A(2) mediation.

Hyperhomocysteinemia (HHcy) is thought to promote arteriosclerosis and peripheral arterial disease, in part by impairing the function of endothelium. Because flow-induced dilation is mediated by the endothelium, we hypothesized that HHcy alters this response by interfering with the synthesis/action of NO and prostaglandins. Thus, changes in the diameter of isolated, pressurized (at 80 mm Hg) gracilis skeletal muscle arterioles (diameter approximately 170 microm) from control and methionine diet-induced HHcy rats were investigated with videomicroscopy. Increases in intraluminal flow (from 0 to 25 microL/min) resulted in dilations of control arterioles (maximum, 34+/-4 microm). In contrast, increases in flow elicited constrictions of HHcy arterioles (-36+/-3 microm). In control arterioles, the NO synthase inhibitor N:(omega)-nitro-L-arginine-methyl ester significantly attenuated (approximately 50%) dilation, whereas the additional administration of indomethacin, an inhibitor of cyclooxygenase, eliminated flow-induced dilation. In the arterioles of HHcy rats, flow-induced constriction was not affected by N:(omega)-nitro-L-arginine-methyl ester, whereas it was abolished by indomethacin or the prostaglandin H(2)/thromboxane A(2) (TXA(2)) receptor antagonist SQ 29,548 or the TXA(2) synthase inhibitor CGS 13,080. Thus, in HHcy, increases in intraluminal flow elicit constrictions of skeletal muscle arterioles due to the impaired NO and enhanced TXA(2) mediation of the response, alterations that likely contribute to the development of peripheral arterial disease.

Animals↗
PubMed2000

First ovulation and ketone body status in the early postpartum period of dairy cows.

The effect of ketone body status on occurrence of first ovulation during early lactation was assessed in 84 multiparous dairy cows under field conditions. Animals were equally distributed across 8 farms and were controlled by the same herd fertility monitoring program. Cows were visited twice antepartum and 6 times postpartum at weekly intervals between 5:30 and 8:30 AM. On these occasions, body condition scores and milk yields were measured, blood and milk samples were taken, cows were gynecologically examined, and parameters of reproduction were determined. The onset of first ovulation was specified by milk progesterone determination and rectal palpation. Cows starting postpartum ovarian cyclicity within or after 30 d were classified as early and late responders (ER and LR, respectively). Resumption of the estrous cycle within 30 d postpartum is considered optimal under practical conditions, and classification based on this threshold value resulted in groups of equal size and equal distribution of ER + LR cows within farms. Ketone bodies measured were beta-hydroxybutyrate in serum and acetoacetate and acetone in serum and milk. Blood serum and milk ketone body concentrations during the first 6 wk of lactation were higher in LR than in ER, whereas plasma glucose and nonesterified fatty acid and milk fat, protein and urea concentrations did not differ between groups. Maximal concentrations of ketone bodies from parturition to first ovulation were better predictors of the onset of the estrous cycle than mean or minimal concentrations over the same period. Milk acetone and serum beta-hydroxybutyrate concentrations provided the most reliable information with regard to resumption of ovarian activity of all ketone bodies.

3-Hydroxybutyric Acid↗
PubMed2000

Concentration of cardiac troponin I in a horse with a ruptured aortic regurgitation jet lesion and ventricular tachycardia.

An 18-year-old Thoroughbred gelding was evaluated because of sudden onset of ventricular tachycardia and signs of colic. Three years earlier, a diastolic decrescendo murmur, consistent with aortic regurgitation, had been detected, but the horse continued to perform well and compete successfully. Cardiac ultrasonographic examination revealed a defect in the interventricular septum below the aortic root, and serum concentrations of cardiac troponin I (cTnI) were higher than those measured in clinically normal horses. Repeated development of tachyarrhythmia during hospitalization prompted a decision to euthanatize the horse. A ruptured endocardial jet lesion below the aortic valve with formation of a cleft into the interventricular septum was found on necropsy. This report of increased serum cTnI concentrations in a horse with myocardial disease and our other findings suggest that assessment of cardiac troponin concentrations may be a useful tool in the evaluation of horses with suspected myocardial disease.

Animals↗
PubMed2000

The peroxin Pex19p interacts with multiple, integral membrane proteins at the peroxisomal membrane.

Pex19p is a protein required for the early stages of peroxisome biogenesis, but its precise function and site of action are unknown. We tested the interaction between Pex19p and all known Pichia pastoris Pex proteins by the yeast two-hybrid assay. Pex19p interacted with six of seven known integral peroxisomal membrane proteins (iPMPs), and these interactions were confirmed by coimmunoprecipitation. The interactions were not reduced upon inhibition of new protein synthesis, suggesting that they occur with preexisting, and not newly synthesized, pools of iPMPs. By mapping the domains in six iPMPs that interact with Pex19p and the iPMP sequences responsible for targeting to the peroxisome membrane (mPTSs), we found the majority of these sites do not overlap. Coimmunoprecipitation of Pex19p from fractions that contain peroxisomes or cytosol revealed that the interactions between predominantly cytosolic Pex19p and the iPMPs occur in the organelle pellet that contains peroxisomes. These data, taken together, suggest that Pex19p may have a chaperone-like role at the peroxisome membrane and that it is not the receptor for targeting of iPMPs to the peroxisome.

Binding Sites↗
PubMed2000

Renal oncocytoma with prominent intracytoplasmic vacuoles of mitochondrial origin.

AIMS: We observed two oncocytomas with prominent intracytoplasmatic vacuoles. To investigate if this previously undescribed finding is a diagnostic feature and compatible with the diagnosis of oncocytoma, we characterized these vacuoles by electron microscopy and immunohistochemistry. METHODS AND RESULTS: The tumours were analysed by transmission electron microscopy. Immunohistochemistry was performed with antimitochondrial antibody, anti-Golgi-zone antibody, anti-lysozyme antibody and anti-human-trans-Golgi-network antibody. By electron microscopy, the vacuoles were found to be double-membrane-bounded, and some contained fragmented christae. Immunohistochemistry showed a positive reaction of the vacuoles with anti-mitochondrial antibody. Staining with anti-Golgi-zone antibody, anti-lysozyme antibody and anti-human-trans-Golgi-network antibody was negative. CONCLUSION: Both tumours are benign oncocytomas. The phenomena of cells with prominent intracytoplasmatic vacuoles is not inconsistent with the diagnosis of oncocytoma. The vacuoles are of mitochondrial origin and may develop, by balloon degeneration, as a mechanism of mitochondrial involution and elimination.

Adenoma, Oxyphilic↗
PubMed2000

Oral creatine supplementation in Duchenne muscular dystrophy: a clinical and 31P magnetic resonance spectroscopy study.

The decrease in intracellular creatine concentration in Duchenne muscular dystrophy may contribute to the deterioration of intracellular energy homeostasis and may thus be one of the factors aggravating muscle weakness and degeneration. Oral creatine supplementation should have potential in alleviating the clinical symptoms. To test this hypothesis, creatine was orally administered over a period of 155 days to a 9-year-old patient with Duchenne muscular dystrophy. In accordance with previous investigations on normal subjects and trained athletes, the patient experienced improved muscle performance during creatine supplementation. Further evidence supporting this hypothesis derived from plasma creatine kinase and lactate dehydrogenase activities and repeated 31P magnetic resonance spectroscopy of the gastrocnemius muscle. These preliminary observations indicate a potential role for creatine supplementation in the symptomatic therapy of patients with muscle disease.

Administration, Oral↗
PubMed2000

Serotonin reuptake inhibitor fluoxetine decreases arteriolar myogenic tone by reducing smooth muscle [Ca2+]i.

Previous studies showed that the serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine (Prozac) dilates skeletal muscle and cerebral arterioles independent of the endothelium. We hypothesized that fluoxetine affects the contractile activity of arteriolar smooth muscle by interfering with Ca2+ signaling pathways. The effects of fluoxetine on pressure-induced tone of isolated rat skeletal muscle arterioles (approximately 110 microm) were investigated by videomicroscopy. Changes in smooth muscle [Ca2+]i were measured simultaneously by the fura-2 ratiometric method. Elevation of intraluminal pressure (from 20 to 120 mm Hg) increased (by approximately 20%) the smooth muscle calcium fluorescence ratio (R(Ca)) and resulted in a significant myogenic constriction (approximately 40%). Fluoxetine and nifedipine significantly decreased R(Ca) (by approximately 30%) and abolished pressure-induced arteriolar tone (EC50, 3.1 x 10(-6) and 6.0 x 10(-9) M, respectively). Constrictions to the L-type Ca2+ channel opener Bay K 8644 also were inhibited and abolished by increasing doses of fluoxetine (3 x 10(-6) and 10(-5) M, respectively). In the presence of 10(-5) M fluoxetine, a concentration that elicited submaximal (approximately 80%) dilation, elevation of extracellular Ca2+ concentration (from 2.5 to 15 mM) normalized R(Ca) and restored arteriolar myogenic tone. Thus, fluoxetine reduces [Ca2+]i and tone of arteriolar smooth muscle, likely by interfering with Ca2+ entry. We speculate that the "calcium antagonist" effect of fluoxetine may be an additional element in the therapeutic actions of this drug.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Import of peroxisomal matrix and membrane proteins.

This review summarizes the progress made in our understanding of peroxisome biogenesis in the last few years, during which the functional roles of many of the 23 peroxins (proteins involved in peroxisomal protein import and peroxisome biogenesis) have become clearer. Previous reviews in the field have focussed on the metabolic functions of peroxisomes, aspects of import/biogenesis the role of peroxins in human disease, and involvement of the endoplasmic reticulum in peroxisome membrane biogenesis as well as the degradation of this organelle. This review refers to some of the earlier work for the sake of introduction and continuity but deals primarily with the more recent progress. The principal areas of progress are the identification of new peroxins, definition of protein-protein interactions among peroxins leading to the recognition of complexes involved in peroxisomal protein import, insight into the biogenesis of peroxisomal membrane proteins, and, of most importance, the elucidation of the role of many conserved peroxins in human disease. Given the rapid progress in the field, this review also highlights some of the unanswered questions that remain to be tackled.

Biological Transport, Active↗
PubMed2000

Reduced NO-dependent arteriolar dilation during the development of cardiomyopathy.

Our previous studies have suggested that there is reduced nitric oxide (NO) production in canine coronary blood vessels after the development of pacing-induced heart failure. The goal of these studies was to determine whether flow-induced NO-mediated dilation is altered in coronary arterioles during the development of heart failure. Subepicardial coronary arterioles (basal diameter 80 microm) were isolated from normal canine hearts, from hearts with dysfunction but no heart failure, and from hearts with severe cardiac decompensation. Arterioles were perfused at increasing flow or administered agonists with no flow in vitro. In arterioles from normal hearts, flow increased arteriolar diameter, with one-half of the response being NO dependent and one-half prostaglandin dependent. Shear stress-induced dilation was eliminated by removing the endothelium. Arterioles from normal hearts and hearts with dysfunction but no failure responded to increasing shear stress with dilation that reached a maximum at a shear stress of 20 dyn/cm(2). In contrast, arterioles from failing hearts showed a reduced dilation, reaching only 55% of the dilation seen in vessels of normal hearts at a shear stress of 100 dyn/cm(2). This remaining dilation was eliminated by indomethacin, suggesting that the NO-dependent component was absent in coronary microvessels after the development of heart failure. Similarly, agonist-induced NO-dependent coronary arteriolar dilation was markedly attenuated after the development of heart failure. After the development of severe dilated cardiomyopathy and heart failure, the NO-dependent component of both shear stress- and agonist-induced arteriolar dilation is reduced or entirely absent.

Animals↗
PubMed2000

In eNOS knockout mice skeletal muscle arteriolar dilation to acetylcholine is mediated by EDHF.

The mechanisms that account for acetylcholine (ACh)-induced responses of skeletal muscle arterioles of mice lacking endothelial nitric oxide (NO) synthase (eNOS-KO) were investigated. Isolated, cannulated, and pressurized arterioles of gracilis muscle from male eNOS-KO (74.1 +/- 2.3 microm) and wild-type (WT, 87.2 +/- 2.1 microm) mice developed spontaneous tone accounting for 63 and 61% of their passive diameter (116.8 +/- 3.4 vs. 143.2 +/- 2.8 microm, respectively) and dilated dose-dependently to ACh (10(-9)-10(-7) M). These dilations were significantly smaller in vessels of eNOS-KO compared with WT mice (29.2 +/- 2.0 microm vs. 46.3 +/- 2.1 microm, at maximum concentration) but responses to the NO donor, sodium nitrite (NaNO(2), 10(-6)-3 x 10(-5) M), were comparable in the vessels of the two strains. N(G)-nitro-L-arginine (L-NNA, 10(-4) M), an inhibitor of eNOS, inhibited ACh-induced dilations by 60-90% in arterioles of WT mice but did not affect responses in those of eNOS-KO mice. In arterioles of eNOS-KO mice, dilations to ACh were not affected by indomethacin but were essentially abolished by inhibitors of cytochrome P-450, clotrimazole (CTZ, 2 x 10(-6) M) or miconazole (MCZ, 2 x 10(-6) M), as well as by either high K(+) (40 mM) or iberiotoxin [10(-7) M, a blocker of Ca(2+)-dependent K(+) channels (K(Ca) channels)]. On the other hand, in WT arterioles CTZ or MCZ inhibited ACh-induced dilations only by approximately 10% and only in the presence of L-NNA. These results indicate that in arterioles of eNOS-KO mice, endothelium-derived hyperpolarizing factor (EDHF), synthesized via cytochrome P-450, accounts entirely for the mediation of ACh-induced dilation via an increase in K(Ca)-channel activity. In contrast, in arterioles of WT mice, endothelium-derived NO predominantly mediates ACh-induced dilation in which participation of EDHF becomes apparent only after inhibition of NO synthesis.

Acetylcholine↗
PubMed2000

Hyperosmolality dilates rat skeletal muscle arterioles: role of endothelial K(ATP) channels and daily exercise.

The purpose of this study was to investigate the mechanism underlying arteriolar responses to hyperosmolality and to determine the effects of daily exercise on this response. Dilator responses were measured in isolated, cannulated, and pressurized skeletal muscle arterioles. Osmolality was increased from approximately 290 to 330 mosmol/kgH(2)O by adding glucose, sucrose, or mannitol to the superfusion solution. All three compounds elicited similar changes in vessel diameter, suggesting that this response was due to changes in osmolality. Responses to glucose were abolished by endothelium removal but were not altered in endothelium-intact vessels by superfusion with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine or the cyclooxygenase inhibitor indomethacin. In endothelium-intact arterioles, responses to glucose superfusion with the ATP-sensitive potassium (K(ATP)) channel inhibitor glibenclamide; however, intraluminal perfusion with glibenclamide nearly abolished the responses to glucose and mannitol. Intraluminal administration of glucose elicited a significantly greater dilation than extraluminal glucose. The response to intraluminal glucose was also inhibited by intraluminal glibenclamide. Four weeks of daily exercise did not significantly alter the responses to hyperosmolality in gracilis or soleus muscle arterioles. These data demonstrate that physiological increases in intraluminal osmolality dilate rat skeletal muscle arterioles via activation of endothelial K(ATP) channels; however, this endothelium-dependent response is not augmented by daily exercise.

Adenosine Triphosphate↗
PubMed2000

Simultaneously increased TxA(2) activity in isolated arterioles and platelets of rats with hyperhomocysteinemia.

We aimed to elucidate the effect of hyperhomocysteinemia (HHcy) on the synthesis of prostaglandins in rat skeletal muscle arterioles and platelets. Male Wistar rats were divided into 2 groups: (1) control rats, with plasma Hcy levels of 6.5+/-0.5 micromol/L (n=50) and (2) rats with HHcy, induced by daily intake of 1 g/kg body weight methionine in the drinking water for 4 weeks (plasma Hcy levels were 20.6+/-3.0 micromol/L, P<0.01 versus controls; n=50). Arterioles (diameter approximately 130 micrometer) were isolated from the gracilis muscle, cannulated, and pressurized (at 80 mm Hg), and changes in their diameters were followed by video microscopy. Constrictions to bradykinin (BK; 10(-10) to 10(-7) mol/L) were significantly greater in HHcy than in control rat arterioles (at 10(-9) mol/L BK, changes were 11+/-3% in control and 41+/-9% in HHcy rats). The cyclooxygenase inhibitor indomethacin (10(-5) mol/L), the prostaglandin H(2)/thromboxane A(2) (PGH(2)/TxA(2)) receptor antagonist SQ 29,548 (10(-6) mol/L), or the TxA(2) synthase inhibitor furegrelate (5x10(-6) mol/L) significantly decreased constrictions to BK in both groups but more so in HHcy arterioles, thus eliminating the difference between responses of HHcy and control arterioles. Constrictions to U46619 (a TxA(2) analogue) were significantly greater in HHcy than in control arterioles (at 10(-8) mol/L U46619, values for controls were 33+/-2% and 54+/-3% for HHcy). Endothelium removal or indomethacin treatment attenuated constrictions to U46619 in HHcy arterioles and eliminated the difference in responses. Also, aggregation of platelets from HHcy rats to collagen and ADP was significantly enhanced compared with controls (with 5 microgram/mL collagen: controls, 23+/-5%; HHcy, 49+/-5%; with 10(-7) mol/L ADP: controls, 25+/-3%; HHcy, 35+/-3%). Indomethacin or SQ 29,548 caused greater inhibition of aggregation of HHcy platelets compared with controls, thereby eliminating the differences between the 2 groups. Thus, HHcy enhances TxA(2) synthesis both in the arteriolar endothelium and platelets. By promoting vascular constriction and platelet aggregation simultaneously, these alterations are likely to contribute to the atherothrombotic vascular diseases described in HHcy.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Shear stress-induced release of prostaglandin H(2) in arterioles of hypertensive rats.

The nitric oxide-mediated portion of shear stress-induced dilation of rat gracilis muscle arterioles was shown to be impaired in spontaneously hypertensive rats (SHR). Because shear stress-induced dilation is primarily mediated by endothelium-derived prostaglandins in rat cremasteric arterioles, we hypothesized that in the cremasteric vascular bed the mediation of shear stress-induced dilation by prostaglandins is altered in hypertension. At a constant intraluminal pressure of 80 mm Hg, the active diameters of isolated rat cremasteric arterioles of normotensive 30-week-old Wistar-Kyoto rats (WKY) and SHR were 58.0+/-3.1 and 51.7+/-3.6 microm, respectively, whereas their passive diameters were 109.4+/-4.4 and 101.9+/-6.7 microm, respectively. Dilations to increases in shear stress elicited by increases in intraluminal flow (from 0 to 25 microL/min) were significantly less (P<0.05) in cremasteric arterioles isolated from SHR than from WKY. Arachidonic acid (10(-5) mol/L) elicited constrictions in SHR arterioles but dilations in WKY arterioles. The prostaglandin H(2)/thromboxane A(2) (PGH(2)/TxA(2)) receptor antagonist SQ 29,548 (10(-6) mol/L) significantly increased basal diameter by 11% and normalized the attenuated shear stress-induced dilation in SHR, whereas it did not affect basal diameter and arteriolar responses of WKY. Furegrelate, a specific inhibitor of TxA(2) synthase, did not affect the response in SHR. Also, SQ 29,548 reversed the arachidonic acid-induced constriction to dilation in SHR arterioles, whereas it did not affect the dilator response in WKY arterioles. Constrictions of arterioles of WKY and SHR to U46,619 (a PGH(2)/TxA(2) receptor agonist) were not different. These results demonstrate that in cremasteric arterioles of hypertensive rats, shear stress elicits an enhanced release of PGH(2), resulting in a reduced shear stress-dependent dilation. Thus, augmented hemodynamic forces can alter the shear stress-induced synthesis of prostaglandins, which may contribute to the elevated vascular resistance in hypertension.

Animals↗