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Biomedical subjects

H R Weiss

Publications and source records attributed to H R Weiss.

At least 19 recordsLinked to original sources
PubMed2006

'SOSORT consensus paper on brace action: TLSO biomechanics of correction (investigating the rationale for force vector selection)'.

BACKGROUND: The effectiveness of orthotic treatment continues to be controversial in international medical literature due to differences in the reported results and conclusions of various studies. Heterogeneity of the samples has been suggested as a reason for conflicting results. Besides the obvious theoretical differences between the brace concepts, the variability in the technical factors can also explain the contradictory results between same brace types. This paper will investigate the degree of variability among responses of scoliosis specialists from the Brace Study Ground of the International Society on Scoliosis Orthopedic and Rehabilitation Treatment SOSORT. Ultimately, this information could be a foundation for establishing a consensus and framework for future prospective controlled studies. METHODS: A preliminary questionnaire on the topic of 'brace action' relative to the theory of three-dimensional scoliosis correction and brace treatment was developed and circulated to specialists interested in the conservative treatment of adolescent idiopathic scoliosis. A particular case was presented (main thoracic curve with minor lumbar). Several key points emerged and were used to develop a second questionnaire which was discussed and full filed after the SOSORT consensus meeting (Milano, Italy, January 2005). RESULTS: Twenty-one questionnaires were completed. The Chêneau brace was the most frequently recommended. The importance of the three point system mechanism was stressed. Options about proper pad placement on the thoracic convexity were divided 50% for the pad reaching or involving the apical vertebra and 50% for the pad acting caudal to the apical vertebra. There was agreement about the direction of the vector force, 85% selecting a 'dorso lateral to ventro medial' direction but about the shape of the pad to produce such a force. Principles related to three-dimensional correction achieved high consensus (80%-85%), but suggested methods of correction were quite diverse. CONCLUSION: This study reveals that among participating SOSORT specialists there continues to be a strongly held and conflicting if not a contentious opinion regarding brace design and treatment. If the goal of a 'treatment consensus' is realistic and achievable, significantly more effort will be required to reconcile these differences.

Journal Article↗
PubMed2006

Effects of 17beta-estradiol on blood-brain barrier disruption during focal cerebral ischemia in younger and older rats.

This study was performed to compare the effects of 17beta-estradiol on blood-brain barrier disruption in focal cerebral ischemia between younger and older rats. Younger (three-month-old) and older (24-month-old) ovariectomized female Fischer 344 rats were studied. In one half of each age group, a 500 microg 17beta-estradiol 21-day release pellet and in another half, a vehicle pellet was implanted 21 days before the experiments. One hour after middle cerebral artery occlusion, the transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid and the volume of 3H-dextran distribution were determined to examine the degree of blood-brain barrier disruption. In all four groups, the Ki in the ischemic cortex was higher than in the corresponding contralateral cortex. There was no significant difference in the Ki in both cortices among the groups. The volume of dextran distribution of the ischemic cortex was only greater than in the corresponding contralateral cortex in the older 17beta-estradiol-treated group, and the volume of that group was greater than the younger 17beta-estradiol-treated group (4.00 +/- 1.29 VS. 2.13 +/- 0.88 ml/100 g). After analyzing the difference in Ki between the ischemic cortex and the contralateral cortex in each animal, the difference was significantly greater in the older 17beta-estradiol-treated rats than the older vehicle-treated rats (3.40 +/- 2.10 VS. 1.26 +/- 1.44 microl/g/min). In the younger rats, however, 17beta-estradiol did not significantly affect the difference. Our data showed that 17beta-estradiol treatment failed to attenuate the BBB disruption in the cerebral ischemic cortex in the older or younger Fischer 344 rats. However, our data also suggest the possibility that 17beta-estradiol could aggravate the BBB disruption in older rats.

Aging↗
PubMed2005

Effects of 17beta-estradiol on blood-brain barrier disruption in focal ischemia during GABA(A) receptor inhibition.

We performed this study to determine whether gamma-aminobutyric acid (GABA(A)) receptor inhibition could reverse the effect of 17beta-estradiol on blood-brain barrier (BBB) disruption in focal cerebral ischemia. Young ovariectomized rats were implanted with a 500 microg 17beta-estradiol 21-day release pellet or with a vehicle pellet 21 days before the experiments. Forty-five minutes after middle cerebral artery (MCA) occlusion, half of each group was infused with bicuculline (a GABA(A) receptor antagonist) 1 mg/kg/min for 2 min followed by 0.1 mg/kg/min up to the end of experiments. The other half was infused with the same volume of normal saline. The transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid and the volume of 3H-dextran distribution (70,000 Daltons) were determined to measure the degree of BBB disruption one hour after MCA occlusion. In the control vehicle-treated animals, the Ki in the ischemic cortex (7.2 +/- 2.6 microl/g/min) was higher than in the contralateral cortex (2.5 +/- 1.4 microl/g/min). After bicuculline infusion, the Ki in the ischemic cortex increased (10.6 +/- 5.4 microl/g/min) although the increase was not statistically significant. In the 17beta-estradiol treated animals, the Ki in the ischemic cortex (3.8 +/- 1.6 microl/g/min) was lower than control vehicle-treated rats. With bicuculline infusion, the Ki in the ischemic cortex (14.5 +/- 6.8 microl/g/min) was markedly increased. In the non-ischemic cortex, there was no significant difference in Ki among the experimental groups. The volume of dextran distribution was not significantly different between the experimental groups in the ischemic or non-ischemic cortex. Our data suggests that part of the reason for the decreased BBB disruption in the focal ischemic area after 17beta-estradiol treatment could be due to the interaction between GABA(A) receptors and 17beta-estradiol.

Algorithms↗
PubMed2004

17beta-estradiol prevents blood-brain barrier disruption induced by VEGF.

We performed this study to determine how pretreatment of the ovariectomized rats with 17beta-estradiol could affect blood-brain barrier disruption caused by the vascular endothelial growth factor (VEGF), an important mediator of vascular permeability. Ovariectomized female rats aged twelve to fourteen weeks were used in the study. A 500 micro g 17beta-estradiol 21-day release pellet was implanted in the 17beta-estradiol group, and a vehicle pellet was implanted in the control group 21 days before the experiments. We performed three craniotomies under isoflurane anesthesia to expose cerebral cortices. Normal saline, 10 (- 10)M and 10 (- 9)M VEGF patches were applied on each hole for 30 min. The transfer coefficient (Ki) of (14)C-alpha-amino isobutyric acid and volume of (3)H-dextran (70,000 dalton) distribution were determined to measure the degree of BBB disruption. Ki was increased by 108 % and 138 % with 10 (- 10)M and 10 (- 9)M VEGF respectively after VEGF application in the control group (p < 0.01). However, there was no significant increase in the Ki with the VEGF application in the 17beta-estradiol group, and their values were significantly lower than the corresponding data of the control group (10 (- 10)M: - 55 %, 10 (- 9)M: - 52 %, p <0.05). The volume of dextran distribution in the control group increased by 47 % with VEGF 10 (- 9)M (p < 0.05), whereas there was no significant change in the volume of dextran distribution with VEGF application in the 17beta-estradiol group and the volume was lower than the corresponding volume of the vehicle-treated control group (10 (- 10)M: - 34 %, 10 (- 9)M: -32 %, p < 0.05). In conclusion, our study demonstrated that chronic 17beta-estradiol treatment prevented BBB disruption induced by the VEGF in the ovariectomized rats.

Animals↗
PubMed2002

Effects of 17beta-estradiol on blood-brain barrier disruption during focal ischemia in rats.

This study was performed to test whether 17beta-estradiol could attenuate the blood-brain barrier disruption caused by middle cerebral artery occlusion in the ovariectomized rats. Rats aged twelve to fourteen weeks were used in this study. Their ovaries were removed one week prior to the implantation of the pellets. For the 17beta-estradiol group, a 500 microg 17beta-estradiol 21 day-release pellet was implanted and for the control group, a vehicle pellet was implanted 21 days before the experiments. One hour after middle cerebral artery occlusion under isoflurane anesthesia, the transfer coefficient of 14C-alpha-aminoisobutyric acid (104 Daltons) and the volume of 3H-dextran (70,000 Daltons) distribution were determined to represent the degree of blood-brain barrier disruption. Blood pressures and blood gases were similar between controls and 17beta-estradiol-treated rats. In both groups, the transfer coefficient of the ischemic cortex was higher than that of the corresponding contralateral cortex (control: Ischemic Cortex 12.5 +/- 5.9 microl/g/min, Contralateral Cortex 3.0 +/- 1.6, p < 0.001; 17beta-estradiol: Ischemic Cortex 6.7 +/- 3.3 micro l/g/min, Contralateral Cortex 2.2 +/- 0.9, p < 0.01). There was no significant difference in the transfer coefficient of the contralateral cortex between these two groups. However, the transfer coefficient of the Ischemic Cortex of the 17beta-estradiol-treated animals was 46 % lower than that of the control, vehicle-treated rats (p < 0.05). The increase of the volume of 3H-dextran distribution with middle cerebral artery occlusion was significant in the vehicle-treated rats (Ischemic Cortex: 6.4 +/- 2.7 ml/100 g, Contralateral Cortex: 3.8 +/- 0.8, p < 0.01) but not in the 17beta-estradiol-treated animals. Our data suggest that chronic 17beta-estradiol treatment was effective in reducing blood-brain barrier disruption during focal ischemia in the ovariectomized rats.

Aminoisobutyric Acids↗
PubMed2001

Interaction between cyclic GMP protein kinase and cyclic AMP may be diminished in stunned cardiac myocytes.

We tested the hypothesis that the importance of the negative functional effects of the cyclic GMP protein kinase would be reduced in stunned (simulated ischemia/reperfusion) cardiac myocytes. Ventricular cardiac myocytes were isolated from New Zealand white rabbits (N=7). Myocytes were studied at baseline and after simulated ischemia (15 min of 95% N(2)-5% CO(2) at 37 degrees C) followed by simulated reperfusion (reoxygenation). Cell shortening was studied with a video edge detector; O(2) consumption was measured using O(2) electrodes. Protein phosphorylation was measured autoradiographically after gel electrophoresis. Functional and metabolic data were acquired after: (1) 8-(4-chlorophenylthio)guanosine-3',5'-monophosphate (PCPT, cGMP protein kinase agonist) 10(-7) or 10(-5) M; (2) 8-Br-cAMP 10(-5) M followed by PCPT 10(-7) or 10(-5) M; (3) beta-phenyl-1, N(2)-etheno-8-bromoguanosine-3',5'-monophosphorothioate, SP-isomer (SP, cGMP protein kinase agonist) 10(-7) or 10(-5) M; (2) 8-Br-cAMP 10(-5) M followed by SP 10(-7) or 10(-5) M. At baseline, percent of shortening (Pcs) and maximal rate of shortening (Rs) were significantly lower in the stunned myocytes (Pcs: 5.0+/-0.2% control vs. 3.8+/-0.3 stunned; Rs: 64.8+/-5.9 microm/s control vs. 46.9+/-4.8 stunned). In both groups, PCPT and SP dose-dependently decreased Pcs and Rs. The effects were slightly, but not significantly, less in stunned myocytes. 8-Br-cyclic AMP significantly increased function in control, but not stunned myocytes (Pcs, 4.5+/-0.5 to 6.2+/-0.8 control vs. 3.1+/-0.2 to 3.6+/-0.2 stunned). The negative functional effects of PCPT and SP were diminished after 8-Br-cyclic AMP in control (from -39% to-29%) and diminished significantly more in the stunned myocytes (-19%). PCPT and cyclic AMP phosphorylated similar protein bands. In stunned myocytes, three (22, 31 and 53 kDa) bands were enhanced less by PCPT.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Effects of endothelin-1 on blood-brain barrier permeability during focal cerebral ischemia in rats.

The purpose of this study was to determine whether the transport of small hydrophilic molecules across the blood-brain barrier (BBB) during focal cerebral ischemia could be altered by a topical application of endothelin-1 (ET-1) in the ischemic cortex (IC). Forty minutes after middle cerebral artery (MCA) occlusion, patches of 10 nM ET-1 (low-endothelin group), 100 nM ET-1 (high-endothelin group), or normal saline (control group) were placed on the IC of rats for a 20-min period. One hour after MCA occlusion, transfer coefficient (Ki) of [14C-alpha-]aminoisobutyric acid (14C-AIB) or regional cerebral blood flow (rCBF) was determined. Vital signs were not significantly different among the experimental groups. In the control group (n=8), the Ki of the IC was significantly higher than that of the contralateral cortex (CC; 11.9+/-5.8 vs 5.0+/-1.9 microl/g per minute). In the low-endothelin group (n=8), the Ki of the IC was still significantly higher than that of the CC (9.4+/-5.2 vs 5.3+/-2.5 microl/g per minute). However, in the High-endothelin group (n=8), the Ki of the IC was not different from that of the CC (6.9+/-2.1 vs 5.6+/-2.3 microl/g per minute) and 42% lower than that of the control group. The rCBF was not affected by 100 nM of ET-1 [control (n=6): IC 53+/-18 ml/100 g per minute, CC 94+/-23 ml/100 g per minute; high-endothelin (n=6): IC 49+/-15 ml/100 g per minute, CC 98+/-24 ml/100 g per minute]. Our data suggest that the application of endothelin-1 in the IC could reduce the transfer coefficient of small hydrophilic molecules across the BBB during focal ischemia.

Animals↗
PubMed2001

Interaction between the opposing functional effects of cyclic AMP and cyclic GMP in hypertrophic cardiac myocytes.

We tested the hypothesis that in isolated cardiac myocytes, the negative functional effects of cyclic GMP would be blunted when the level of cyclic AMP was increased and that this interaction would be altered in renal hypertensive (One-Kidney-One-Clip, 1K1C) cardiac hypertrophic rabbits. Using isolated control and 1K1C ventricular myocytes, cyclic AMP and cell shortening (%) data were collected: 1) at baseline, 2) after the addition of 8-Br-cGMP 10(-7), -6, -5 M, and 3) after forskolin (10(-6) M), an adenylate cyclase activator, followed by 8-Br-cGMP 10(-7), -6, -5 M. Basal levels of cyclic AMP were similar in control vs. 1K1C myocytes (10.2 +/- 1.6 vs. 11.3 +/- 2.6 pmol/10(5) myocytes). We found that 8-Br-cGMP decreased the percent shortening in a dose related manner in both control myocytes (5.1 +/- 0.6 to 3.2 +/- 0.4%) and hypertrophic myocytes (5.2 +/- 0.4 to 3.6 +/- 0.5). The level of cyclic AMP significantly increased after the addition of 8-Br-cGMP in control myocytes (14.1 +/- 2.1), but not in 1K1C myocytes. Forskolin increased the percent shortening in the control myocytes (3.8 +/- 0.1 to 4.8 +/- 0.4), but no significant increase was noted in the hypertrophic myocytes (3.6 +/- 0.3 to 3.7 +/- 0.3). The level of cyclic AMP significantly increased after the addition of forskolin in both control (13.9 +/- 2.0), and 1K1C cells (14.6 +/- 3.8). Forskolin attenuated the negative functional effects of 8-Br-cGMP in the control (4.8 +/- 0.4 to 3.2 +/- 0.1) and 1K1C myocytes (3.7 +/- 0.3 to 2.7 +/- 0.3). The addition of 8-Br-cGMP did not affect the level of cyclic AMP after forskolin in either control (13.9 +/- 2.0 to 14.8 +/- 2.5) or 1K1C myocytes (14.6 +/- 3.8 to 13.8 +/- 1.9). These data indicated that in hypertrophic cardiac myocytes the negative functional effects of 8-Br-cGMP were similar to control, but the positive functional effects of cyclic AMP were blunted. There was an increase in cyclic AMP levels after addition of 8-Br-cGMP in control but not 1K1C cells. We conclude that in control and hypertrophic myocytes, the effects of cyclic GMP were blunted after forskolin, but this did not seem to be related to cyclic AMP phosphodiesterase activity.

Animals↗
PubMed2001

Effects of mild hypothermia on blood-brain barrier disruption during isoflurane or pentobarbital anesthesia.

BACKGROUND: This study was performed to determine whether mild hypothermia (32 degrees C) could attenuate the degree of blood-brain barrier (BBB) disruption caused by a hyperosmolar solution and whether the degree of disruption would vary depending on anesthetic agents. METHODS: Rats were assigned to one of four groups: normothermic isoflurane, normothermic pentobarbital, hypothermic isoflurane, and hypothermic pentobarbital. During isoflurane (1.4%; normothermic or hypothermic) or pentobarbital (50 mg/kg administered intraperitoneally; normothermic or hypothermic) anesthesia, the external carotid artery and the femoral artery and vein were catheterized. Body temperature was maintained at 37 and 32 degrees C for the normothermic and hypothermic groups, respectively. To open the BBB, 25% mannitol was infused through the right carotid artery at the rate of 0.25 ml x kg(-1) x s(-1) for 30 s. The transfer coefficient of 14C-alpha-aminoisobutyric acid was determined. RESULTS: Blood pressure was similar among the four groups of animals. The degree of the BBB disruption by hyperosmolar mannitol was less with isoflurane than pentobarbital anesthesia in the normothermic groups (transfer coefficient: 29.9 +/- 17.1 and 50.4 +/- 17.5 microl x g(-1) x min(-1) for normothermic isoflurane and pentobarbital, respectively; P < 0.05). Mild hypothermia decreased the BBB disruption during anesthesia with both anesthetic agents (hypothermic isoflurane: 9.8 +/- 8.3 microl x g(-1) x min(-1), P < 0.05 vs. normothermic isoflurane; hypothermic pentobarbital: 30.2 +/- 13.9 microl x g(-1) x min(-1), P < 0.05 vs. normothermic pentobarbital), but the disruption was less during isoflurane anesthesia (hypothermic isoflurane vs. hypothermic pentobarbital, P < 0.005). In the contralateral cortex, there were no significant differences among these four experimental groups. CONCLUSIONS: The data demonstrated that hypothermia was effective in attenuating BBB disruption by hyperosmolar mannitol during isoflurane as well as pentobarbital anesthesia. The degree of disruption appeared smaller during isoflurane than during pentobarbital anesthesia in both the normothermic as well as the hypothermic groups.

Algorithms↗
PubMed2001

Ethanol-induced reduction in myocardial oxygen consumption can be attenuated by inhibiting guanylyl cyclase.

We tested the hypothesis that low-dose ethanol-induced reductions in myocardial metabolism were related to increased cyclic guanosine monophosphate (GMP). Anesthetized open chest rabbits were divided into four groups: control (Ringers lactate and vehicle), ETOH (250 mg/kg i.v. ethanol and vehicle), ODQ (Ringers lactate and 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ 10(-4) M ), and ETOH-ODQ (ethanol and ODQ). ODQ, a soluble guanylyl cyclase inhibitor, or vehicle was applied topically to the epicardium for 15 min, while either Ringers lactate or ethanol was administered intravenously. Oxygen consumption (VO2 ) in both the subepicardium (EPI) and subendocardium (ENDO) was determined from coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry). Cyclic GMP was determined by radioimmunoassay. ETOH significantly decreased VO2 in the subepicardium (9.2 +/- 1.0-5.6 +/- 0.7 ml O2 /min/100 g) and subendocardium (9.7 +/- 0.8-7.1 +/- 0.8) and increased cyclic GMP in the subepicardium (10.2 +/- 1.7-13.8 +/- 0.8 pmol/g) and subendocardium (11.0 +/- 0.5-13.7 +/- 0.9). With ODQ, there was no significant change in the subepicardial (9.5 +/- 1.3) or subendocardial (9.0 +/- 0.9) VO2. However, ODQ caused a significant increase in both wall thickening (12.9 +/- 0.9-17.2 +/- 1.2%) and maximal rate of change in wall thickness (10.8 +/- 0.9-16.3 +/- 1.9 mm/s) and decreased subepicardium (8.3 +/- 1.3) and subendocardium (7.8 +/- 1.2) cyclic GMP. The ETOH-ODQ group had cyclic GMP (subepicardium 9.0 +/- 1.8, subendocardium 8.6 +/- 2.4) and VO2 (subepicardium 7.9 +/- 0.5, subendocardium 8.4 +/- 0.4) values similar to control. Thus, the ethanol-induced rise in cyclic GMP was associated with a decrease in myocardial O2 consumption. When this rise was blocked with a soluble guanylyl cyclase inhibitor, the reduction in metabolic demand was also eliminated. This demonstrated that the alcohol-induced reduction in myocardial metabolism was related to increased cyclic GMP and suggests a novel mechanism for the effect of ethanol.

Administration, Topical↗
PubMed2001

Nitric oxide and cGMP protein kinase activity in aged ventricular myocytes.

We tested the hypothesis that nitric oxide-induced negative functional effects through cGMP would be reduced in aged cardiac myocytes. Maximum rate of shortening (R(max)) and percent shortening of ventricular myocytes from young (6 mo) and old (3 y) rabbits were studied using a video edge detector. cGMP-dependent phosphorylation was examined by electrophoresis and autoradiography. Myocytes received a nitric oxide donor S-nitroso-N-acetyl-penicillamine (SNAP, 10(-7), 10(-6), and 10(-5) M) followed by KT-5823 (10(-6) M), a cGMP protein kinase inhibitor. Baseline function was similar in young and old myocytes (89.1 +/- 4.5 young vs. 86.4 +/- 8.3 microm/s old R(max), 5.6 +/- 0.3 vs. 5.2 +/- 0.7%shortening). SNAP (10(-5) M) decreased R(max) in both young (25%, n = 6) and old myocytes (24%, n = 7). SNAP also reduced percent shortening by 28% in young and 23% in old myocytes. The negative effects of SNAP were partially reversed by KT-5823 only in young myocytes. Multiple proteins were phosphorylated by cGMP, and KT-5823 could reduce this effect. The degree of phosphorylation was significantly less in old myocytes. These results suggest that the functional response of ventricular myocytes to nitric oxide was preserved during aging. However, the importance of cGMP-dependent protein phosphorylation was decreased, indicating a shift to other pathways.

Aging↗
PubMed2000

Reduction in the level of cardiac cyclic GMP worsens contractile delay in myocardial stunning.

We tested the hypothesis that a reduction in the level of myocardial cyclic GMP would worsen the contractile delay associated with myocardial stunning. Two groups of 12 anesthetized open-chest New Zealand white rabbits were utilized. Myocardial stunning was produced by two 15-min occlusions of the left anterior descending coronary artery followed by 15 min of reperfusion. Either control vehicle (saline + 1% DMSO) or 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ 10(-4) M, a guanylate cyclase inhibitor) was topically applied to the left ventricular surface of the rabbit hearts. Left ventricular and aortic pressures along with wall thickness parameters were determined. Coronary blood flow (microspheres) and O(2) extraction (microspectrophotometry) were used to determine myocardial O(2) consumption. Myocardial stunning was observed in the control group through an increased delay in onset of wall thickening (46.2 +/- 7.3 vs 76.6 +/- 17.5 ms). There was no significant effect of stunning on the rate of wall thickening (21.8 +/- 9.5 vs 18.1 +/- 3.4 mm/s) or O(2) consumption (stun 4.6 +/- 0.6, control 4.8 +/- 0.4 ml O(2)/min/100 g). After treatment with ODQ 10(-4) M, both delay (43.9 +/- 9.6 vs 134.1 +/- 30.0 ms) and myocardial O(2) consumption (stun 5.9 +/- 0.6, control 5.9 +/- 0. 7) increased significantly compared to control. There was no significant change in the rate of wall thickening. We conclude that decreasing cyclic GMP worsens stunning by increasing delay in onset of wall thickening and increasing local O(2) costs in the stunned region.

Animals↗
PubMed2000

Cyclic GMP attenuates cyclic AMP-stimulated inotropy and oxygen consumption in control and hypertrophic hearts.

We tested the hypothesis that increasing myocardial cyclic GMP would attenuate cyclic AMP induced positive inotropy and O2 consumption, in part, through changes in cyclic AMP and that renal hypertension-induced cardiac hypertrophy (HYP) would alter this relationship. Anesthetized, open chest rabbits (N = 48) were divided into four groups of control (CON) and HYP animals which received vehicle (VEH), isoproterenol 10(-6)M (ISO), 3-morpholinosyndnonimine 10(-4)M, (SIN-1), or a combination of ISO+SIN-1. Coronary blood flow (microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption in both subepicardium (EPI) and subendocardium (ENDO). Left ventricular change in wall thickness (%) was increased significantly by ISO in both CON (16 +/- 4 to 31 +/- 6) and HYP (17 +/- 2 to 24 +/- 3). Percent change in wall thickness was similar in the CON, SIN-1, and ISO+SIN-1 groups. Myocardial O2 consumption (ml O2/min/100 g) was increased by ISO in CON (10.3 +/- 1.0 to 13.6 +/- 2.0 EPI; 10.9 +/- 1.0 17.1 +/- 1.7 ENDO) and HYP (8.2 +/- 1.4 to 12.3 +/- 2.2 EPI; 6.6 +/- 1.4 to 14.8 +/- 1.8 ENDO). Oxygen consumption was unaffected by SIN-1 in CON and HYP animals. ISO+SIN-1 caused attenuated ISO-induced increases in O2 consumption in CON in EPI and ENDO, and in EPI in HYP. Cyclic GMP (pmol/g) was unchanged by ISO in CON and HYP, and increased by SIN-1 in CON (8.1 +/- 1.3 to 19.2 +/- 2.3 EPI) and HYP (9.1 +/- 1.5 to 12.8 +/- 2.0 EPI). Cyclic GMP remained elevated with ISO+SIN-1 in both groups. Cyclic AMP (pmol/g) was increased significantly by ISO in CON (496 +/- 43 to 725 +/- 106 EPI; 534 +/- 44 to 756 +/- 148 ENDO) and insignificantly in HYP (435 +/- 50 to 566 +/- 35 EPI; 497 +/- 51 to 583 +/- 47 ENDO). Cyclic AMP levels were unaffected by SIN-1 in either group. Isoproterenol induced increases in cyclic AMP were blunted by ISO+SIN-1 in CON (496 +/- 43 to 537 +/- 59 EPI) and not affected in HYP. The current study demonstrated attenuation of cyclic AMP mediated increased inotropy and O2 consumption by increasing cyclic GMP, which appeared, in part, related to cyclic GMP-induced reduction in cyclic AMP. This effect of cyclic GMP on cyclic AMP was not observed in myocardial hypertrophy.

Animals↗
PubMed2000

Down regulation of myocardial beta1-adrenoceptor signal transduction system in pacing-induced failure in dogs with aortic stenosis-induced left ventricular hypertrophy.

We recently demonstrated that rapid ventricular pacing caused cardiac failure (Failure) in dogs with aortic stenosis-induced left ventricular hypertrophy (Hypertrophy) and isoproterenol caused no significant increases in function, O2 consumption and intracellular cyclic AMP level in the failing hypertrophied hearts. We tested the hypothesis that alterations in the beta1-adrenoceptor-signal transduction pathway would correlate with the reduced functional and metabolic responses to beta-adrenergic stimulation during the transition from the compensated hypertrophy to failure. Pressure overload-induced left ventricular hypertrophy was created using aortic valve plication in 10 dogs over a 6-month period. Five months after aortic valve plication, congestive heart failure was induced in 5 dogs by rapid ventricular pacing at 240 bpm for 4 weeks. The density of myocardial beta1-adrenoceptors (fmoles/mg membrane protein; fmoles/g wet tissue) was significantly reduced in the Failure dogs (176+/-19; 755+/-136) when compared to those of the Control (344+/-51; 1,551+/-203) and the Hypertrophy (298+/-33; 1,721+/-162) dogs. The receptor affinities were not significantly different among all groups. There was a small but significant decrease in the percentage of beta1-adrenoceptors of the failing hypertrophied hearts (62+/-3%) when compared to that of the hypertrophied hearts (77+/-5%). The basal myocardial adenylyl cyclase activity (pmoles/mg protein/min) was significantly lower in the Failure dogs (45+/-4) than in the Control (116+/-14) and Hypertrophy (86+/-6) dogs. The forskolin (0.1 mM)-stimulated adenylyl cyclase activity was also significantly lower in the Failure dogs (158+/-17) than in the Control dogs (296+/-35) and slightly lower than in the Hypertrophy dogs (215+/-10). There were no significant differences in low Km cyclic AMP-phosphodiesterase activities among all groups. We conclude that down regulation of beta1-adrenoceptors and reduced adenylyl cyclase activities contribute to the decreases in myocardial functions and beta-adrenergic responses in the failing hypertrophied hearts induced by rapid ventricular pacing.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Effect of AMPA on cerebral cortical oxygen balance of ischemic rat brain.

We tested the hypothesis that the excitatory neurotransmitter receptor agonist, alpha amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), would worsen cerebral cortical oxygen supply/consumption balance during focal ischemia. In this study, we compared regional cerebral blood flow, arterial and venous O2 saturation, O2 extraction and oxygen consumption of ischemic and AMPA treated ischemic and control regions of rat brain. Ischemia was induced by middle cerebral artery (MCA) occlusion in isoflurane (1.4%) anesthetized Wistar rats. Twenty minutes after MCA occlusion, 10(-5) M AMPA was applied to the ischemic cortex (IC) for a period of 40 min; the fluid was changed every 10 min. After 1 hr of ischemia, animals were sacrificed and regional cerebral blood flow (rCBF) was determined using the C14-iodoantipyrine autoradiographic technique. Regional arterial and venous oxygen saturation were determined microspectrophotometrically. In control, the cerebral blood flow and oxygen consumption of the IC were significantly lower than the contralateral cortex (rCBF: 46 +/- 20 vs. 81 +/- 39 ml/min/100g, O2 consumption: 2.8 +/- 1.4 vs. 3.6 +/- 1.4 ml O2/min/100g). 10(-5) M AMPA did not significantly alter regional cerebral blood flow and oxygen consumption of the IC, but did decrease the average venous O2 saturation of the IC from 50.2 +/- 3.9% to 46.7 +/- 1.6%. AMPA also significantly increased the frequency of small veins with less than 45% O2 saturation in the IC (8 out of 56 veins in IC vs. 18 out of 56 veins in AMPA treated IC). Thus, topical application of 10(-5) M AMPA to the ischemic area worsens cerebral O2 balance and suggests that excitatory amino acids contribute to the degree of cerebral ischemia.

Animals↗
PubMed2000

Opposing functional effects of cyclic GMP and cyclic AMP may act through protein phosphorylation in rabbit cardiac myocytes.

1. We tested the hypothesis that the negative functional effects of cyclic GMP (cGMP) oppose the positive effects of cyclic AMP (cAMP) in cardiac myocytes through interaction at the level of their respective protein kinases. 2. Cell shortening was studied using a video-edge detector. The O2 consumption of a suspension of rabbit ventricular myocytes was measured using O2 electrodes. Protein phosphorylation was measured autoradiographically following SDS-PAGE. Data were collected with: (1) 8-bromo-cGMP (8-Br-cGMP) 10(-7) or 10(-5) M; (2) 8-bromo-cAMP (8-Br-cAMP) 10(-7) or 10(-5) M; (3) 8-Br-cAMP 10(-5) M followed by 8-Br-cGMP 10(-7) or 10(-5) M; (4) 8-Br-cGMP 10(-5) M followed by 8-Br-cAMP 10(-7) or 10(-5) M; (5) 8-Br-cGMP 10(-7) or 10(-5) M followed by KT 5720 (cAMP-dependent protein kinase inhibitor) or KT 5823 (cGMP-dependent protein kinase inhibitor) 10(-6) M; and (6) 8-Br-cAMP 10(-7) or 10(-5) M followed by KT 5720 or KT 5823 10(-6) M. 3. 8-Br-cGMP 10(-5) M decreased percent shortening (Pcs) from 6.3+/-0.6 to 3.6+/-0.4% and rate of shortening (Rs) from 66.7+/-4.4 to 41.8+/-4.2 microm s(-1). 8-Br-cAMP 10(-5) M increased Pcs (from 3.7+/-0.2 to 4.8+/-0.2) and Rs (from 50.0+/-3.0 to 60.0+/-3.1). With 8-Br-cAMP 10(-5) M, 8-Br-cGMP 10(-5) M decreased Pcs and Rs less. The positive functional effects of 8-Br-cAMP 10(-7) or 10(-5) M were also diminished with 8-Br-cGMP 10(-5) M. Following 8-Br-cGMP 10(-7) or 10(-5) M, KT 5720 10(-6) M further decreased Pcs to 2.5+/-0.3 and Rs to 30.0+/-4.1. KT 5823 10(-6) M returned Pcs to 4.7+/-0.4 and Rs to 61.3+/-5.3. Following 8-Br-cAMP 10(-7) or 10(-5) M, KT 5720 decreased the elevated Pcs and Rs significantly and KT 5823 10(-6) M further increased these parameters. 4. cGMP and cAMP phosphorylated the same five protein bands. With KT 5720 or KT 5823, all of the bands were lighter at the same concentration of 8-Br-cAMP and 8-Br-cGMP. 5. We conclude that, in rabbit ventricular myocytes, the opposing functional effects of cGMP and cAMP are related to the interaction at the level of their respective protein kinases.

Animals↗
PubMed2000

Effects of beta-adrenoceptor stimulation on pacing-induced failure of dog hypertrophic hearts.

1. We tested the hypothesis that the transition to pacing-induced failure in hypertrophic hearts would result in reduced functional and metabolic responses to beta-adrenoceptor stimulation. 2. Isoproterenol (ISO; 0.1 microg/kg per min) was infused into a coronary artery in five anaesthetized open-chest control, five aortic stenosis-induced left ventricular hypertrophy (LVH) and five LVH pacing-induced failure dogs. 3. In both control and LVH dogs, but not in failure dogs, ISO significantly increased local regional work (1,923+/-665 vs 2,656+/-715, 1,185+/-286 vs 1,906+/-562 and 835+/-106 vs 849+/-216g.mm/min, respectively), force (11.1+/-1.4 vs 16.9+/-2.6, 8.6+/-1.5 vs 13.7+/-2.3 and 12.2+/-1.1 vs 11.0+/-1.8g, respectively) and myocardial O2 consumption (7.3+/-2.0 vs 10.0+/-1.5, 8.2+/-1.6 vs 11.6+/-2.6 and 4.4+/-1.5 vs 5.5+/-1.8 mL O2/min per 100 g, respectively). 4. Isoproterenol also significantly increased cAMP in control and LVH dogs (474+/-67 vs 600+/-91 and 473+/-34 vs 619+/-53 pmol/g, respectively). In heart failure, cAMP was significantly lower and there was no significant increase in cAMP in response to ISO (245+/-43 vs 314+/-40pmol/g, respectively). 5. We conclude that there were no significant myocardial functional, O2 consumption or cAMP responses to ISO after the transition from hypertrophy to cardiac failure.

Adrenergic beta-Agonists↗