Spinal cord injuries are an important cause of longterm disability with current estimates of thei... more Spinal cord injuries are an important cause of longterm disability with current estimates of their frequency at a range of 30-50 cases per million population. Over the last decade, our knowledge of the pathophysiological mechanisms associated with spinal cord injury has increased dramatically. Clinical and basic science research have improved our ability to preserve and restore function following these devastating injuries. In this chapter, we will briefly review some of the important advancements that have been gained through basic science research, and in particular review our experimental findings utilizing a model of compressive spinal cord injury.
American Journal of Physiology-heart and Circulatory Physiology, Aug 1, 1977
Red blood cell velocity was measured in capillaries of the rabbit tenuissimus muscle during expos... more Red blood cell velocity was measured in capillaries of the rabbit tenuissimus muscle during exposure to a low-oxygen-tension (PO2 = 5 mmHg) and a high-oxygen-tension (room-air PO2 = 150 mmHg) suffusion solution. Control capillary red blood cell velocity was significantly reduced (44%) by elevating the suffusion solution PO2 from 5 to 150 mmHg. The reactive hyperemias that occurred after a 120-s aortic occlusion under these two conditions were compared. The mean RBC velocity during the hyperemia in the 1st min following the removal of occlusion was significantly reduced by increasing oxygen tension, as was the duration of the hyperemia. Peak capillary red blood cell velocities in the hyperemic phase during exposures to low and high PO2 were not significantly different. It can be concluded from this study that although oxygen tension does affect postocclusive reactive hyperemia, other factors such as myogenically induced vascular relaxation also contribute to the production of this phenomenon.
White blood cells (WBCs) have been postulated to contribute to postischemic damage in a number of... more White blood cells (WBCs) have been postulated to contribute to postischemic damage in a number of tissues including the heart, brain, and skeletal muscle [11]. Results from our laboratory [29] provided evidence that leukocytes are also involved in cerebral ischemia and reperfusion injury. In this investigation a comparison was made of the alteration of cortical electrical activity following transient, incomplete cerebral ischemia between control and leukopenic rats by monitoring somatosensory evoked potentials and EEG activity. Animals that were rendered leukopenic had better preservation of somatosensory evoked potentials both during ischemia and following reperfusion (Figs. 1–3). These results are consistent with the results of similar studies from other laboratories [2, 5].
The effects of injury in the microcirculation have been studied for about 100 years, initially mo... more The effects of injury in the microcirculation have been studied for about 100 years, initially more or less accidentally. The English ophthalmic surgeon Wharton-Jones (1851) descri~d arteriolar thromboembolism in the frog’s web, and the German physiologist Zahn (1872) observed the process of hemostasis in the frog’s mesentery. He described the arrest of bleeding by the formation of “ein weisslicher, nach Innen und Aussen kolbenformig verdickter Thrombus. Genauere Untersuchung desselben erwiess, doss er, mit Ausnahme einiger wenigen eingeklemmten roter Blutkorperchen, lediglich ausfarblosen Zellen bestand.” In this description, the presence of platelets in the hemostatic plug was noted for the first time.
American Journal of Physiology-Heart and Circulatory Physiology, 1989
Trigramin, a cysteine rich, RGD (Arg-Gly-Asp)-containing peptide from Trimeresurus gramineus snak... more Trigramin, a cysteine rich, RGD (Arg-Gly-Asp)-containing peptide from Trimeresurus gramineus snake venom (Mr 7,500) has been previously reported to inhibit fibrinogen binding to ADP-activated platelets and platelet aggregation (disassociation constant 10(-8) M). The present study demonstrates that the infusion of trigramin (17-212 micrograms/100 g body wt) significantly prolonged the bleeding time of severed mesenteric arteries in hamsters (anesthetized with 65 mg/kg pentobarbital), whereas the infusion of RGDS (Arg-Gly-Asp-Ser, 0.45-1.0 mg/100 g body wt) failed to increase the bleeding time in this model. The bleeding time immediately returned to normal after cessation of trigramin infusion. The pattern of the disappearance of 125I-labeled trigramin from the circulation fit a two-compartment model with the half-life for the fast component between 0.7 and 2.0 min and with the half-life for the slow component between 31 and 105 min. It appeared that the kidney and liver are major rou...
American Journal of Physiology-Heart and Circulatory Physiology, 1977
Red blood cell velocity and diameter were measured in vessels of the wing of the unanesthetized b... more Red blood cell velocity and diameter were measured in vessels of the wing of the unanesthetized bat (Myotis lucifugus) from the supplying artery to the capillaries. These data were used to determine the manner in which velocity, shear rate, volume flow, and blood pressure depend on the vessel's hierarchical position within the vascular network. The results show that velocity decreases in an almost linear fashion as the capillary is approached but that the shear rate increases as one progresses distally from the supplying artery. Blood volume flow was found to decrease as an exponential function of the branching order. Comparison with available date in some animal species, including man, indicates some agreement in capillary velocity, although significantly lower values have been reported in some preparations. Using a method whereby blood pressure distribution could be obtained from anatomical data and center-line blood velocity, the rheologic alterations accompanying consecutive...
This study investigated the possibility that the aging process results in alterations in the stru... more This study investigated the possibility that the aging process results in alterations in the structure and/or functional reactivity of the microvessels that could contribute to increased resistance to blood flow in working skeletal muscle. Initially, latex casts were made of the cremaster muscle microvasculature in adult (12 mo) and senescent (24 mo) male Fischer 344 rats. Although the average diameter was not different between age groups, segmental length (distance between adjacent branches) increased significantly (3rd order) during aging. Additionally, in vivo experiments were performed to determine the response of the vessels to the topical application of norepinephrine and adenosine. There was no increase in vasoconstriction produced by norepinephrine; however, the vasodilation in response to adenosine declined dramatically (1st and 2nd order) with advancing age. It can be concluded that the increase in skeletal muscle vascular resistance during contraction in aged male rats could be explained by morphological changes and/or the diminished vasodilation elicited by adenosine.
With the development of laser-Doppler flowmetry (LDF) (see chapters 1, 2), a new field has opened... more With the development of laser-Doppler flowmetry (LDF) (see chapters 1, 2), a new field has opened for quantitative studies of microvascular perfusion in various tissues. LDF allows quick, continuous, and noninvasive assessments of microvascular flow, both in clinical practice and in laboratory animal research. The potential benefits of LDF for the advancement of cardiovascular science have attracted considerable attention among researchers, who have already provided a variety of new insights and applications for this emerging technology. This chapter outlines the applications of LDF for studies of the skeletal muscle circulation. It summarizes existing studies of the skeletal muscle circulation using LDF, and focuses in detail upon comparisons of laser-Doppler flowmeter signals with independent measures of microvascular flow. The final section of the chapter illustrates several new applications of LDF for the study of blood flow in skeletal muscle.
We evaluated the effects of the non-psychoactive cannabinoid cannabidiol (CBD) on the inflammator... more We evaluated the effects of the non-psychoactive cannabinoid cannabidiol (CBD) on the inflammatory response and recovery of function following spinal cord injury (SCI). Female C57Bl/6 mice were exposed to spinal cord contusion injury (T9-10) and received vehicle or CBD (1.5 mg/kg IP) injections for 10 weeks following injury. The effect of SCI and CBD treatment on inflammation was assessed via microarray, qRT-PCR and flow cytometry. Locomotor and bladder function and changes in thermal and mechanical hind paw sensitivity were also evaluated. There was a significant decrease in pro-inflammatory cytokines and chemokines associated with T-cell differentiation and invasion in the SCI-CBD group as well as a decrease in T cell invasion into the injured cord. A higher percentage of SCI mice in the vehicle-treated group (SCI-VEH) went on to develop moderate to severe (0-65.9% baseline thermal threshold) thermal sensitivity as compared with CBD-treated (SCI-CBD) mice. CBD did not affect recov...
Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes ... more Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes in animal models of stroke. We have previously reported a protective effect of the CB1 antagonist, SR141716A, in a transient reperfusion mouse model of cerebral ischemia. This protective effect was in part mediated by activation of the 5HT1A receptor. Here we have examined its effect in a mouse model of permanent ischemia induced by photoinjury. The CB1 antagonist was found to be protective in this model. As was the case following transient ischemia reperfusion, SR141716A (5mg/kg) resulted in smaller infarct fractions and stroke volumes when utilized both as a pretreatment and as a post-treatment. In contrast to the effect in a transient ischemia model, the pretreatment effect did not depend on the 5HT1A receptor. Neurological function correlated favorably to the reduction in stroke size when SR141716A was given as a pretreatment. With the incidence of stroke predicted to rise in paralle...
Xiang Ni 1 , Ellen B Geller 2 , Michael J Eppihimer 4 , Toby K Eisenstein 3 , Martin W Adler 2 an... more Xiang Ni 1 , Ellen B Geller 2 , Michael J Eppihimer 4 , Toby K Eisenstein 3 , Martin W Adler 2 and ... Ronald F Tuma* ,1 1 Department of Physiology, Temple University, 3420 N. Broad Street, Philadelphia, PA 19140, USA; ... Abuse Research and Department of ...
It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate... more It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of Δ -tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB /CB receptor agonists or produces these pharmacological effects on its own. The effects of THC or the CB /CB receptor full agonist WIN55212 alone, CBD alone or their combination were tested across a range of doses. Cognitive effects were assessed in C57BL/6 mice in a conditional discrimination task and in the Barnes maze. Cannabinoid withdrawal signs were assessed following precipitated withdrawal by acute administration of the CB receptor antagonist SR141716, the 5-HT receptor antagonist WAY100635, the TRPV1 receptor antagonist capsazepine or the adenosine A receptor antagonist SCH58261. THC produced significant motor and cognitive impairment in the Barnes maze task, none of which were attenuated by the addition of CBD. CBD alone did ...
The molecular substrates underlying cocaine reinforcement and addiction have been studied for dec... more The molecular substrates underlying cocaine reinforcement and addiction have been studied for decades, with a primary focus on signaling molecules involved in modulation of neuronal communication. Brain-derived neurotrophic factor (BDNF) is an important signaling molecule involved in neuronal dendrite and spine modulation. Methyl CpG binding protein 2 (MeCP2) binds to the promoter region of BDNF to negatively regulate its expression and cocaine can recruit MeCP2 to alter the expression of genes such as BDNF that are involved in synaptic plasticity. For several decades, BDNF has been implicated in mediating synaptic plasticity associated with cocaine abuse, and most studies report that neurons are the primary source for BDNF production in the brain. The current study assessed the effects of intravenous cocaine self-administration on microglial activation, and MeCP2 and BDNF expression in reward regions of the brain in vivo, as well as determined specific effects of cocaine exposure o...
We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increase... more We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increases in infarct size and volume and significant worsening in clinical score, using two mouse models, one of permanent ischemia and one of ischemia/reperfusion. Focal cerebral infarcts were created using either photo induced permanent injury or transient middle cerebral artery occlusion. Infarct volume and motor function were evaluated in cannabinoid receptor 1/cannabinoid receptor 2 double knockout mice. The results surprisingly revealed that CB1/CB2 double knockout mice showed improved outcomes, with the most improvements in the mouse model of permanent ischemia. Although the number of individuals suffering from stroke in the United States and worldwide will continue to grow, therapeutic intervention for treatment following stroke remains frustratingly limited. Both the cannabinoid 1 receptor (CB1R) and the cannabinoid 2 receptor (CB2R) have been studied in relationship to stroke. Deletion...
Spinal cord injuries are an important cause of longterm disability with current estimates of thei... more Spinal cord injuries are an important cause of longterm disability with current estimates of their frequency at a range of 30-50 cases per million population. Over the last decade, our knowledge of the pathophysiological mechanisms associated with spinal cord injury has increased dramatically. Clinical and basic science research have improved our ability to preserve and restore function following these devastating injuries. In this chapter, we will briefly review some of the important advancements that have been gained through basic science research, and in particular review our experimental findings utilizing a model of compressive spinal cord injury.
American Journal of Physiology-heart and Circulatory Physiology, Aug 1, 1977
Red blood cell velocity was measured in capillaries of the rabbit tenuissimus muscle during expos... more Red blood cell velocity was measured in capillaries of the rabbit tenuissimus muscle during exposure to a low-oxygen-tension (PO2 = 5 mmHg) and a high-oxygen-tension (room-air PO2 = 150 mmHg) suffusion solution. Control capillary red blood cell velocity was significantly reduced (44%) by elevating the suffusion solution PO2 from 5 to 150 mmHg. The reactive hyperemias that occurred after a 120-s aortic occlusion under these two conditions were compared. The mean RBC velocity during the hyperemia in the 1st min following the removal of occlusion was significantly reduced by increasing oxygen tension, as was the duration of the hyperemia. Peak capillary red blood cell velocities in the hyperemic phase during exposures to low and high PO2 were not significantly different. It can be concluded from this study that although oxygen tension does affect postocclusive reactive hyperemia, other factors such as myogenically induced vascular relaxation also contribute to the production of this phenomenon.
White blood cells (WBCs) have been postulated to contribute to postischemic damage in a number of... more White blood cells (WBCs) have been postulated to contribute to postischemic damage in a number of tissues including the heart, brain, and skeletal muscle [11]. Results from our laboratory [29] provided evidence that leukocytes are also involved in cerebral ischemia and reperfusion injury. In this investigation a comparison was made of the alteration of cortical electrical activity following transient, incomplete cerebral ischemia between control and leukopenic rats by monitoring somatosensory evoked potentials and EEG activity. Animals that were rendered leukopenic had better preservation of somatosensory evoked potentials both during ischemia and following reperfusion (Figs. 1–3). These results are consistent with the results of similar studies from other laboratories [2, 5].
The effects of injury in the microcirculation have been studied for about 100 years, initially mo... more The effects of injury in the microcirculation have been studied for about 100 years, initially more or less accidentally. The English ophthalmic surgeon Wharton-Jones (1851) descri~d arteriolar thromboembolism in the frog’s web, and the German physiologist Zahn (1872) observed the process of hemostasis in the frog’s mesentery. He described the arrest of bleeding by the formation of “ein weisslicher, nach Innen und Aussen kolbenformig verdickter Thrombus. Genauere Untersuchung desselben erwiess, doss er, mit Ausnahme einiger wenigen eingeklemmten roter Blutkorperchen, lediglich ausfarblosen Zellen bestand.” In this description, the presence of platelets in the hemostatic plug was noted for the first time.
American Journal of Physiology-Heart and Circulatory Physiology, 1989
Trigramin, a cysteine rich, RGD (Arg-Gly-Asp)-containing peptide from Trimeresurus gramineus snak... more Trigramin, a cysteine rich, RGD (Arg-Gly-Asp)-containing peptide from Trimeresurus gramineus snake venom (Mr 7,500) has been previously reported to inhibit fibrinogen binding to ADP-activated platelets and platelet aggregation (disassociation constant 10(-8) M). The present study demonstrates that the infusion of trigramin (17-212 micrograms/100 g body wt) significantly prolonged the bleeding time of severed mesenteric arteries in hamsters (anesthetized with 65 mg/kg pentobarbital), whereas the infusion of RGDS (Arg-Gly-Asp-Ser, 0.45-1.0 mg/100 g body wt) failed to increase the bleeding time in this model. The bleeding time immediately returned to normal after cessation of trigramin infusion. The pattern of the disappearance of 125I-labeled trigramin from the circulation fit a two-compartment model with the half-life for the fast component between 0.7 and 2.0 min and with the half-life for the slow component between 31 and 105 min. It appeared that the kidney and liver are major rou...
American Journal of Physiology-Heart and Circulatory Physiology, 1977
Red blood cell velocity and diameter were measured in vessels of the wing of the unanesthetized b... more Red blood cell velocity and diameter were measured in vessels of the wing of the unanesthetized bat (Myotis lucifugus) from the supplying artery to the capillaries. These data were used to determine the manner in which velocity, shear rate, volume flow, and blood pressure depend on the vessel's hierarchical position within the vascular network. The results show that velocity decreases in an almost linear fashion as the capillary is approached but that the shear rate increases as one progresses distally from the supplying artery. Blood volume flow was found to decrease as an exponential function of the branching order. Comparison with available date in some animal species, including man, indicates some agreement in capillary velocity, although significantly lower values have been reported in some preparations. Using a method whereby blood pressure distribution could be obtained from anatomical data and center-line blood velocity, the rheologic alterations accompanying consecutive...
This study investigated the possibility that the aging process results in alterations in the stru... more This study investigated the possibility that the aging process results in alterations in the structure and/or functional reactivity of the microvessels that could contribute to increased resistance to blood flow in working skeletal muscle. Initially, latex casts were made of the cremaster muscle microvasculature in adult (12 mo) and senescent (24 mo) male Fischer 344 rats. Although the average diameter was not different between age groups, segmental length (distance between adjacent branches) increased significantly (3rd order) during aging. Additionally, in vivo experiments were performed to determine the response of the vessels to the topical application of norepinephrine and adenosine. There was no increase in vasoconstriction produced by norepinephrine; however, the vasodilation in response to adenosine declined dramatically (1st and 2nd order) with advancing age. It can be concluded that the increase in skeletal muscle vascular resistance during contraction in aged male rats could be explained by morphological changes and/or the diminished vasodilation elicited by adenosine.
With the development of laser-Doppler flowmetry (LDF) (see chapters 1, 2), a new field has opened... more With the development of laser-Doppler flowmetry (LDF) (see chapters 1, 2), a new field has opened for quantitative studies of microvascular perfusion in various tissues. LDF allows quick, continuous, and noninvasive assessments of microvascular flow, both in clinical practice and in laboratory animal research. The potential benefits of LDF for the advancement of cardiovascular science have attracted considerable attention among researchers, who have already provided a variety of new insights and applications for this emerging technology. This chapter outlines the applications of LDF for studies of the skeletal muscle circulation. It summarizes existing studies of the skeletal muscle circulation using LDF, and focuses in detail upon comparisons of laser-Doppler flowmeter signals with independent measures of microvascular flow. The final section of the chapter illustrates several new applications of LDF for the study of blood flow in skeletal muscle.
We evaluated the effects of the non-psychoactive cannabinoid cannabidiol (CBD) on the inflammator... more We evaluated the effects of the non-psychoactive cannabinoid cannabidiol (CBD) on the inflammatory response and recovery of function following spinal cord injury (SCI). Female C57Bl/6 mice were exposed to spinal cord contusion injury (T9-10) and received vehicle or CBD (1.5 mg/kg IP) injections for 10 weeks following injury. The effect of SCI and CBD treatment on inflammation was assessed via microarray, qRT-PCR and flow cytometry. Locomotor and bladder function and changes in thermal and mechanical hind paw sensitivity were also evaluated. There was a significant decrease in pro-inflammatory cytokines and chemokines associated with T-cell differentiation and invasion in the SCI-CBD group as well as a decrease in T cell invasion into the injured cord. A higher percentage of SCI mice in the vehicle-treated group (SCI-VEH) went on to develop moderate to severe (0-65.9% baseline thermal threshold) thermal sensitivity as compared with CBD-treated (SCI-CBD) mice. CBD did not affect recov...
Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes ... more Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes in animal models of stroke. We have previously reported a protective effect of the CB1 antagonist, SR141716A, in a transient reperfusion mouse model of cerebral ischemia. This protective effect was in part mediated by activation of the 5HT1A receptor. Here we have examined its effect in a mouse model of permanent ischemia induced by photoinjury. The CB1 antagonist was found to be protective in this model. As was the case following transient ischemia reperfusion, SR141716A (5mg/kg) resulted in smaller infarct fractions and stroke volumes when utilized both as a pretreatment and as a post-treatment. In contrast to the effect in a transient ischemia model, the pretreatment effect did not depend on the 5HT1A receptor. Neurological function correlated favorably to the reduction in stroke size when SR141716A was given as a pretreatment. With the incidence of stroke predicted to rise in paralle...
Xiang Ni 1 , Ellen B Geller 2 , Michael J Eppihimer 4 , Toby K Eisenstein 3 , Martin W Adler 2 an... more Xiang Ni 1 , Ellen B Geller 2 , Michael J Eppihimer 4 , Toby K Eisenstein 3 , Martin W Adler 2 and ... Ronald F Tuma* ,1 1 Department of Physiology, Temple University, 3420 N. Broad Street, Philadelphia, PA 19140, USA; ... Abuse Research and Department of ...
It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate... more It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of Δ -tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB /CB receptor agonists or produces these pharmacological effects on its own. The effects of THC or the CB /CB receptor full agonist WIN55212 alone, CBD alone or their combination were tested across a range of doses. Cognitive effects were assessed in C57BL/6 mice in a conditional discrimination task and in the Barnes maze. Cannabinoid withdrawal signs were assessed following precipitated withdrawal by acute administration of the CB receptor antagonist SR141716, the 5-HT receptor antagonist WAY100635, the TRPV1 receptor antagonist capsazepine or the adenosine A receptor antagonist SCH58261. THC produced significant motor and cognitive impairment in the Barnes maze task, none of which were attenuated by the addition of CBD. CBD alone did ...
The molecular substrates underlying cocaine reinforcement and addiction have been studied for dec... more The molecular substrates underlying cocaine reinforcement and addiction have been studied for decades, with a primary focus on signaling molecules involved in modulation of neuronal communication. Brain-derived neurotrophic factor (BDNF) is an important signaling molecule involved in neuronal dendrite and spine modulation. Methyl CpG binding protein 2 (MeCP2) binds to the promoter region of BDNF to negatively regulate its expression and cocaine can recruit MeCP2 to alter the expression of genes such as BDNF that are involved in synaptic plasticity. For several decades, BDNF has been implicated in mediating synaptic plasticity associated with cocaine abuse, and most studies report that neurons are the primary source for BDNF production in the brain. The current study assessed the effects of intravenous cocaine self-administration on microglial activation, and MeCP2 and BDNF expression in reward regions of the brain in vivo, as well as determined specific effects of cocaine exposure o...
We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increase... more We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increases in infarct size and volume and significant worsening in clinical score, using two mouse models, one of permanent ischemia and one of ischemia/reperfusion. Focal cerebral infarcts were created using either photo induced permanent injury or transient middle cerebral artery occlusion. Infarct volume and motor function were evaluated in cannabinoid receptor 1/cannabinoid receptor 2 double knockout mice. The results surprisingly revealed that CB1/CB2 double knockout mice showed improved outcomes, with the most improvements in the mouse model of permanent ischemia. Although the number of individuals suffering from stroke in the United States and worldwide will continue to grow, therapeutic intervention for treatment following stroke remains frustratingly limited. Both the cannabinoid 1 receptor (CB1R) and the cannabinoid 2 receptor (CB2R) have been studied in relationship to stroke. Deletion...
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