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Biomedical subjects

Bruce I Tranmer

Publications and source records attributed to Bruce I Tranmer.

9 recordsLinked to original sources
PubMed2006

Oxyhemoglobin-induced suppression of voltage-dependent K+ channels in cerebral arteries by enhanced tyrosine kinase activity.

Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) has devastating consequences. Oxyhemoglobin (oxyhb) has been implicated in SAH-induced cerebral vasospasm as it causes cerebral artery constriction and increases tyrosine kinase activity. Voltage-dependent, Ca(2+)-selective and K(+)-selective ion channels play an important role in the regulation of cerebral artery diameter and represent potential targets of oxyhb. Here we provide novel evidence that oxyhb selectively decreases 4-aminopyridine sensitive, voltage-dependent K(+) channel (K(v)) currents by approximately 30% in myocytes isolated from rabbit cerebral arteries but did not directly alter the activity of voltage-dependent Ca(2+) channels or large conductance Ca(2+)-activated (BK) channels. A combination of tyrosine kinase inhibitors (tyrphostin AG1478, tyrphostin A23, tyrphostin A25, genistein) abolished both oxyhb-induced suppression of K(v) channel currents and oxyhb-induced constriction of isolated cerebral arteries. The K(v) channel blocker 4-aminopyridine also inhibited oxyhb-induced cerebral artery constriction. The observed oxyhb-induced decrease in K(v) channel activity could represent either channel block, or a decrease in K(v) channel density on the plasma membrane. To explore whether oxyhb altered trafficking of K(v) channels to the plasma membrane, we used an antibody generated against an extracellular epitope of K(v)1.5 channels. In the presence of oxyhb, staining of K(v)1.5 on the plasma membrane surface was markedly reduced. Furthermore, oxyhb caused a loss of spatial distinction between staining with K(v)1.5 and the general anti-phosphotyrosine antibody PY-102. We propose that oxyhb-induced suppression of K(v) currents occurs via a mechanism involving enhanced tyrosine kinase activity and channel endocytosis. This novel mechanism may contribute to oxyhb-induced cerebral artery constriction following SAH.

4-Aminopyridine↗
PubMed2005

Emergence of a R-type Ca2+ channel (CaV 2.3) contributes to cerebral artery constriction after subarachnoid hemorrhage.

Cerebral aneurysm rupture and subarachnoid hemorrhage (SAH) inflict disability and death on thousands of individuals each year. In addition to vasospasm in large diameter arteries, enhanced constriction of resistance arteries within the cerebral vasculature may contribute to decreased cerebral blood flow and the development of delayed neurological deficits after SAH. In this study, we provide novel evidence that SAH leads to enhanced Ca2+ entry in myocytes of small diameter cerebral arteries through the emergence of R-type voltage-dependent Ca2+ channels (VDCCs) encoded by the gene CaV 2.3. Using in vitro diameter measurements and patch clamp electrophysiology, we have found that L-type VDCC antagonists abolish cerebral artery constriction and block VDCC currents in cerebral artery myocytes from healthy animals. However, 5 days after the intracisternal injection of blood into rabbits to mimic SAH, cerebral artery constriction and VDCC currents were enhanced and partially resistant to L-type VDCC blockers. Further, SNX-482, a blocker of R-type Ca2+ channels, reduced constriction and membrane currents in cerebral arteries from SAH animals, but was without effect on cerebral arteries of healthy animals. Consistent with our biophysical and functional data, cerebral arteries from healthy animals were found to express only L-type VDCCs (CaV 1.2), whereas after SAH, cerebral arteries were found to express both CaV 1.2 and CaV 2.3. We propose that R-type VDCCs may contribute to enhanced cerebral artery constriction after SAH and may represent a novel therapeutic target in the treatment of neurological deficits after SAH.

Animals↗
PubMed2004

Diagnosis and management of pediatric closed head injury.

Closed head injury in the pediatric population accounts for almost half of all new cases of traumatic brain injury. The incidence of severe brain injury appears to be less in children as compared to the adult population. Over the past several years, advances in recognition and treatment of traumatic brain injury have led to improved outcomes in both children and adults. It is imperative, therefore, for the pediatric surgeon dealing with head trauma to have an understanding of the common brain injuries in the pediatric population, their early recognition and initial management. In this article, early diagnosis and initial management of the most common forms of pediatric closed head injury are reviewed.

Adolescent↗
PubMed2004

Inhibition of Ca++ sparks by oxyhemoglobin in rabbit cerebral arteries.

OBJECT: Oxyhemoglobin (HbO2) causes cerebral artery constriction and is one component of blood that likely contributes to the pathogenesis of cerebral vasospasm after aneurysm rupture. This study was designed to examine the acute effect of HbO2 on subcellular Ca(++) release events (Ca(++) sparks) in cerebral artery myocytes. Calcium sparks provide a tonic hyperpolarizing and relaxing influence to vascular smooth muscle by the activation of plasmalemmal large-conductance Ca(++)-activated K+ channels. Evidence is provided that HbO2 may contract cerebral vascular muscle in part by free radical-mediated inhibition of Ca(++) sparks. METHODS: Calcium sparks were visualized in intact pressurized rabbit cerebral arteries by using laser scanning confocal microscopy and a Ca(++) indicator dye. Calcium spark frequency was reduced by approximately 65% after a 15-minute application of HbO2 (10(-4) M). The HbO2-induced decrease in Ca(++) spark frequency was prevented by a combination of the free radical scavengers superoxide dismutase and catalase. Isometric force measurements were used to characterize the role of the vascular endothelium and smooth-muscle Ca(++) channels in HbO2-induced cerebral artery contraction. The HbO2-induced contractions were independent of the vascular endothelium, but were abolished by diltiazem, a blocker of L-type voltage-dependent Ca(++) channels (VDCCs). Ryanodine, a blocker of ryanodine-sensitive Ca(++) release channels located on the sarcoplasmic reticulum, also reduced HbO2-induced contractions by approximately 50%. CONCLUSIONS: These results support the hypothesis that HbO2 may contract cerebral artery segments in part by inhibition of Ca(++) sparks, leading to decreased large-conductance Ca(++)-activated K+ channel activity, membrane potential depolarization, and enhanced Ca(++) entry through VDCCs.

Animals↗
PubMed2003

A whole-body mathematical model for intracranial pressure dynamics.

Most attempts to study intracranial pressure using lumped-parameter models have adopted the classical "Kellie-Monro Doctrine," which considers the intracranial space to be a closed system that is confined within the nearly-rigid skull, conserves mass, and has equal inflow and outflow. The present work revokes this Doctrine and develops a mathematical model for the dynamics of intracranial pressures, volumes, and flows that embeds the intracranial system in extensive whole-body physiology. The new model consistently introduces compartments representing the tissues and vasculature of the extradural portions of the body, including both the thoracic region and the lower extremities. In addition to vascular connections, a spinal-subarachnoid cerebrospinal fluid (CSF) compartment bridges intracranial and extracranial physiology allowing explict buffering of intracranial pressure fluctuations by the spinal theca. The model contains cerebrovascular autoregulation, regulation of systemic vascular pressures by the sympathetic nervous system, regulation of CSF production in the choroid plexus, a lymphatic system, colloid osmotic pressure effects, and realistic descriptions of cardiac output. To validate the model in situations involving normal physiology, the model's response to a realistic pulsatile cardiac output is examined. A well-known experimentally-derived intracranial pressure-volume relationship is recovered by using the model to simulate CSF infusion tests, and the effect on cerebral blood flow of a change in body position is also examined. Cardiac arrest and hemorrhagic shock are simulated to demonstrate the predictive capabilities of the model in pathological conditions.

Blood Pressure↗
PubMed2002

Enhanced myogenic tone in cerebral arteries from a rabbit model of subarachnoid hemorrhage.

Cerebral artery vasospasm is a major cause of death and disability in patients experiencing subarachnoid hemorrhage (SAH). Currently, little is known regarding the impact of SAH on small diameter (100-200 microm) cerebral arteries, which play an important role in the autoregulation of cerebral blood flow. With the use of a rabbit SAH model and in vitro video microscopy, cerebral artery diameter was measured in response to elevations in intravascular pressure. Cerebral arteries from SAH animals constricted more (approximately twofold) to pressure within the physiological range of 60-100 mmHg compared with control or sham-operated animals. Pressure-induced constriction (myogenic tone) was also enhanced in arteries from control animals organ cultured in the presence of oxyhemoglobin, an effect independent of the vascular endothelium or nitric oxide synthesis. Finally, arteries from both control and SAH animals dilated as intravascular pressure was elevated above 140 mmHg. This study provides evidence for a role of oxyhemoglobin in impaired autoregulation (i.e., enhanced myogenic tone) in small diameter cerebral arteries during SAH. Furthermore, therapeutic strategies that improve clinical outcome in SAH patients (e.g., supraphysiological intravascular pressure) are effective in dilating small diameter cerebral arteries isolated from SAH animals.

Animals↗
PubMed2002

Ca2+ sparks and their function in human cerebral arteries.

BACKGROUND AND PURPOSE: Local Ca2+ release events (Ca2+ sparks) caused by the opening of ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum have been suggested to oppose constriction in cerebral arteries through the activation of large-conductance Ca2+-activated K+ (BK) channels. We report the first identification and characterization of Ca2+ sparks and associated BK channel currents in smooth muscle cells isolated from human cerebral arteries. METHODS: Membrane currents and intracellular Ca2+ were measured with the use of the patch-clamp technique and laser scanning confocal microscopy. RESULTS: Ca2+ sparks with a peak fractional fluorescence change (F/F0) of 2.02 +/- 0.04 and size of 8.2 +/- 0.5 microm2 (n=108) occurred at a frequency of approximately 1 Hz in freshly isolated, cerebral artery myocytes from humans. At a holding potential of -40 mV, the majority of, but not all, Ca2+ sparks (61 of 85 sparks) were associated with transient BK currents. Consistent with a role for Ca2+ sparks in the control of cerebral artery diameter, agents that block Ca2+ sparks (ryanodine) or BK channels (iberiotoxin) were found to contract human cerebral arteries. CONCLUSIONS: This study provides evidence for local Ca2+ signaling in human arterial myocytes and suggests that these events may play an important role in control of cerebral artery diameter in humans.

Adult↗