S–17Mechanisms of visceral/cardiac pain perception

Robert D. ForemanUniversity of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Visceral/cardiac pain, and its treatment, depends on the neuralhierarchy of the brain, spinal cord and the visceral organs to modulatecomplex mechanisms underlying visceral disease. Recent research fromour laboratory has shown that the C1-C2, and T2-T4 segments of the spinalcord are important areas for processing and modulating cardiac afferentinformation in the neural hierarchy. The spinal cord, especially the uppercervical region, is capable of making important adjustments in sensoryprocessing of cardiac nociceptive information without requiring the directinvolvement of supraspinal pathways. The goal of the presentation is toemphasize and highlight processing capabilities of the spinal cord. Thisinformation will add to our understanding about the central nervoussystem integration of noxious visceral information. The study of the neuralhierarchy associated with the processing of nociceptive informationshould help us develop more effective strategies for relieving pain ofvisceral origin.

doi:10.1016/j.vascn.2009.04.011

S–24Mechanisms of platelet-mediated thrombosis

John D. FoltsUniversity of Wisconsin, Madison, WI, United States

Thrombosis is a critical and necessary response to stop the bleeding fromvascular injury to small arteries, capillaries and venules. Platelets collect atthe cut in the artery and provide the release of thrombin and fibrin tostaunch the bleeding.

When platelets become over-active, however, they contribute to thedevelopment of atherosclerosis and thrombosis by a variety of mechanisms.There is extensive evidence that antiplatelet therapy reduces cardiovasculardisease. Platelet hyperactivity is increased by cigarette smoking, increases inreactive oxygen species, inflammatory mediators, hypertension, hyperlipi-demia, and in diabetes. Platelets release growth factors that promote smoothmuscle cell proliferation, inflammation, hypertension, release of reactiveoxygen species. They also produce vasospasm and narrowing of arteries. Thisnarrowing leads to the development of thrombotic occlusion of the artery,causing strokes and heart attacks. Knowledge of platelet physiology has ledto antiplatelet therapy with Aspirin and other agents which have been shownto reduce cardiac events and to prolong life in patients with cardiovasculardisease. The Folts In Vivo Cyclic Flow Animal Model as an approach to studyplatelets/coagulation in the whole body is discussed.

doi:10.1016/j.vascn.2009.04.012

S–25Central mechanisms of baroreflex control of blood pressure

Jeanne SeagardMedical College of Wisconsin, Milwaukee, WI, United States

This presentation will examine central components of baroreflex controlof blood pressure, focusing on the integration of baroreceptor afferent inputby neurons in the brainstem. This is a pivotal regulatory moment, becausethe signal conditioning at these gateway synapses determine the magnitude,pattern and duration of the baroreceptor signals transmitted to distalsynapses in the central network to coordinate baroreflex output and ensuingcontrol of blood pressure. Mechanisms involved in the integration andtransmission of baroreceptor input, including neurotransmitters and mod-ulators of baroreceptor input, will be discussed.

doi:10.1016/j.vascn.2009.04.013

S–33Integration of functional endpoints into repeat-dose toxicity studies

W.S. Redfern, S. Storey, H. Prior, L. Ewart, J.-P. ValentinSafety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, SK10 4TG,United Kingdom

Safety pharmacology studies almost invariably involve a single admin-istration of test compound, followed by functional measurements for up to24 h. Whereas pharmacological responses tend to be fairly rapid in onset, andare therefore detectable after a single dose, some may diminish on repeateddosing (tolerance), whereas others increase in magnitude. Also, many toxiceffects of drugs are either delayed in onset or require multiple exposuresbefore they develop (e.g., neuropathy). Therefore, single-dose safetypharmacology studies may sometimes miss these late-onset effects. Toaddress this, functional measurements can be incorporated into repeat-dosetoxicity studies, either routinely (e.g., ECG) or on an ad hoc basis. There aredifficulties in doing this: the availability of suitable technical and scientificexpertise in the test facility; suboptimal laboratory conditions; simultaneous(as opposed to staggered) dosing; prioritisation of toxicokinetic sampling;manual data processing; unsuitability of certain techniques (e.g., use ofanaesthesia; surgical implantation); low portability of certain equipment.Nevertheless, ‘fit-for-purpose’ data can still be acquired, in both rodents anddogs. Examples in our facility include assessment of activity, sensorimotorfunction, visual function (visual acuity and pupil control), salivation,ambulatory ECG, and respiratory function. This is entirely achievable ifmeasurements are relatively unobtrusive, both with respect to the animalsand the toxicology study.

doi:10.1016/j.vascn.2009.04.014

S–36Long-term regulation of arterial blood pressure

Kim HoaglandMerck & Co. Inc., West Point, PA, United States

In order to develop and maintain adequate tissue perfusion, manycomplex and redundant mechanisms have evolved to provide a constant day-to-day level of arterial blood pressure. The feedback control mechanismsresponsible for moment-to-moment and long-term blood pressure controlare fundamentally different. There are two prevailing hypotheses withregards to long-term regulation of arterial blood pressure: (1) the nervoussystem detects changes in blood pressure and adjusts levels of sympathetic/parasympathetic tone to stabilize blood pressure and can change the long-term “set point” around which blood pressure is controlled (2) the kidneyscan detect and correct arterial blood pressure by adjusting body fluidvolumes via the mechanism of pressure-diuresis and natriuresis. Rapidchanges in arterial blood pressure related to changes in posture and otherdaily activities are stabilized by reflex neuro-humoral mechanisms (hypoth-esis #1), which were addressed in a previous symposium at this meeting. Inthis presentation, the dominant role of kidney in long-term arterial bloodpressure regulation and the pressure-diuresis volume regulation mechanism(hypothesis #2) are addressed. The interaction between arterial bloodpressure and renal excretion of water and electrolytes and how thismechanism is modulated by neural, endocrine and autocoid factors will bediscussed.

doi:10.1016/j.vascn.2009.04.016

S–38Drug-induced activation of immune function: Mechanisms and potentialadverse effects

Curtis MaierGlaxoSmithKline Pharmaceuticals, King of Prussia, PA, United States

The immune system has developed highly specialized mechanisms todestroy invading pathogens and eliminate errant cells. The immune system is

Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 259–262 261