A mathematical model of the dynamic interaction between the ventricles over a complete cardiac cycle is presented. The ventricles are modeled as a three-walled system, each of which is individually characterized by a time-varying pressure-volume relationship. The model produces qualitative predictions of free wall and septal motions similar to those detected via M-mode echocardiography. The mode and degree of ventricular interaction are quantified using the concept of dynamic interaction gain. This model of ventricular interaction is then integrated into a lumped-parameter model of the canine closed-loop circulation, consisting of the right heart, pulmonary circulation, left heart, and the systemic circulation. The complete model generates realistic, continuous pressure waveforms, as well as, reasonable estimates of physiologic parameters for a normal dog. The complete model is utilized to assess the influence of ventricular interaction and the pericardium on cardiac mechanics and circulatory hemodynamics.

A mathematical model has been developed for the rabbit sinoatrial node (SAN) cardiac pacemaker cell, that is based on experimental results from whole-cell voltage clamp and action potential studies on single enzymatically-isolated pacemaker cells. The model consists of two parts, a model of sarcolemma, and a fluid compartment model of the intra and extracellular media. The sarcolemmal membrane model is of Hodgkin-Huxley form, and includes mathematical descriptions of the major ion channels present in mammalian cardiac pacemaker cells, as well as, descriptions of the Na$\sp+$/K$\sp+$ and Ca$\sp{2+}$ pump and the Na$\sp+$/Ca$\sp{2+}$ exchanger currents. The fluid compartment model is based on a material balance for the ion concentrations in the intracellular medium (Na$\sp+$, K$\sp+$ and Ca$\sp{2+}$); concentrations of these ions are considered constant in the extracellular medium. Provision is made in this model for Ca$\sp{2+}$ buffering in the intracellular medium, as well as the uptake and release of Ca$\sp{2+}$ by the sarcoplasmic reticulum (SR). Our model is able to provide good fits to both voltage clamp and action potential data from several published sources, and has provided insights into the biophysical interactions and the functional roles of several currents underlying the pacemaker potential of the rabbit SAN cell.

Pathologic arterial thrombosis is the leading cause of death in many countries. Current therapies provide only moderate protection from heart attack, stroke, and other clinical manifestations of thrombosis. To develop more potent therapeutics, molecular mechanisms that mediate platelet thrombosis are being researched. Thrombosis depends on complex interactions between the vascular wall, circulating components, and blood flow conditions. Under arterial shear conditions, platelet thrombosis requires von Willebrand factor (vWf) binding to platelet glycoprotein (GP) Ib-IX-V and GP IIb-IIIa complexes. In this work, dynamic experimental models of the vascular system are used in three studies investigating the role of GP Ib-IX-V and GP IIb-IIIa in arterial thrombosis. First, experimental results indicate two compounds that inhibit GP Ib-vWf binding have strong potential as anti-thrombotic agents. Findings with these compounds also suggest that soluble and immobilized vWf have different structural conformations. Second, a novel experimental model was developed to examine vWf-GP Ib-IX-V interactions that mediate platelet adhesion to exposed subendothelium. The system consists of vWf-coated glass slides, mammalian cells expressing full or partial GP Ib-IX-V complexes, and a parallel plate flow chamber with phase contrast video microscopy and digital image processing. Results with this system suggest the novel finding that optimal binding between immobilized vWf and GP Ib$\alpha$ requires the presence of GP V within the GP Ib-IX-V complex. The results also demonstrate that the role of immobilized vWf with respect to GP Ib-IX-V binding does not change after exposure to high shear. Third, platelet and leukocyte function were evaluated using whole blood samples from patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and receiving one of three standard therapies: abciximab, a GP IIb-IIIa inhibitor, ticlopidine, an orally active anti-platelet agent, or both treatments. Combined abciximab/ticlopidine therapy produces the most prolonged inhibition of in vitro mural thrombosis and the most consistent reduction in shear-induced platelet aggregation. At 2 hours post-PTCA, abciximab therapy, with or without ticlopidine, promotes leukocyte rolling on the collagen/vWf-platelet surface. However, abciximab-enhanced leukocyte rolling is almost completely inhibited by monoclonal antibodies to P-selectin or P-selectin glycoprotein ligand-1. Basic mechanism studies like these increase understanding of thrombosis pathophysiology and accelerate anti-thrombotic agent development.

We have developed a mathematical model of the human atrial myocyte, based on averaged voltage-clamp data recorded from isolated single myocytes. This formulation can reconstruct action potential data which are representative of recordings from a majority of human atrial cells in our laboratory, and therefore provides a biophysically based account of the underlying ionic currents. This work is based in part on a model of the rabbit atrial myocyte, and was motivated by differences in some of the repolarizing currents between human and rabbit atrium. We have therefore given particular attention to the sustained outward $K\sp+$ current, $I\sb{sus}$, which putatively has a prominent role in determining the duration of the human atrial action potential. Our results demonstrate that the action potential shape during the peak and plateau phases is determined primarily by $I\sb{t}$, $I\sb{sus}$, and $I\sb{Ca,L}$, and that the role of $I\sb{sus}$ in the human atrial action potential can be modulated by the baseline sizes of $I\sb{Ca,L}$, $I\sb{sus}$, and $I\sb{K,r}.$ As a result, our simulations suggest that the functional role of $I\sb{sus}$ can depend on the physiological/disease state of the cell. We have furthermore used our single-cell model to formulate a multicellular model of one-dimensional propagation in an idealized human atrial strand. Three different formulations for this model was explored: the classical cable equations with fixed ion concentrations, an "electrodiffusion" formulation which accounts for variable ion concentrations due to axial and radial transport, and an intermediate cable equation formulation which accounts for variable ion concentrations due to radial transport only. Comparative simulations show that the variable-concentration cable equation formulation can accurately simulate ion concentration dynamics during propagation, and therefore provides a less computationally demanding alternative to the electrodiffusion formulation. Simulations using the multicellular model predict that conduction velocity in the human atrium has a similar dependence on extracellular $\lbrack K\sp+\rbrack$ as in ventricular cells, including a region of "supernormal conduction" at moderate $\lbrack K\sp+\rbrack\sb{o}$-elevations, but that this response spans a smaller range of conduction velocities in the atrium. Our results suggest that this difference can he explained in terms of the smaller $I\sb{K1}$, and higher input resistance, of atrial cells.

The baroreceptor, a stretch-sensitive neuron, senses static and dynamic arterial blood pressure and responds by producing a frequency-modulated train of action potentials. The size and anatomy of baroreceptor nerve endings precludes direct experimental study of the details of baroreceptor behavior; however, studies of output firing frequency in response to arterial pressure changes reveal a highly nonlinear input-output characteristic. While many models of the baroreceptor have been developed, most of these models have failed to provide a comprehensive view of the mechanisms under-lying baroreceptor function. We present a new baroreceptor model which provides a physiologically-based, comprehensive description of all aspects of the system. This model combines a mechanical model of the arterial wall with Hodgkin-Huxley-type models of the transducer and encoder sections of the neuron. The complete model not only mimics a wide range of experimental results, it also provides a means of making predictions about baroreceptor behavior and of examining the mechanisms underlying baroreceptor function.

Stress is implicated in various diseases such as cancer, ischemia, and inflammatory diseases. Many different forms of stress may result in impaired physiological functions. Therefore, it is important to understand the mechanisms by which cells compensate and adapt to stress. Defining the changes that occur in nuclear structure and transport between the nucleus and cytoplasm in a cell are of specific interest and will contribute significantly to our understanding of stress response. / I have demonstrated that classical nuclear import is inhibited by oxidative stress in living HeLa cells as a result of relocalization and degradation of nuclear factors important for the nuclear transport apparatus. Specifically, hydrogen peroxide redistributes Ran, the GTPase important for the directionality of transport, importin-beta, a subunit of the nuclear import receptor, and Nup153, a component of the nuclear pore complex. Moreover, the stress-induced relocalization and degradation does not rely on the activation of MAPK pathways. / Heat shock proteins have established roles in normal cellular homeostasis as well as in stress response. In unstressed conditions, proteins of the hsp70/hsc70 family shuttle between the nucleus and the cytoplasm. Upon stress, cytoplasmic hsp70s/hsc70s accumulate in the nucleus. I have further characterized the effect of stress on hsc70s localization in HeLa cells. Heat-induced nuclear concentration of hsc70s depends on cell density. Moreover, protein phosphorylation negatively regulates hsc70 nuclear accumulation in response to heat. During recovery from heat stress hsc70s redistribute as they are exported into the cytoplasm. Hsc70 export is temperature- and energy-dependent, but is independent of the Crm1/exportin1-mediated pathway. Moreover, export of hsc70 is inhibited by depolymerization of nuclear actin. / In higher eukaryotes, lamins and other lamina-associated proteins provide links between the nuclear envelope and chromatin. The protein circumferin is located at the nuclear periphery in yeast and higher eukaryotes. I have demonstrated that stress relocalizes circumferin, which is released from the nuclear periphery into the nucleoplasm upon heat shock. These studies are the first to demonstrate that nuclear envelope organization in yeast and mammalian cells is modulated by stress. / Taken together, these results indicate that both nuclear transport and nuclear organization are affected by stress.

While parasympathetic activation is well-known to promote AF, the effects of sympathetic stimulation on AF have not been systematically studied. The present study was designed to study effects of sympathetic stimulation on AF, and the relative effects of sympathetic and vagal stimulation on AF duration for a comparable degree of wavelength and refractory period abbreviation. The results showed that, for a comparable degree of wavelength abbreviation, sympathetic stimulation is much less effective in promoting AF than vagal stimulation. Vagal stimulation markedly increased the heterogeneity of atrial refractoriness, while sympathetic stimulation did not. The heterogeneity in atrial refractory properties may be important in determining the ability to sustain AF and the effect of autonomic interventions on the arrhythmia.

Little is known about the pathway leading from a stressful stimulus such as hyperthermia or cadmium to a malformation, and the possibility of the heat shock response being linked to this phenomenon prompted the studies in this thesis. In order to determine the relationship between the ability of heat or cadmium to induce a heat shock response and the ability of these stressors to induce abnormal embryogenesis, rat embryos were cultured during organogenesis and the steady-state mRNAs of two heat shock proteins were used as indicators of the stress response in these embryos. The extent of mRNA accumulation for each heat shock protein varied depending on the tissue examined. When embryos were cultured in the presence of cadmium chloride, hsp27 and hsp70 mRNAs took much longer to accumulate compared to those observed following heat shock. Thus, the time course of heat shock protein mRNA accumulation was quite different in embryos exposed to cadmium from those exposed to hyperthermia. In addition, the concentrations of hsp27 and hsp70 mRNA appears to be differentially regulated in both embryo and yolk sac tissues for embryos treated with heat or cadmium. In conclusion, mammalian embryos are able to mount a heat shock response through the accumulation of hsp27 and hsp70 mRNAs in response to hyperthermia or cadmium treatments. The extent of this response appears to correlate with the teratogenicity effects of hyperthermia but not with those of cadmium.

To determine whether muscle contractions can increase muscle blood flow independently from metabolic factors, we isolated the diaphragmatic vasculature of 16 anesthetized and mechanically ventilated dogs. Phrenic inflow (Qphr) was controlled with a constant pressure source and the pressure (Pa) was decreased in steps to obtain the pressure-flow relation (P-Q). The vasculture was maximally vasodilated and contractions occurred spontaneously (n = 6) or were induced by twitches (n = 12) or tetanic trains (n = 7). The P-Q relations with contractions were compared to those with vasodilatation alone. With spontaneous contractions, the pressure intercept decreased from 47.35 $ pm$ 17.44 to 33.77 $ pm$ 16.82 mmHg (p $<$ 0.05) and the slope remained unchanged so that at Pa = 100 mmHg, Qphr increased from 36.22 $ pm$ 34.85 to 43.91 $ pm$ 38.22 ml/min/100g (p $<$ 0.05). Flow increased slightly with twitches but not with trains. We also elicited twitches, 12/min and 60/min trains in vascularly isolated gastrocnemius muscles (n = 6) and found no change in flow. In conclusion, the muscle pump has only a small effect on muscle blood flow.

The purpose of this study was to show that nifedipine, a calcium channel blocker, can decrease gallbladder contractility in guinea pigs and in man. Gallbladder contraction was measured in response to repeated injections of cholecystokinin both before and after the injection of nifedipine in three groups of five animals each. The mean amplitude of gallbladder contraction in response to cholecystokinin was decreased by 45, 73 and 67% (p $<$ 0.01) in response to intravenous nifedipine doses of 100, 200 and 300 $ mu$g respectively. In nine healthy human volunteers, gallbladder emptying was measured by radionuclide cholescintigraphy in response to cholecystokinin infusion before and after a 10 mg oral dose of nifedipine. Gallbladder ejection fraction was significantly decreased by 29% (p $<$ 0.001). These data demonstrate that nifedipine is a potent inhibitor of gallbladder contractility.