David L. Kreulen - US grants

The aim of this research is to delineate the role of nerve pathways involving the abdominal prevertebral ganglia in controlling mesenteric blood vessels and to determine the organization of the abdominal nerve-vessel system. Experiments have been designed to determine: (1) characteristics of vascular afferent pathways from mesenteric arteries veins to the sympathetic ganglia; (2) the characteristics of neuromuscular transmissions from sympathetics nerves to mesenteric arteries and veins; (3) the characteristics of intestinal noncholinergic sensory pathways to the prevertebral ganglia: 4) whether there are reflexes between different vascular regions in the mesentery and/or between the mesenteric vasculature and the musculature of the gastrointestinal tract (5) the pharmacologic properties of the reflex pathways within the ganglia and at the nerve-blot vessel junction. These studies will involve anatomical physiological and pharmacologic approaches to these questions. In vitro preparations from guinea pigs, rabbits, rats and cats that consist of the celiac plexus and inferior mesenteric ganglion attached to selected abdominal organs will be used. Preganglionic, postganglionic and afferent nerve fibers will be electrically stimulated. Electrophysiological techniques will be used to determine intracellular responses of neurons in the prevertebral ganglia and vascular smooth muscle cells. Pressure recording techniques will be used to distend and record the contractile responses of mesenteric vascular and gastrointestinal segment. Pharmacologic techniques will be used to determine the mechanisms which modulate neurotransmission in the ganglia and to the blood vessels to determine how these mechanism can be altered with drug therapy. The goal of these studies will be to understand how to autonomic nervous system controls blood vessels and what role reflexes between the viscera plays in this control. This knowledge will help us to understand and design better treatment for diseases which involve the autonomic nervous system; the nerves the selves well as the organs they innervate.

DESCRIPTION: (Adapted from the application) The control of the vascular system by the sympathetic nervous system depends on the organization of sympathetic neurons into function-specific pathways. The postganglionic sympathetic neuron plays a critical role in this organization. Characteristic morphological, neurochemical and electrophysiological features of these sympathetic neurons contribute to their specific functional pathways. Although it is known that sympathetic neurons in vascular pathways have distinct neurochemical characteristics, it is not known whether there are distinctions between neurons innervating arteries and veins. The functional separation between vascular resistance and capacitance is an important part of cardiovascular regulation. Four specific aims are proposed: 1. Test the uniqueness of the localization and transmitter phenotype of the neurons in prevertebral ganglia that innervate mesenteric arteries and veins. 2. Test the uniqueness of the electrophysiological characteristics of the neurons in prevertebral ganglia that innervate mesenteric arteries and veins. 3. Characterize the source and effects of selected sensory neurotransmitters in prevertebral ganglia that are related to the target organ (artery or vein). 4. Compare the release of ATP from sympathetic nerves innervating mesenteric arteries and veins. Achieving the objectives will define the nervous mechanisms underlying the separate control of resistance and capacitance vessels. The splanchnic circulation receives 30% of the cardiac output and contains about one-third of the total blood volume. In essential hypertension, vascular capacitance is initially reduced and this is followed by changes in resistance. The studies outlined in this proposal will enhance our understanding of the underlying mechanisms of this and related phenomena.

Sustained elevated blood pressure-hypertension is a prominent cause of morbidity and deaths throughout the world. Hypertension is associated with increased activity in the sympathetic nervous system resulting in constriction of blood vessels, increased heart contractility and retention of sodium and water. It is the central hypothesis of this project that veins and arteries are innervated by separate neurons in sympathetic ganglia and that alterations in properties of vein neurons contribute to venoconstriction in hypertension. In normotensive and DOCA-salt hypertensive rats we will compare the properties of identified arterial and venous neurons in the prevertebral sympathetic ganglia that innervate the splanchnic blood vessels and and determine their properties with respect to firing behavior, generation of reactive oxygen species and function of the norepinephrine uptake system. We also will compare the properties of prevertebral neurons to those in stellate ganglia that provide the sympathetic innervation to the heart and associated great vessels in the thorax. We will pursue the following specific aims. 1) Determine the localization and electrophysiologic characteristics of arterial and venous sympathetic neurons in the intact inferior mesenteric ganglion of the rat and characterize arterial and venous neurons in primary dissociated cell culture. 2) Determine the localization and regulation of ROS-generating enzymes within the arterial and venous neurons of celiac ganglia and within stellate ganglion neurons. 3) Determine the mechanisms of regulation of sympathetic neuron function by ETB receptors. 4) Compare the properties of celiac ganglion neurons (peripheral volume regulation) to those of stellate ganglion neurons (central volume regulation). Our long-term objective is to discover novel properties of the sympathetic nervous system that will be susceptible to treatment of human hypertension. LAY SUMMARY: High blood pressure is a major health problem. The sympathetic nervous system, the part of the nervous system that functions when the body is stressed, is hyperactive in hypertension. This overactivity is a cause of the disease and many of the bad effects that accompany it. This study tries to find out what malfunctions in the nerve cells that are outside the brain and spinal cord that innervate the arteries, veins and heart. We think that the nerves that innervate veins cause them to contract too much and this is one cause of high blood pressure. We hope to discover a treatment based on this idea.