Vernon S. Bishop - US grants

This study is designed to examine the combined and separate roles of the aortic and carotid arterial baroreceptors in the regulation of arterial pressure in the subhuman primate (Papio anubis) and to determine if there is an interaction between the arterial baroreflexes with cardiopulmonary vagal afferents and renal-fluid regulatory mechanisms in the regulation of basal arterial pressure. Specific objectives are to determine the effects of partial and total arterial baroreceptor denervation on the 24-hour average arterial pressure and heart rate in the conscious baboon. In addition, we will determine the separate roles of the aortic and carotid baroreflexes in the reflex control of arterial pressure, plasma catecholamine and vasopressin concentrations. Finally, a major goal is to determine the factors responsible for the return of arterial pressure toward control levels following sinoaortic denervation. We postulate that two mechanisms, cardiopulmonary vagal afferents and renal-fluid regulatory mechanisms, act to prevent a sustained hypertension following sinoaortic deafferentation in the conscious baboon. To address the hypothesis, renal fluid and electrolyte balance studies and body fluid volume measurements will be performed before and periodically following sinoaortic deafferentation. Likewise, we will determine if the inhibitory influence of vagal afferents increase during the postdeafferentation period.

The major objective is to determine if endogenous vasopressin (reflexly stimulated secretion) contributes to the neural regulation of the circulation. The underlying hypothesis is that vasopressin at low concentrations may increase the gain of the arterial baroreflex to inhibit sympathetic nerve activity while at higher concentrations vasopressin may decrease the gain of the arterial baroreflex. At these higher concentrations of vasopressin, the reflex increase in sympathetic nerve activity to decreases in arterial pressure will be reduced. A second hypothesis is that the area postrema is necessary for the interaction of vasopressin with the arterial and cardiopulmonary baroreflexes. The third hypothesis is that circulating vasopressin may increase the arterial and cardiopulmonary inhibitions of vasopressin release thereby providing a mechanism whereby vasopressin might feedback to regulate its own release. Studies will be performed in conscious rabbits instrumented with arterial and venous catheters and electrodes on the renal, splanchnic and lumbar sympathetic nerves. By altering plasma vasopressin concentrations (osmotically or reflexly) we will be about to determine if endogenous vasopressin alters the arterial and cardiopulmonary baroreflex control of sympathetic nerve activity. The studies will be repeated in rabbits with lesion of the area postrema. We expect that in the lesioned rabbit the interactions of vasopressin with the arterial and cardiopulmonary baroreflex will be abolished. Additional studies are proposed to determine the arterial pressure, heart rate and sympathetic nerve responses to chemical and electrical stimulation of the area postrema.

neurotransmitters; sympathetic nervous system; neural information processing; blood pressure; hypertension;

biomedical equipment purchase;

This application for continuation of our program project focuses on the modulation of the sympathetic nervous system and the integrative role of the sympathetic nervous system on local blood flow regulation. The program has been expanded from five projects and two cores to eight projects and two cores. Four of the eight projects represent expansion of the program which involves the disciplines of pharmacology, physiology and molecular biology. PROJECT I entitled Neurogenic Hypertension in the Subhuman Primate involves the characterization of interactions between the sympathetic nervous system and mechanisms involved in sodium homeostasis in the sinoaortic denervated baboon. PROJECT II entitled Sympathetic Nervous System and Sodium Dependent Hypertension will investigate central mechanisms responsible for the increased activation of the sympathetic nervous system during sodium retention. The major objective of PROJECT III entitled Area Postrema Modulation of the Arterial Baroreflex is to determine the importance of the area postrema in modulating the arterial baroreflex. The goals of PROJECT IV entitled Metabolic Modulation of Sympathetic Vasoconstriction are to determine how vasodilator metabolites modulate the vascular response to increases in sympathetic outflow. PROJECT V entitled Somatic Afferent Inputs to Nucleus Tractus Solitarius will investigate the integration of somatic afferents in the nucleus tractus solitarius and the potential consequence on the regulation of sympathetic outflow. PROJECT VI entitled Sympathetic Regulation of Skin Blood Flow in Humans will examine the involvement of sympathetic vasoconstrictor and vasodilator mechanisms in the regulation of skin blood flow. PROJECT VII entitled Interactions of SHR-Derived Endothelium and Vascular Smooth Muscle will study the interactions between endothelial and vascular development and function in spontaneously hypertensive rats. PROJECT VIII entitled Mechanisms of Enhanced Tyrosine Hydroxylase Transcription will investigate the molecular genetic mechanisms which are involved in regulating tyrosine hydroxylase. These strongly related projects, which are supported by an Administrative Core A and Biochemical Assay Core B form the structure of this program project. The individual goals of each project will allow us to achieve the overall goal of the program.

The major objective is to determine if endogenous vasopressin (reflexly stimulated secretion) contributes to the neural regulation of the circulation. The underlying hypothesis is that vasopressin at low concentrations may increase the gain of the arterial baroreflex to inhibit sympathetic nerve activity while at higher concentrations vasopressin may decrease the gain of the arterial baroreflex. At these higher concentrations of vasopressin, the reflex increase in sympathetic nerve activity to decreases in arterial pressure will be reduced. A second hypothesis is that the area postrema is necessary for the interaction of vasopressin with the arterial and cardiopulmonary baroreflexes. The third hypothesis is that circulating vasopressin may increase the arterial and cardiopulmonary inhibitions of vasopressin release thereby providing a mechanism whereby vasopressin might feedback to regulate its own release. Studies will be performed in conscious rabbits instrumented with arterial and venous catheters and electrodes on the renal, splanchnic and lumbar sympathetic nerves. By altering plasma vasopressin concentrations (osmotically or reflexly) we will be about to determine if endogenous vasopressin alters the arterial and cardiopulmonary baroreflex control of sympathetic nerve activity. The studies will be repeated in rabbits with lesion of the area postrema. We expect that in the lesioned rabbit the interactions of vasopressin with the arterial and cardiopulmonary baroreflex will be abolished. Additional studies are proposed to determine the arterial pressure, heart rate and sympathetic nerve responses to chemical and electrical stimulation of the area postrema.

This application for continuation of our program project focuses on the modulation of the sympathetic nervous system and the integrative role of the sympathetic nervous system on local blood flow regulation. The program has been expanded from five projects and two cores to eight projects and two cores. Four of the eight projects represent expansion of the program which involves the disciplines of pharmacology, physiology and molecular biology. PROJECT I entitled Neurogenic Hypertension in the Subhuman Primate involves the characterization of interactions between the sympathetic nervous system and mechanisms involved in sodium homeostasis in the sinoaortic denervated baboon. PROJECT II entitled Sympathetic Nervous System and Sodium Dependent Hypertension will investigate central mechanisms responsible for the increased activation of the sympathetic nervous system during sodium retention. The major objective of PROJECT III entitled Area Postrema Modulation of the Arterial Baroreflex is to determine the importance of the area postrema in modulating the arterial baroreflex. The goals of PROJECT IV entitled Metabolic Modulation of Sympathetic Vasoconstriction are to determine how vasodilator metabolites modulate the vascular response to increases in sympathetic outflow. PROJECT V entitled Somatic Afferent Inputs to Nucleus Tractus Solitarius will investigate the integration of somatic afferents in the nucleus tractus solitarius and the potential consequence on the regulation of sympathetic outflow. PROJECT VI entitled Sympathetic Regulation of Skin Blood Flow in Humans will examine the involvement of sympathetic vasoconstrictor and vasodilator mechanisms in the regulation of skin blood flow. PROJECT VII entitled Interactions of SHR-Derived Endothelium and Vascular Smooth Muscle will study the interactions between endothelial and vascular development and function in spontaneously hypertensive rats. PROJECT VIII entitled Mechanisms of Enhanced Tyrosine Hydroxylase Transcription will investigate the molecular genetic mechanisms which are involved in regulating tyrosine hydroxylase. These strongly related projects, which are supported by an Administrative Core A and Biochemical Assay Core B form the structure of this program project. The individual goals of each project will allow us to achieve the overall goal of the program.

DESCRIPTION: (Adapted from the Investigator's Abstract) Major goals for this project are to establish the roles of Ang II and Na in resetting of the arterial baroreflex (ABR) in AngII-induced hypertension. Experiments will determine the integrative roles of the area postrema (AP), the paraventricular nucleus (PVN), and hepatoportal osmo/Na receptors in ABR resetting and the accompanying HT. The hypotheses to be tested are (1) HT due to low dose infusions of Ang II and NaCl involves an upward resetting of the ABR and (2) Converging projections from the AP, PVN, and hepatoportal osmo/Na receptors within the NTS determine the integrative neuronal response to baroreceptor afferent input. Both the resetting and changes in NTS neuronal responses involve activation in the AP and PVN. Activity within the AP is due to circulating Ang II, while the PVN is sensitive to Na. When Na is increased, hepatoportal reflexes will oppose ABR resetting and the Ang II-induced HT. To test these hypotheses, the combined and separate roles of AngII and Na on ABR control of RSNA, MAP and HT will be determined in conscious rats. Hepatoportal denervation, lesioning and AT1 receptor blockade of the AP and PVN, and selective activation of afferents in the three regions will be determined. One goal is to determine if AP and PVN inputs attenuate NTS neuronal responses to baroreceptor afferent inputs. Other goals are to determine if hepatoportal afferents facilitate baroreceptor-evoked single unit discharge, thereby opposing the inhibitory influence of AP and PVN inputs. Proposed studies are unique in that they are the first to investigate potential interactions between the brainstem (AP), descending hypothalamic (PVN) and ascending peripheral afferent (hepatoportal) inputs on the reflex regulation of sympathetic outflow and arterial pressure. Proposed studies will build upon our understanding of how circulating factors can influence the ABR and will provide a foundation for future studies to determine the specific neurotransmitter mechanisms that are active in modulating ABR function in health and disease.

DESCRIPTION: (Adapted from the Investigator's Abstract) Major goals for this project are to establish the roles of Ang II and Na in resetting of the arterial baroreflex (ABR) in AngII-induced hypertension. Experiments will determine the integrative roles of the area postrema (AP), the paraventricular nucleus (PVN), and hepatoportal osmo/Na receptors in ABR resetting and the accompanying HT. The hypotheses to be tested are (1) HT due to low dose infusions of Ang II and NaCl involves an upward resetting of the ABR and (2) Converging projections from the AP, PVN, and hepatoportal osmo/Na receptors within the NTS determine the integrative neuronal response to baroreceptor afferent input. Both the resetting and changes in NTS neuronal responses involve activation in the AP and PVN. Activity within the AP is due to circulating Ang II, while the PVN is sensitive to Na. When Na is increased, hepatoportal reflexes will oppose ABR resetting and the Ang II-induced HT. To test these hypotheses, the combined and separate roles of AngII and Na on ABR control of RSNA, MAP and HT will be determined in conscious rats. Hepatoportal denervation, lesioning and AT1 receptor blockade of the AP and PVN, and selective activation of afferents in the three regions will be determined. One goal is to determine if AP and PVN inputs attenuate NTS neuronal responses to baroreceptor afferent inputs. Other goals are to determine if hepatoportal afferents facilitate baroreceptor-evoked single unit discharge, thereby opposing the inhibitory influence of AP and PVN inputs. Proposed studies are unique in that they are the first to investigate potential interactions between the brainstem (AP), descending hypothalamic (PVN) and ascending peripheral afferent (hepatoportal) inputs on the reflex regulation of sympathetic outflow and arterial pressure. Proposed studies will build upon our understanding of how circulating factors can influence the ABR and will provide a foundation for future studies to determine the specific neurotransmitter mechanisms that are active in modulating ABR function in health and disease.