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The sympathetic branch of the autonomic system is a key regulator of blood pressure. Secretory vesicles of chromaffin cells and sympathetic axons release co-stored transmitters by exocytosis into the bloodstream or synaptic clefts, where they contact cardiovascular target cells. In addition to catecholamines, the secretory "quantum" includes neuropeptides (such as NPY), and chromogranins, precursors of active peptides which influence vascular responses to sympathoadrenal activation, and hence blood pressure.
This Program links four Projects with long-standing collaborations in synthesis, release, and actions (pre- and post-synaptic) of these transmitters, integrating their effects on blood pressure. Central hypotheses and themes focus interactive efforts. Projects 1 and 2 include human studies, and Project 2 probes sympathetic neuroeffector mechanisms in intact rodents, while Projects 4 and 2 clarify cellular mechanisms in transmitter biosynthesis and release, and also exploit ex vivo biological materials from Projects 1 and 2 for phenotyping. Human studies probe the genetic basis of heritable alterations in autonomic activity in pedigrees with hypertension (Project 1; Core D), and each Project (1 and 4) participates in phenotyping unique autonomic traits in pedigree members. Already, significant, novel genetic linkages have emerged, with intriguing allelic variations found in the alpha-1-beta-adrenergic receptor and the renal kallikrein promoter.
Five Core facilities provide defined cell populations, signal probes, genotyping, physical mapping, informatics, catecholamine and vasoactive peptide assays, and imaging. Using molecular biological and informatic tools, the program aims to achieve a new level of understanding of the dynamic complexity of the sympathetic neuroeffector junction, and how its components contribute to heritable changes in blood pressure, and ultimately to human hypertension.
This Program therefore represents a unique
opportunity to define the genetic basis of autonomic dysfunction
in human essential hypertension.
Note: The following Diagram is an image map with links
from the Investigator Names to Projects and Cores.
Move the mouse over on of the investigator Names, and click.
Schematic diagram of
the sympathetic neuroeffector junction, showing how
application of each Project to a particular pre- or post-synaptic
process.
1. The physiologic and anatomic focus: the sympathetic neuroeffector junction.
The sympathoadrenal efferent branch of the autonomic nervous system plays a key minute-to-minute role in regulation of blood pressure, and excessive sympathoadrenal activity is clearly implicated in the pathogenesis of hypertension, both primary (genetic, essential) and secondary (acquired), in both humans and experimental animals.
This system acts by co-release through exocytosis (all-or-none discharge) of co-transmitters from secretory vesicles of postganglionic sympathetic axons and chromaffin cells (MA Takiyyuddin, JH Cervenka, PA Sullivan, MR Pandian, JA Barbosa, RJ Parmer, DT O'Connor. Is physiologic sympathoadrenal catecholamine release exocytotic in humans? Circulation 81:185-95, 1990; abstract), into the bloodstream or neuroeffector junctions (synaptic clefts), wherein co-transmitters impinge on cardiovascular target cells, such as vascular smooth muscle, myocardiocytes, and endothelial cells, thereby regulating blood pressure.
While the best-studied sympathoadrenal co-transmitters are the catecholamines (norepinephrine and epinephrine), a complex "cocktail" of substances is co-released by exocytosis from storage vesicles, including not just the catecholamines themselves, but also neuropeptides such as neuropeptide Y (MA Takiyyuddin, MR Brown, TQ Dinh, JH Cervenka, SD Braun, RJ Parmer, B Kennedy, DT O'Connor. Sympathoadrenal secretion in humans: factors governing catecholamine and storage vesicle peptide co-release. J Autonom Pharmacol 14:177-190, 1994; abstract), and several large acidic proteins, the chromogranins / secretogranins, which are cleaved to biologically active peptides which modulate both neurosecretion and vascular smooth muscle relaxation (MA Takiyyuddin, JH Cervenka, RJ Hsiao, JA Barbosa, RJ Parmer, DT O'Connor. Chromogranin A: storage and release in hypertension. Hypertension 15:237-46, 1990; abstract).
It has become clear that co-transmitters other than the catecholamines themselves also participate in the vascular responses to sympathoadrenal activation. Evidence in support of this principle includes the observation that the vasoconstriction of sympathetic activation is only partially reversed by alpha- (even in combination with beta-) adrenergic blockade; NPY is also involved (Kennedy B; Shen GH; Ziegler MG. Neuropeptide Y-mediated pressor responses following high-frequency stimulation of the rat sympathetic nervous system. Journal of Pharmacology and Experimental Therapeutics. 281:291-6, 1997; abstract). Both pre- and postsynaptic function may be disturbed in hypertension (J de Champlain. Pre- and postsynaptic adrenergic dysfunction in hypertension. J Hypertension 8:S77-S85, 1990; abstract).
Several UCSD laboratories (see the sympathetic neuroeffector junction diagram above) have long-standing collaborative interests in the synthesis and release of these sympathetic junctional co-transmitters, as well as their pre- and post-synaptic actions. In the past several years, each of the investigators in this program project grant application have turned increasingly to the tools of cell and molecular biology and biophysics, to probe the biosynthetic regulation and actions of these neuroeffector junction components, at the most fundamental level. This Program links together these cell and molecular biologic investigators, but also interlocks with two Projects (Projects 1 and 2) studying intact organisms, and focuses attention on blood pressure as the biological "read-out" of integration of the co-transmitters' signals in the noradrenergic cleft.
As outlined below, one of the overall, unifying hypotheses of this Program is that the integral activity of the sympathetic neuroeffector junction is clearly more than the simple sum of its parts. Integrating functional themes about such junctions can best be approached or attained in a format merging multiple interests (i.e., the individual neurotransmitters) with multiple contributing methodologies (i.e., structural biology, molecular biology, biochemistry, and organ or organismal physiology).
2. Program Project Hypotheses.
A. Regulation. Release of sympathetic neurotransmitters is subject to multiple levels of anatomic and biochemical control:
B. Catecholamine-peptide (co-transmitter) interactions. Multiple co-transmitters are co-released during exocytotic catecholamine secretion by postganglionic sympathetic axons and chromaffin cells. Such co-transmitters include catecholamines, neuropeptide Y (NPY), and active fragments of the chromogranins/secretogranins. In the neuroeffector junction, these co-transmitters not only activate post-synaptic targets (such as vascular smooth muscle), but also impinge upon the pre-synaptic terminal itself, modulating further pre-synaptic neurosecretion. The co-transmitters (especially catecholamines and peptides) influence each other at the control levels of both biosynthesis and release.
C. The complete integrated post-synaptic signal. The sympathetic neuroeffector junction is thus a complex, dynamic unit whose multiple individual transmitters and receptors are locally and functionally cross-coupled. The whole (integrated post-synaptic signal) is therefore far more complex than the sum of its parts (multiple individual co-transmitters). As a corollary, drawing conclusions from the cardiovascular effects any individual neurotransmitter in isolation may provide at best a partial view of even normal functioning.
D. Blood pressure responses to efferent sympathetic stimulation thus represent a final common path integrating a multitude of signals, pre- and post-synaptic.
E. Thus, an interactive study of the multiple sympathetic co-transmitters, at distinct biochemical (synthesis, release, receptor binding, signal transduction) and anatomic (pre- versus post-junctional) levels, is likely to yield a superior approximation of the overall sympathetic contribution to blood pressure.
F. Anchor points. Since autonomic function is altered early in the course of human essential (hereditary) hypertension, sympathetic neuroeffector traits constitute logical phenotypic anchor points (or "intermediate phenotypes") for a linkage study of hypertension.
3. Program
project themes.
We will test the above hypotheses by exploring the following local
(neuroeffector junction) interactive themes:
A. Mechanism of transmitter co-release: exocytosis (all-or-none). The functional consequences of exocytotic co-release of multiple co-transmitters (catecholamines and peptides) will be probed. Such consequences may result from:
1. Reciprocal effects of one co-transmitter upon biosynthesis or release of another. For example, the chromogranin A fragment "catestatin" inhibits nicotinic cholinergic-stimulated catecholamine release.
2. Co-transmitter interactions at a target cell.
B. Anatomy of transmitter co-release: focus on the sympathetic neuroeffector junction. Synaptic mechanisms will be probed at two levels of the synapse:
1. Pre-junctional
(transmitter biosynthesis and release), and,
2. Post-junctional (blood pressure actions of released
transmitters).
Each of these themes is explored by:
1. >2 particular Projects, with Core support.
2. Specific synergistic collaborations among >2 Projects.
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Latest modification: December, 1999
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