The principal objective of the proposed study is to examine aspects of sympathoadrenal function and catecholamine inactivation in animal models of diabetes with specific emphasis on the vasculature. Rats and rabbits will be rendered diabetic by treatment with a diabetogenic agent. Selected blood vessels will be removed from diabetic and age matched control rats and the following neuroeffector processes examined: (1) release of neuronal norepinephrine (NE) and dopamine hydroxylase (DBH) with stimulation of sympathetic nerves in the rat; (2) the inactivation of catecholamines by neuronal and extraneuronal metabolism; (3) pharmacological responses to electrical stimulation in the absence and presence of agents known to block neuronal and/or extraneuronal uptake; and (4) the activities of the NE synthesizing enzymes in vascular tissue. In all of the preceeding experiments, focus will be directed toward the early (onset) and late (established) stages of diabetes as well as the effects of insulin replacement, thyroid hormone therapy and adrenalectomy. The methodological procedures will include incubation of segments of blood vessels in the presence of tritiated NE, (3H NE) analysis of the tritiated metabolites of 3H NE by paper chromatography and radiochemical assay of the activities of the NE metabolizing enzymes [monoamine oxidase and catechol-O-methy (transferase)] and NE synthesizing enzymes (DBH, and Tyrosine Hydroxylase). Endogenous catecholamine concentrations will also be measured using high pressure liquid chromatography combined with electrochemical detection. A second aspect of the proposed investigation explores the possibility that adrenoceptors may influence the severity of vestigation explores the possibility that adrenoceptors may influence the severity of diabetes produced by administration of a diabetogenic agent. The long-term objectives are two-fold. Firstly, to better understand the functioning of the sympathetic neurons systems in the diabetic state, and secondly, to explore the possibility that changes in function of the sympathetic nerves innervating the vasculature may play a role in the development of the pathological vascular disease states associated with diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL001228-02
Application #
3073686
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1984-01-01
Project End
1988-12-31
Budget Start
1985-01-01
Budget End
1985-12-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
West Virginia University
Department
Type
School of Medicine & Dentistry
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Head, R J (1991) Hypernoradrenergic innervation and vascular smooth muscle hyperplastic change. Blood Vessels 28:173-8
Panek, D U; Stitzel, R E; de la Lande, I S et al. (1989) Application of amperometric detection to the analysis of the diffusion and O-methylation of a catecholamine and a catechol steroid across the blood vessel wall. J Pharmacol Methods 21:171-82
Head, R J (1989) Hypernoradrenergic innervation: its relationship to functional and hyperplastic changes in the vasculature of the spontaneously hypertensive rat. Blood Vessels 26:1-20
Donohue, S J; Stitzel, R E; Head, R J (1988) Time course of changes in the norepinephrine content of tissues from spontaneously hypertensive and Wistar Kyoto rats. J Pharmacol Exp Ther 245:24-31
Cassis, L A; Stitzel, R E; Head, R J (1988) Influence of cold-induced increases in sympathetic nerve activity on norepinephrine content in the vasculature of the spontaneously hypertensive rat. Blood Vessels 25:82-8
Head, R J; Longhurst, P A; Panek, R L et al. (1987) A contrasting effect of the diabetic state upon the contractile responses of aortic preparations from the rat and rabbit. Br J Pharmacol 91:275-86
Barone, S; Panek, D; Bennett, L et al. (1987) The influence of oestrogen and oestrogen metabolites on the sensitivity of the isolated rabbit aorta to catecholamines. Naunyn Schmiedebergs Arch Pharmacol 335:513-20
Panek, D U; Azzaro, A J; Stitzel, R E et al. (1987) Inhibition of tyrosine hydroxylase in rabbit mesenteric artery and vas deferens by catechol oestrogens. Naunyn Schmiedebergs Arch Pharmacol 335:243-9
Rice, P J; Taylor, D A; Valinski, W A et al. (1987) Norepinephrine depletion and sensitivity changes in rat heart induced by pretreatment with reserpine. J Pharmacol Exp Ther 240:764-71
Reid, J J; Stitzel, R E; Head, R J (1986) Evidence that 6-hydroxydopamine is an inhibitor of catechol-O-methyltransferase in intact tissue. J Pharm Pharmacol 38:46-50

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