Several clinically available antihypertensive drugs are known to act within the central nervous system to produce a reduction in arterial pressure. Clonidine and methyldopa typify this class of drugs and both compounds are central alpha-adrenergic agonists although their structure and neuronal metabolism are quite different. While central alpha-adrenergic receptors are important for their antihypertensive action brain catecholaminergic neurons are not required, and the maintenance of experimental hypertension may not be dependent on this central neuronal system. Recent studies in this laboratory have suggested an alternate hypothesis. We have found that both clonidine and methylopa produce marked inhibition of central cholinergic neuronal activity in the spontaneously hypertensive rat (SHR). Also, it appears that cholinergic neuronal activity is enhanced in certain brain regions of this model. The purpose of this project is to provide further evidence for the role of central cholinergic neurons in mediating the antihypertensive action of drugs like clonidine and methyldopa. This will be accomplished by 1) examining the ability of clonidine and methyldopa to inhibit the synthesis of regional brain acetylcholine (ACh) in other models of experimental hypertension, DOCA-salt hypertension, Grollman renal hypertension, and salt induced hypertension in the Dahl, salt-sensitive strain; 2) examining the effects on brain ACh metabolism of other clonidine-like drugs, i.e., guanfacine and xylazine; 3) comparing the relative rates of ACh biosynthesis in the models of hypertension and their respective normotensive controls and 4) examining the effects of pharmacologic inhibition of presynaptic central cholinergic activity through the formation of a cholinergic 'false neurotransmitter'. In all studies arterial pressure will be measured directly from unanesthetized rats. ACh biosynthesis will be estimated biochemically by tracer injection of the precursor 3H-choline with subsequent measurement of the rate of formation of labeled ACh. Correlation of both neurochemical and neuropharmacological data will be employed to test our central cholinergic hypothesis of experimental hypertension. This study will aid in understanding the nature of central adrenergic-cholinergic interactions in hypertensive disease and in the mechanism of action of clonidine and related drugs.
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