The aim of the proposed research is to further our understanding of the role of the sympathetic neuron calcium current in the pathogenesis and maintenance of hypertension. Recent studies have shown that an exaggerated release of norepinephrine (NE) from peripheral adrenergic nerve terminals may e one of the mechanisms producing hypertension in the spontaneously hypertensive rat (SHR) model of primary hypertensin. Although the mechanism underlying this phenomenon remains obscure, it has been proposed that a dysfunction in the presynaptic receptor mediated regulation of calcium-dependent exocytotic NE release may be responsible. Thus, the hypotheses to be tested are that: 1) an alteration in the biophysical properties and/or 2) an alteration in the neurotransmitter modulation, of the sympathetic ganglion voltage-gated calcium current is associated with the development and/or maintenance of hypertension in SHR. Accordingly, the Specific Aims of the proposal are to compare the properties ad neurotransmitter modulation of the voltage-gated calcium current of superior cervical ganglion (SCG) neurons acutely isolated from SHR and age-matched normotensive Wistar-Kyoto (WKY) rats. This will be accomplished using the patch-clamp technique in the whole-cell voltage- clamp mode. The following calcium current processes will be studied: 1) biophysical properties, i.e. activation, dihyrodopyridine sensitivity, and current density; and 2) the effect of and concentration-response relationship for NE and adenosine, agents which inhibit NE release, and isoproterenol and angiotensin II, agents which stimulate NE release. These studies will be done on both young SGR (4-6 weeks) in the """"""""prehypertensive phase"""""""" ad older SHR (20-24 weeks) in the """"""""established phase"""""""" of hypertension to explore the relationship between development of hypertensin and calcium current properties. In addition, studies will be performed to determine whether calcium current alterations are specific to the genetic SHR model of hypertensin. Although there is considerable evidence suggesting a role for the peripheral sympathetic nervous system in the pathogenesis and maintenance of hypertension in SHR, the electrophysiology of sympathetic ganglion neurons in SHR has received little attention. It is hoped that the proposed study will help fill this void in our understanding of the pathobiology of hypertension and provide a basis for the development of improved antihypertensive agents.
