Recent work has demonstrated that increased sympathetic nerve activity and/or increased norepinephrine (NE) release is associated with the development or maintenance of hypertension in the spontaneously hypertensive rat (SHR). These effects are likely to encompass the neurons which control kidney function and the increased NE release per impulse could be associated with an enhancement or defective regulation of the Ca2+ current in the SHR. Thus the hypothesis to be tested is that: the SHR exhibits an alteration in the properties and/or neurotransmitter modulation of voltage-dependent Ca2+ channels in renal efferent sympathetic neurons, and that these alterations contribute to the development and maintenance of hypertension in the SHR.
The specific aims of the proposal are to: compare the properties of and neurotransmitter modulation of Ca2+ currents of renal efferent sympathetic neurons of SHR and age matched WKY rats using the whole-cell patch-clamp technique. The Ca2+ channels will be characterized in terms of: channel density, single channel conductance and open probability, activation and inactivation voltage ranges, voltage-dependence of current time course and Ca2+ channel type. Ca2+ channel modulation will be investigated by constructing concentration response curves for NE, adenosine and somatostatin, agents known to inhibit Ca2+ currents and/or CA2+ dependent exocytotic NE release. The effects of nitric oxide donors which can increase Ca2+ currents and/or Ca2+-dependent exocytotic NE release will be investigated. The role of signal transduction mechanisms in the neurotransmitter modulation of the Ca2+ channels will be investigated using nonhydolyzable guanine nucleotide analogs and pertussis toxin as well as activators and inhibitors of protein kinases. Parallel investigations of neurons which do not innervate the kidney will be undertaken to investigate if alterations of the biophysical properties of the Ca2+ channels of SHR are unique to renal efferent sympathetic neurons. Alterations in Ca2+ channel behavior which are causative of the hypertension will be differentiated from those that are secondary to the hypertension by 1) using SHR and WKY rats from different age groups, alterations of Ca2+ channels not causative of hypertension would not be expected in SHR in the """"""""prehypertensive"""""""" stage and 2) chronic antihypertensive drug therapy will be used to differentiate changes in Ca2+ channel behavior which are secondary to the hypertension. The experiments are expected to yield valuable data concerning the cellular mechanism(s) of increased NE release from key sympathetic neurons in hypertension.
| Vari, R C; Emaduddin, M; Schofield, G G (1999) Renal function and Ca(2+) currents after dye-labeling identification of renal sympathetic neurons. Am J Physiol 277:R1513-21 |
