SUMMARY The combined and individual carotid sinus and aortic baroreceptor control of sympathetic nerve activity (SNA) and mean arterial pressure (MAP) were studied by direct measurement In groups of spontaneously hypertensive rats (SHR) and normotensive Kyoto Wistar rats (WKY) of 5 to 40 weeks of age. The SHR showed a significantly greater SNA and resultant MAP increase as a function of age compared to that of the WKY rats. Both SHR and WKY rats showed a significant rise in SNA and MAP with ablation of all four major baroreceptors. The proportionate change of SNA and MAP after ablation was greater in the younger SHR than In the younger WKY groups and the change in these decreased as a function of age in the SHR. The reflex inhibition of SNA via baroreceptor stimulation also decreased as a function of age in the SHR, due to a 43% loss of aortic inhibitory function; no significant loss of carotid sinus function was found in either the SHR or WKY. The decrement in aortic function occurred after the rapid phase of blood pressure development; therefore baroreceptor dysfunction cannot be the cause of the high SNA and MAP observed in young SHR. An upward resetting of central sympathetic centers was evaluated via the baroreceptor deafferentatlon; and, it appears that the hyperactive sympathetic nervous system and resultant hypertension in the SHR is due to central resetting of sympathetic centers rather than baroreceptor dysfunction. T HE sympathetic nervous system has been shown to be hyperactive in the spontaneously hypertensive rat (SHR), and to be a significant factor in the development and maintenance of high blood pressure in this genetic model of hypertension. 16 The factors responsible for the elevated sympathetic nerve activity (SNA) in the SHR are unknown. Historically, it was hypothesized that in experimental renal hypertension a loss of carotid sinus and aortic reflex inhibitory control of SNA resulted in an increase in SNA which in turn produced the hypertensive condition. However, in such studies, the arterial baroreceptors have been shown to adapt or reset during hypertension, such that they have an increased stimulus pressure threshold, a normal firing frequency, and an extended operational range."
The potential for catheter-based in vivo delivery of genetic material to the arterial wall is incompletely explored. We evaluated the level of recombinant protein production as well as the anatomic distribution and duration of gene expression following adenoviral vector-mediated gene transfer into sheep arteries via a double balloon catheter. Catheters were positioned in the carotid or femoral arteries of 20 sheep via a combined percutaneous and surgical approach, and virions infused over a 30-min period. Three days later, recombinant gene expression was identified in approximately 30% (range 0-80%) of the luminal endothelial cells within the targeted area of the artery. Persistent recombinant protein expression was identified histochemically for up to 4 weeks, although the number of positive cells decreased steadily. High levels of both beta-galactosidase (beta-Gal) activity and protein (mean 20 mU and 44 ng per vessel) were measured in vessel extracts 3 days after gene transfer, again decreasing significantly over a 4-week period. Transgene expression was limited almost entirely to the intima and adventitia; adventitial gene transfer occurred virtually exclusively along the vasa vasorum. In comparison to previous studies of catheter-based gene transfer, adenoviral vectors delivered by double balloon catheter resulted in a particularly high efficiency of endothelial cell gene transfer. The efficiency and amount of recombinant gene expression achieved in this study suggest that catheter-based gene delivery may eventually be applicable to the treatment of focal human arterial disease.
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