Sympathetic nerve activity (SNA) and high pressure baroreceptor regulation of SNA were studied in the Okamoto strain of spontaneously hypertensive rat (SHR). Mean arterial pressure (MAP) and SNA were not significantly affected by anesthesia with low doses of pentobarbital (20-25 mg/kg). Thus, most of these studies were performed in anesthetized rats. SNA in visceral sympathetic nerves increased rapidly with age up to 24 weeks and slowly thereafter. MAP increased with SNA, following the same time course. Both SNA and MAP in SHR were significantly greater than that found in normotensive Wistar control rats of comparable ages. Abolition of ganglionic transmission with hexamethonium in both SHR and normotensive controls reduced postganglionic SNA and MAP to comparable levels. In SHR less than 16 weeks old, increased baroreceptor stimulation effectively inhibited SNA with the same sensitivity as found in Wistar control rats. However, older SHR appeared to lose their ability to completely inhibit SNA during induced hypertension, whereas in Wistar control rats as old as 52 weeks, elevation of blood pressure to 165.3 +/- 2.3 mm Hg completely suppressed SNA. These results suggest that SNA may play an important role in the development and maintenance of hypertension in SHR, and that central sympathetic centers, uninhibited by baroreceptor afferents, become active during the development of hypertension in the SHR.

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."

SUMMARY The genetic basis of hyperactivity of the sympathetic nervous system (SNA) in spontaneously hypertensive rats (SHR) was assessed by measuring SNA in animals derived from a backcross (BC) breeding program designed to isolate single gene differences causing changes in blood pressure. Selective breeding of the male hypertensive rats with inbred normotensive female Wistar/Lewis rats yielded progeny with a range of blood pressures, but whose group mean pressures were lower than the group mean pressures of the original SHR. Progressive generations had progressively lower group mean pressures. There was a positive correlation between SNA and mean arterial pressure in BC rats. These results indicate that the genetic defect in SHR may be an abnormality in SNA, and the hypertension in these animals is a secondary result of this primary defect. Baroreceptor function was also assessed in SHR and in BC rats. In young (8 to 24 weeks old) SHR, baroreceptor function was similar to that in BC rats, whereas SNA was markedly increased. Only in older (24 to 40 weeks old) SHR was there an abnormality in the gain of baroreceptors. The development of hypertension in SHR therefore appears to be due to increased SNA resulting from a defect in the central nervous system. Changes in baroreceptor function are secondary to the hypertension and occur after the hypertension is established. (Hypertension 1: 598-604, 1979) KEY WORDS • spontaneous hypertension • sympathetic nervous system • backcross rat • genetics • blood pressure E XCESSIVE activity of the sympathetic nervous system has been shown to be a significant causative factor in the hypertension of the Okamoto strain of the spontaneously hypertensive rat (SHR). Directly measured sympathetic nerve activity (SNA) is markedly increased in the SHR compared to normotensive Wistar rats, 15 and surgical or pharmacological abolition of SNA leads to greater reductions in blood pressure in the SHR. 611 The mechanisms responsible for the increased SNA, which results in hypertension in the SHR, are unknown. Two proposed mechanisms are adaptive changes in arterial baroreceptors, '12~14 or neurochemical changes in the central nervous system's (CNS) sympathetic centers, 1516 both of which have been postulated to result in increased SNA and the consequent hypertension.Although the SHR has been widely used as a model of essential hypertension, the results and conclusions derived from studies using this animal have been undermined by questions of the appropriateness of the control rat used in the experiments. Most investigators agree that the Kyoto Wistar strain of normotensive rats, the parent strain of the SHR, is an adequate control animal. However, their usefulness has been modest because of their limited availability. To provide another control strain genetically related to the SHR, one of the authors (P.L.Y.) initiated a backcross breeding program in 1972 to develop hypertensive and normotensive lines of rats from a cross between SHR and a normotensive, inbred strain (Wistar/Lewis). In ad...

SUMMARY We examined the effect of L-dopa, after peripheral L-amino acid decarboxylase inhibition, on sympathetic nerve activity (SNA) and blood pressure in spontaneously hypertensive rats (SHR) and in normotensive control rats. L-Dopa reduced SNA in both groups of animals. The SHRs were significantly more sensitive to the depressor effect of L-dopa than were the control animals, the threshold dose for reduction of SNA being 3 mg/kg in SHR and 15 mg/kg in control rats. Similarly, the magnitude of inhibition of SNA was substantially greater in the SHR than in normotensive rats. The reduction in SNA in the SHR was accompanied by a parallel fall in blood pressure. In contrast, blood pressure in control rats did not change significantly, even though SNA was diminished. Studies of the penetration of L-dopa into the cerebral parenchyma revealed that equivalent amounts of the amino acid entered the brains of the two groups of rats. These results suggest that the SHRs are more sensitive to the SNA-inhibiting effects of L-dopa than are normotensive rats. In addition, they confirm our previous suggestion that excessive SNA plays a causative role in the hypertension of the SHR.A GROWING body of evidence indicates that a significantly causative factor in the hypertension of the Okamoto strain of spontaneously hypertensive rat (SHR) is excessive sympathetic nerve activity (SNA). The major observations supporting such a conclusion are that pharmacological or surgical abolition of SNA leads to a reduction in blood pressure in the SHR, 1 " 4 and that directly measured SNA is markedly increased. 510 In addition, studies of baroreceptor regulation of blood pressure demonstrate a decreased baroreceptor sensitivity in the SHR compared to normotensive control rats.7 ' H> 12 Although the mechanism underlying the excessive SNA and decreased baroreceptor sensitivity is not known, it seems reasonable to postulate that the abnormality resides in certain vasomotor regulatory centers in the brain. Further, in light of the knowledge that the antihypertensive agents which are thought to act substantially or primarily in the central nervous system (CNS) interact with adrenergic nerves or receptors, it appears possible that a CNS abnormality in the SHR which leads to hypertension involves brain catecholamine metabolism, as previously suggested by other investigators. 13One approach to studying CNS adrenergic regulation of physiological responses in intact animals is to use drugs to either inhibit or activate CNS adrenergic systems. Such an approach, using agents such as reserpine, intra- Received October 31, 1977; accepted for publication February 22, 1978. cerebral 6-hydroxydopamine, alpha-methyl dopa, clonidine, intracerebral dopamine, or ergot derivatives, has been applied to the study of depression, extrapyramidal disorders, hypertension, and the regulation of hypothalamic releasing factors.14 " 18 By using L-dopa, an amino acid precursor of catecholamines, we and others have shown that an increase in CNS catecholamine content results i...

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