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...