Abstract
Objective: Patients with reduced nonlinear component of heart rate regulation show a poor prognosis. We previously reported that the linear correlation between renal sympathetic nerve activity(RSNA) and blood pressure(BP) or RSNA and renal blood flow(RBF) was significantly higher and the nonlinear correlation was lower in spontaneously hypertensive rats(SHR) than in Wistar-Kyoto rats. In the present study, we examined whether the linear and nonlinear correlation between RSNA and BP or RBF would change in SHR orally treated with angiotensin IIreceptor blocker(candesartan) or calcium channel blocker(amlodipine) for 2 weeks. Also, to elucidate mechanisms underlying the reduced linearity by amlodipine, we examined whether the linear and nonlinear correlation between RSNA and BP or RBF would change in SHR treated with amlodipine and L-NAME orally for 2 weeks.
Methods: By recording BP, RSNA, heart rate, and ipsilateral RBF simultaneously in conscious state, we compared the linear(coherence of transfer function) and nonlinear(mutual information method) correlations among RSNA, BP and RBF in SHR treated with drugs.
<Protocol 1> Candesartan(1mg/kg/day, n=13), amlodipine(5mg/kg/day, n=7) or vehicle (n=7) was given orally for 2 weeks to SHRs.
<Protocol 2> Combination of amlodipine(5mg/kg/day) and L-NAME(1.5mg/kg/day, n=9), amlodipine(5mg/kg/ day, n=7), or vehicle was given orally for 2 weeks to SHRs.
Results: <Protocol 1>Mean RSNA was significantly decreased in the candesartan group despite lower BP and larger RBF, whereas RSNA did not decrease in the amlodipine group. The coherence between RSNA and BP or between RSNA and RBF at 0-1.0 Hz was significantly reduced in both candesartan and amlodipine groups compared with vehicle group. In contrast , mutual information of the correlation between RSNA and BP or RSNA and RBF increased in both candesaratan and amlodipine groups. <Protocol 2> The coherence between RSNA and BP or RBF was significantly higher and mutual information was lower in SHR treated with amlodipine plus L-NAME compared with SHR treated with only amlodipine.
Conclusions: The data regarding candesartan suggest that blockade of the renin-angiotensin system and sympathetic nervous system contributes to the reduced linearity and increased nonlinearity. However, since this is not the case with amlodipine, increased nitric oxide contributed to the improved neural regulation by the calcium channel blocker. Since potentiated sympathetic nerve activity and high linearity/low nonlinearity are risk factors for cardiovascular events, drugs that reduce sympathetic nerve activity and normalize the neural regulation are beneficial to prevent cardiovascular events in hypertensive patients.
