Cardiovascular autonomic modulation by nitric oxide synthases accounts for the augmented enalapril-evoked hypotension in ethanol-fed female rats

Abstract

In this study, we investigated the role of nitric oxide synthase (NOS) isoforms in the enhanced enalapril-evoked hypotension in ethanol-fed female rats by examining the effect of the selective inhibitors of eNOS [N(5)-(1-iminoethyl)-l-ornithine; l-NIO], nNOS (N(ω)-propyl-l-arginine; NPLA), or iNOS (1400W) inhibition on the cardiovascular effects of enalapril in ethanol- (5% w/v) fed rats and in their pair-fed controls. In liquid diet-fed control rats, enalapril- (10 mg/kg) evoked hypotension was abolished by l-NIO (20 mg/kg), but not by NPLA (1 mg/kg) or 1400W (5 mg/kg), suggesting a preferential role for eNOS in this response. Enalapril had no effect on spectral indices of hemodynamic variability or +dP/dtmax (myocardial contractility). However, in ethanol-fed rats, the greater enalapril-evoked hypotension was associated with reductions in (i) +dP/dtmax, (ii) low-frequency/high-frequency ratio of interbeat intervals (IBILF/HF), suggesting cardiac parasympathetic dominance, and (iii) low-frequency spectral band of systolic blood pressure (BP), a marker of vasomotor sympathetic tone. While NPLA or 1400W attenuated the enalapril-evoked hemodynamic and autonomic responses in ethanol-fed rats, l-NIO virtually abolished the hypotensive response and was more efficacious in rectifying autonomic responses to enalapril. Together, these findings implicate NOS isoforms, particularly eNOS, in the altered cardiovascular autonomic control that leads to the augmented enalapril-evoked hypotension in ethanol-fed female rats.

Figure 1

The effect of chronic ethanol (5% w/v) or control liquid diet feeding on changes in mean arterial pressure (MAP, left panels) and heart rate (HR, right panels) evoked by i.p. enalapril (10 mg/kg) in the absence or presence of i.p. L-NIO (eNOS inhibitor, 20 mg/kg, panels A and B), NPLA (nNOS inhibitor, 1 mg/kg, panels C and D), or 1400W (iNOS inhibitor, 5 mg/kg, panels E and F) in conscious telemetered female rats. Values are means ± S.E.M. of 6–7 observations. ^*P < 0.05 vs. saline values, ⁺P < 0.05 vs. enalapril (control) values, ^#P < 0.05 vs. L-NIO+enalapril (control) values, ^$P < 0.05 vs. L-NIO+enalapril (ethanol) values.

Figure 2

The effect of chronic ethanol (5% w/v) or control liquid diet feeding on changes in myocardial contractility index (+dP/dt_max) evoked by i.p. enalapril (10 mg/kg) in the absence or presence of L-NIO (eNOS inhibitor, 20 mg/kg, panel A), NPLA (nNOS inhibitor, 1 mg/kg, panel B), or 1400W (iNOS inhibitor, 5 mg/kg panel C) in conscious telemetered female rats. Values are means ± S.E.M. of 6–7 observations. ^*P < 0.05 vs. saline values, ⁺P < 0.05 vs. enalapril (control) values, ^#P < 0.05 vs. L-NIO+enalapril (control) values, ^$P < 0.05 vs. L-NIO+enalapril (ethanol) values.

Figure 3

The effect of chronic ethanol (5% w/v) or control liquid diet feeding on changes in high-frequency (IBI-HF_nu, 0.75–3 Hz, left panels) and low-frequency (IBI-LF_nu, 0.25–0.75 Hz, right panels) spectral bands of IBI evoked by i.p. enalapril (10 mg/kg) in the absence or presence of i.p. L-NIO (eNOS inhibitor, 20 mg/kg, panels A and B), NPLA (nNOS inhibitor, 1 mg/kg, panels C and D), or 1400W (iNOS inhibitor, 5 mg/kg, panels E and F) in conscious telemetered female rats. Values are means ± S.E.M. of 6–7 observations. ^*P < 0.05 vs. saline values, ^#P < 0.05 vs. L-NIO+enalapril (control) values, ^$P < 0.05 vs. L-NIO+enalapril (ethanol) values.

Figure 4

The effect of chronic ethanol (5% w/v) or control liquid diet feeding on changes in LF/HF ratio of IBI evoked by i.p. enalapril (10 mg/kg) in the absence or presence of i.p. L-NIO (eNOS inhibitor, 20 mg/kg, panel A), NPLA (nNOS inhibitor, 1 mg/kg, panel B), or 1400W (iNOS inhibitor, 5 mg/kg panel C) in conscious telemetered female rats. Values are means ± S.E.M. of 6–7 observations. ^*P < 0.05 vs. saline values, ⁺P < 0.05 vs. enalapril (control) values, ^#P < 0.05 vs. L-NIO+enalapril (control) values, ^$P < 0.05 vs. L-NIO+enalapril (ethanol) values.

Figure 5

The effect of chronic ethanol (5% w/v) or control liquid diet feeding on changes in low-frequency SBP spectral density (SBP-LF, 0.25–0.75 Hz) evoked by i.p. enalapril (10 mg/kg) in the absence or presence of i.p. L-NIO (eNOS inhibitor, 20 mg/kg, panel A), NPLA (nNOS inhibitor, 1 mg/kg, panel B), or 1400W (iNOS inhibitor, 5 mg/kg panel C) in conscious telemetered female rats. Values are means ± S.E.M. of 6–7 observations. ^*P < 0.05 vs. saline values, ⁺P < 0.05 vs. enalapril (control) values, ^#P < 0.05 vs. L-NIO+enalapril (control) values, ^$P < 0.05 vs. L-NIO+enalapril (ethanol) values.