Abnormal baroreflex function is dissociated from central angiotensin II receptor expression in chronic heart failure

Abstract

Neurohumoral disturbances characterize chronic heart failure (CHF) and are reflected, in part, as impairment of baroreflex sensitivity (BRS) and sympathetic function. However, the mechanisms that trigger these neurohumoral abnormalities in CHF are not clear. We hypothesized that the BRS is blunted early in CHF and that the humoral effects occur later and contribute to progressive loss of cardiovascular control in CHF. We assessed the BRS (beats/min per mmHg) and recorded renal sympathetic nerve activity (RSNA) in four groups of conscious rabbits at varying time intervals: control, 1-week CHF, 2-week CHF, and 3-week CHF. Chronic heart failure was induced by ventricular pacing at 360 beats/min and was assessed by echocardiography. Arterial blood pressure and heart rate were recorded by an implanted telemetric device and RSNA through an implanted electrode. A significant fall in the ejection fraction, fractional shortening, and an increase in left ventricular end-systolic diameter and left ventricular end-diastolic diameter were observed in all CHF groups. The BRS was significantly reduced in all the CHF groups with no significant change in the basal RSNA (% of maximum) after 1 week of pacing; a small but insignificant rise in RSNA was seen at 2 weeks, and a significant rise in RSNA was observed at 3 weeks. Angiotensin II type 1 (AT-1) receptor protein (Western Blot) and mRNA (reverse transcriptase-polymerase chain reaction) expression in the rostral ventrolateral medulla exhibited a progressive increase with the duration of CHF, reaching significance after 3 weeks, the same time point in which RSNA was significantly elevated. These data are the first to examine early changes in central AT-1 receptors in CHF and suggest that the fall in BRS and hemodynamic changes occur early in the development of CHF followed by sympathoexcitation and overexpression of AT-1 receptors with the progression of CHF, causing further impairment of cardiovascular control.

Figure 1

A: Plasma concentration of ANG II in control and in CHF rabbits after left ventricular pacing for 1,2, or 3 weeks. B: Basal RSNA expressed as the percentage of the maximal response to smoke inhalation in control animals and after pacing for 1, 2. or 3 weeks. Results are represented as mean±SEM; n=6 each group. * P<0.05: significantly different from the control.

Figure 2

Mean data of maximum sensitivity of arterial baroreflex for tachycardia (increase in HR) response to fall in MAP by SNP infusion (A) and bradycardia (fall in HR) response to rise in MAP by PE infusion (B) in rabbits prior to and after CHF induced by 1,2, or 3 weeks of left ventricular pacing. Results are represented as means±SEM; n=6 each group. * P<0.05: significantly different from the pre-pace of the same group.

Figure 3

A: RT-PCR analysis for mRNA expression of the AT1 receptor (AT1) in the RVLM of control and chronic heart failure (after 1,2 or 3 weeks of LV pacing) rabbits. M, marker; C, control animals without LV pacing; WK, weeks of LV pacing. Top, A representative RT-PCR image showing upregulation of AT1 receptor mRNA expression in the RVLM after 2 and 3 weeks of pacing. β-Actin was used as an internal control. Bottom, results of densitometric analysis representing means±SEM, ** P<0.01 compared with control; n=6 each group. B: Western blot analysis for protein expression of the AT1 receptor in the RVLM of control and chronic heart failure (after 1,2 or 3 weeks of LV pacing) rabbits. Top, Representative Western blots showing the upregulation of AT1 receptor protein expression in the RVLM after 2 and 3 weeks of pacing Bottom. Results of densitometric analysis representing means±SEM. ** P<0.01 compared with control; n=6 each group.

Figure 4

A: RT-PCR analysis for mRNA of gp91^phox in the RVLM of control and chronic heart failure (after 1, 2 or 3 weeks of LV pacing) rabbits. M, marker; C, control animals without LV pacing, WK, weeks of LV pacing. Top: A representative RT-PCR image showing the upregulated gp91^phox mRNA expression in the RVLM after 2 and 3 weeks of pacing. β-Actin was used as an internal control. Bottom: Results of densitometric analysis representing means±SEM. n=6 each group. B: Western blot analysis for protein expression of gp91^phox in the RVLM of control and chronic heart failure (after 1, 2 or 3 weeks of pacing) rabbits. Top, A representative Western blot result showing the upregulation of gp91^phox protein expression in the RVLM after 2 and 3 weeks of LV pacing. Bottom: Results of densitometric analysis representing means±SEM; * P<0.05 compared with control; n=6 each group.