Effects of carvedilol on cardiac autonomic nerve activities during sinus rhythm and atrial fibrillation in ambulatory dogs

Abstract

Aims: We hypothesized that carvedilol can effectively suppress autonomic nerve activity (ANA) in ambulatory dogs during sinus rhythm and atrial fibrillation (AF), and that carvedilol withdrawal can lead to rebound elevation of ANA. Carvedilol is known to block pre-junctional β2-adrenoceptor responsible for norepinephrine release.

Methods and results: We implanted radiotransmitters to record stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and superior left ganglionated plexi nerve activity (SLGPNA) in 12 ambulatory dogs. Carvedilol (12.5 mg orally twice a day) was given for 7 days during sinus rhythm (n = 8). Four of the eight dogs and an additional four dogs were paced into persistent AF. Carvedilol reduced heart rate [from 103 b.p.m. (95% confidence interval (CI), 100-105) to 100 b.p.m. (95% CI, 98-102), P = 0.044], suppressed integrated nerve activities (Int-NAs, SGNA by 17%, VNA by 19%, and SLGPNA by 12%; all P < 0.05 vs. the baseline), and significantly reduced the incidence (from 8 ± 6 to 3 ± 3 episodes/day, P < 0.05) and total duration (from 68 ± 64 to 16 ± 21 s/day, P < 0.05) of paroxysmal atrial tachycardia (PAT). Following the development of persistent AF, carvedilol loading was associated with AF termination in three dogs. In the remaining five dogs, Int-NAs were not significantly suppressed by carvedilol, but SGNA significantly increased by 16% after carvedilol withdrawal (P < 0.001).

Conclusion: Carvedilol suppresses ANA and PAT in ambulatory dogs during sinus rhythm.

Keywords: Arrhythmia; Atrial fibrillation; Atrium; Autonomic nervous system; Carvedilol.

Figure 1

Effects of carvedilol on heart rate. (A) Diagram of the study protocol. Two weeks after the operation, a carvedilol loading study was performed during sinus rhythm. A rapid atrial pacing protocol was then initiated and maintained until the development of persistent (>48 h) AF. Afterwards, the carvedilol loading study was repeated. (B) Heart rate during sinus rhythm before carvedilol (PRE), during carvedilol (CVD), and after carvedilol withdrawal (POST) in phase 1 (sinus rhythm) of the study. (C) Circadian variation of heart rate before, during, and after the administration of carvedilol. b.p.m., beats per minute; CVD, carvedilol. *P < 0.05 vs. PRE; ^†P < 0.05 PRE vs. CVD; ^‡P < 0.05 PRE vs. POST.

Figure 2

Change of Int-NAs before (PRE), during (CVD), and after (POST) carvedilol loading during sinus rhythm. Stellate ganglion nerve activity (SGNA) (A), VNA (B), and SLGPNA (C) decreased after carvedilol loading compared with the baseline. All three nerve activities remain suppressed after carvedilol withdrawal. Among these nerve activities, only SGNA showed a morning surge (asterisk). The morning surge of SGNA disappeared after carvedilol loading and remained suppressed after carvedilol withdrawal. *P < 0.05 vs. PRE.

Figure 3

Carvedilol selectively suppressed VNA and SLGPNA. (A) L-shaped correlation between SGNA and VNA at baseline (b). Carvedilol loading eliminated the lower arm of the L-shape on Days 5 (D5) and 6 (D6), resulting in isolated SGNA without VNA on those two days. The VNA–SLGPNA correlation remains linear during D5 and D6, but the high output portion of the graph (arrowhead, D3) was eliminated. That portion of the graph recovered 3 days after carvedilol withdrawal (POST3). (B, C) Representative examples of ANA. (B) Simultaneous discharges of SGNA, VNA, and SLGPNA. (C) Carvedilol selectively suppressed VNA and SLGPNA, but not SGNA.

Figure 4

Effects of carvedilol on circadian variation of SGNA–VNA correlation. The correlation between SGNA and VNA was significantly better during daytime than during night-time (A, C). After carvedilol loading, this difference was no longer present (B, D). *P < 0.05 vs. 8 PM–12 AM.

Figure 5

Incidence and duration of PAT before (PRE), during (CVD), and after (POST) carvedilol loading. Carvedilol loading significantly reduced the incidence (A, B) and duration (C, D) of PAT between Days 2 and 7. After withdrawal of carvedilol, the incidence and duration of PAT returned to baseline level. *P < 0.05 vs. PRE.

Figure 6

The change in Int-NA before (PRE), during (CVD), and after (POST) carvedilol loading during AF rhythm (n = 5 dogs). Stellate ganglion nerve activity (SGNA) (A), VNA (B), and SLGPAN (C) did not decrease during carvedilol loading. Interestingly, all three nerve activities increased after carvedilol withdrawal. *P < 0.05 vs. PRE.