Stimulation of cardiopulmonary afferents by bolus injections of
phenylbiguanide (7 - 40 pg kg-'i) into the right atrium of urethane anaesthetised rabbits evoked reflex changes in all variables measured. Taking the whole group of animals in which the cardiopulmonary reflex was elicited (n = 44; protocols 1, 2 and 4), control stimulations caused a reflex increase in R-R interval of 39 ± 3 ms from a baseline value of 240 ± 4 ms and a fall in the ongoing activity of the renal nerve of 46 ± 3 %. Mean arterial blood pressure was also reduced by 30 ± 1 mmHg from a baseline level of 81 ± 2 mmHg. Stimulation of cardiopulmonary afferents with PBG also caused an increase in phrenic nerve burst rate of 31 ± 2 bursts min-'i from a baseline rate of 71 ± 2 bursts min-1.
The reflex changes in R-R interval, renal nerve activity and blood pressure usually occurred within 2 seconds of the injection of PBG and had returned to baseline levels within 30 seconds. The increase in phrenic nerve burst rate also usually occurred within 2 seconds however it often lasted longer than the other reflex effects and could take up to 2 minutes to return to normal baseline
values. Control responses evoked by stimulating cardiopulmonary afferents are shown in figures 3.3, 3.4 and 3.9.
The effects of buspirone on the cardiopulmonary reflex were examined in protocols 1 and 2, however, the results obtained were virtually identical in both, therefore only those obtained from protocol 1 are described below. The results from protocol 4 in which the effects of i.e. WAY-100635 on the cardiopulmonary reflex were examined are also described.
Saline 20^1 i.e.
After administration of the vehicle control saline, the reflex responses evoked by stimulating cardiopulmonary afferents with PBG were not
obtained before administration of saline were compared with those at each time point after saline using the Students paired t-test.
Buspirone 200 jjg kgr'^ i.e. (1.23 - 1.78 jumol)
Intracisternal administration of the buspirone had significant modulatory effects on the reflex responses evoked by stimulating cardiopulmonary afferents when compared to saline (figure 3.6 and table 5.4). Buspirone
potentiated the reflex increase in R-R interval evoked by bolus injection of PBG by 124 ± 56 ms 20 minutes after its administration. After 5 minutes, buspirone also significantly reduced the reflex renal sympathoinhibition and the
hypotension by 69 ± 22 % and 12 ± 4 mmHg respectively. These inhibitory effects were also seen during the subsequent reflex stimulations. 5 minutes after i.e. administration of buspirone, the reflex increase in phrenic burst rate was significantly attenuated. At this time point, the reflex tachypnoea was 23 ± 7 bursts min-'i less than the control response.
Experimental traces showing the effects of buspirone after 20 minutes on the responses evoked by stimulating cardiopulmonary afferents with PBG are presented in figure 3.3.
WAY’ 100635 100 jug kg“^ i.v.
Pre-treatment with an intravenous injection of WAY-100635 had no significant effect on any of the reflex responses evoked by stimulating cardiopulmonary afferents when compared to saline (table 5.6).
(1 .1 4 - 1.33 fumoi)
Buspirone 200 fig kg"'^ i.c^(pre-treated with WAY~100635 100 jug kg^'ii.v.) Most of the effects of buspirone on the cardiopulmonary reflex were significantly reduced by pre-treatment with WAY-100635 (figure 3.6 and table 5.8). After pre-treatment with WAY-100635, buspirone still potentiated the reflex increase in R-R interval by 24 ± 9 ms after 20 minutes. This potentiation was
significant when compared to saline however, this was significantly less than the potentiation of 124 ± 56 ms produced by buspirone alone at the same time.
Pre-treatment with WAY-100635 significantly inhibited the effects of buspirone on the reflex renal sympathoinhibition. At 35 and 50 minutes after administration of buspirone alone, the reflex sympathoinhibitions were reduced by 45 ± 19 and 48 ± 18%. After pre-treatment with WAY-100635 the
sympathoinhibitions evoked at the same times were actually increased by 2 1 ± 32 and 19 ± 27%. Pre-treatment with WAY-100635 also significantly attenuated the inhibition of the reflex hypotension caused by buspirone. After 5 minutes in the pre-treated group, the reflex hypotension was reduced by 1 ± 4 mmHg whereas buspirone alone caused a reduction of 12 ± 4 mmHg.
In addition, WAY-100635 also blocked the effect of buspirone on the tachypnoea evoked by stimulating cardiopulmonary afferents with PBG. In the buspirone alone group, the reflex tachypnoea was reduced by 23 ± 7 bursts min-1 after 5 minutes whereas in the pre-treated group, the respiratory response was only reduced by 3 ± 2 bursts min“l.
Experimental traces showing the effects of i.e. buspirone after i.v. pre treatment with WAY-100635 on the responses evoked by stimulating cardiopulmonary afferents are presented in figure 3.4.
Buspirone 200 pg kg“^ i.v.
Intravenous administration of buspirone caused a small potentiation of the reflex increase in R-R interval after 5 minutes (figure 3.8 and table 5.10). This was significant when compared to saline, but was not statistically different from the effect caused by buspirone i.e. at the same time point. In contrast to
buspirone administered i.c, buspirone i.v. had no significant effects on the reflex increases in R-R interval at any of the other time points.
Intravenous administration of buspirone reduced the reflex renal sympathoinhibitions. These effects were however later in onset than those caused by buspirone i.e. and only reached significance at 50 minutes when the
response was reduced by 36 ± 5%. 5 minutes after its administration, buspirone also significantly reduced the reflex hypotension evoked by cardiopulmonary afferent stimulation by 10 ± 1 mmHg. Similar effects were seen after 20 and 35 minutes. These effects did not differ significantly from those caused by
buspirone administered i.c.
Similar to i.e. administration, buspirone i.v. significantly reduced the reflex increase in phrenic burst rate after 5 minutes. At this time point, the tachypnoea was reduced by 14 ± 8 bursts min'T
WAY'100635 100 jug kg-^ i.c. (0.44 - 0.56 jumol)
Intracisternal administration of WAY-100635 attenuated all the effects of cardiopulmonary afferent stimulation on the variables recorded (figure 3.11 and table 5.12). 5 minutes after administration, the reflex increase in R-R interval was significantly reduced by 46 ± 6 ms. At this time point, WAY-100635 also
reduced the reflex renal sympathoinhibitions, however this only reached statistical significance after 15 minutes when a decrease of 35 ± 12 % was observed. The reflex hypotensions evoked by cardiopulmonary afferent
stimulation were significantly reduced 5 and 15 minutes after i.e. administration of WAY-100635 by 22 ± 4 and 9 ± 1 mmHg respectively. After 5 minutes, the reflex tachypnoea was also significantly reduced by 16 ± 8 bursts min"'*
Experimental traces showing the effects of WAY-100635 i.e. after 5
minutes on the responses evoked by stimulating cardiopulmonary afferents are presented in figure 3.9.
The effects of the 5-HT'ia receptor ligands on the reflex responses evoked by stimulating cardiopulmonary afferents with PBG are summarised in table 3.2.
Table 3.2
Summary of the effects of S-HT^a receptor ligands on the reflex decrease in mean arterial blood pressure (MABP) and integrated renal nerve activity (IRNA) and the increase in R-R interval and phrenic burst rate (PBR) evoked by stimulating cardiopulmonary afferents with PBG.
0 = no significant change
t = significant increase within 2 0 minutes of drug administration
1 = significant decrease within 2 0 minutes of drug administration
( i) = significant decrease more than 2 0 minutes after drug administration
Drug Decrease MABP Increase R-R interval increase PBR Decrease RNA Buspirone i.e. : Î : WAY-100635 i.v. 0 0 0 0
Buspirone i.e. / WAY-100635 i.v. 0 Î 0 0
Buspirone i.v. Î (4.)
Figure 3.3
The responses evoked by stimulating cardiopulmonary afferents with phenylbiguanide (PBG) during the control period and 20 minutes after administration of buspirone ( 2 0 0 |xg kg-'i i.c.) in an atenolol (1 mg kg-'i) pre-treated rabbit.
From the top, the traces show arterial blood pressure (ABR), heart rate (HR), phrenic nerve activity (RNA) and integrated renal nerve activity (IRNA).
Constant doses of phenylbiguanide were injected into the right atrium at the points marked by the arrows.
control A B P (m m H g) H R (bpm) 150-1