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1 University Laboratory of
Physiology, Administration of
nitric oxide (NO) donors in vivo is accompanied by a
baroreflex-mediated increase in heart rate (HR). In vitro, however, NO
donors can increase HR directly by stimulating a pathway that involves
NO, cGMP, and the hyperpolarization-activated current
(If). The aim
of this study was to assess the functional significance of this pathway
in vivo by testing whether NO donors can increase HR in the
anesthetized rabbit independent of the autonomic nervous system. New
Zealand White rabbits were vagotomized, cardiac sympathectomized, and
treated with propranolol (0.3 mg/kg iv). The NO donor molsidomine (0.2 mg/kg iv) caused a progressive increase (
sodium nitroprusside; molsidomine; baroreflex; rabbit
NITRIC OXIDE (NO) donors reduce arterial blood pressure
(ABP) by decreasing vascular resistance and are, therefore, widely used
to assess the sensitivity of the baroreceptor heart rate (HR) reflex,
in particular its sympathetic component. Interpretation of these data,
however, may be complicated, since nitrates can inhibit the gain of the
baroreceptor-cardiac reflex (16, 18) and have additional effects on the
heart itself that may be independent of reflex activation.
Specifically, NO donors can reduce norepinephrine release (25) and the
HR response to sympathetic nerve stimulation in vitro (4). Conversely,
they can also directly increase HR in the isolated guinea pig double
atria preparation by activating the hyperpolarization-activated inward
pacemaking current (If) via a cGMP-dependent
pathway (21). However, it has not been established whether NO donors
have a direct effect on HR in vivo that is independent of cardiac
autonomic activation.
To test this hypothesis, we assessed whether the systemic
administration of the NO donors
N-ethoxycarbonyl-3-morpholino-sydnonimine [molsidomine (Mol)] and sodium nitroprusside (SNP) can
increase HR independent of cardiac autonomic reflexes in anesthetized
rabbits that had been cardiac sympathectomized, vagotomized, and
pretreated with propranolol. The effect of SNP on HR was also tested in
the isolated (denervated) working rabbit heart preparation, in which both preload and afterload were held constant. We found that Mol and
SNP can have a direct positive chronotropic effect in vivo and in vitro
and that the magnitude of the tachycardia was significantly reduced by
the If
blocker
4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6(methylamino)pyrimidinium chloride (ZD-7288; Zeneca) (2, 10, 15). This suggests the involvement
of an
If-sensitive
pathway. Some of the results have been previously communicated in
abstract form (8).
Experiments were performed in accordance with the
Guide for the Care and Use of Laboratory
Animals (National Institutes of Health)
and the Animals (Scientific Procedures) Act 1986 (UK) under project
license PPL 30/1133.
Anesthesia
ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
) in HR (HR, 14 ± 3 beats/min; P < 0.01). This effect was significantly reduced by the
If blocker
ZD-7288 (0.2 mg/kg iv; HR, 2 ± 3 beats/min;
P = not significant).
Similar results were seen with sodium nitroprusside. The positive
chronotropic effect of sodium nitroprusside (50 µM) was confirmed in
the isolated working rabbit heart preparation (HR, 17 ± 3 beats/min; P < 0.01). In conclusion,
NO donors exert a small, but significant, positive chronotropic effect
in vivo that is independent of the autonomic nervous system. These
results are also consistent with data in sinoatrial node cells that
show that NO donors increase HR by stimulating
If.
INTRODUCTION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
Surgery
Tracheostomy was performed, and a 3.5- or 4-mm ID. endotracheal tube (Portex) was introduced 4 cm into the trachea. Administration of halothane in O2 was then continued through the endotracheal tube while spontaneous ventilation was maintained. Stainless steel electrodes were inserted subcutaneously into each limb to monitor electrocardiogram. Catheters (Portex) were inserted into the right femoral artery for withdrawal of blood samples and into the left carotid artery for measurement of blood pressure. The animals were partially thoracotomized to facilitate artificial ventilation (Oxford Mk II ventilator). To abolish the cardiac autonomic response to a drop in ABP, animals were vagotomized, and the aortic depressor nerves and sympathetic nerves were ligated and cut low down at the thoracic inlet. Propranolol (0.3 mg/kg iv) was also given to block any residual sympathetic activity. Efficacy of blockade was confirmed by an absence in the HR response to isoprenaline.Measurements
Systemic ABP was measured via a saline-filled pressure transducer (SensoNor 840) and was calibrated in the midaxillary line. HR traces were triggered from both ABP and electrocardiogram, respectively, and were digitally displayed. All signals were recorded onto a penwriter (MT8P, Lectromed). A Macintosh computer (Quadra 950) was used for to record and analyze data. The analog inputs were sampled at 250 Hz by a real-time data-acquisition program (Acqknowledge 3.2, model MP100, Biopac Systems), displayed on a computer monitor, and stored on compact disk. Body temperature was monitored with a rectal thermister.Intensive Care
Animals inspired 100% O2 throughout the experiment. Arterial blood samples (90 µl/sample) were regularly analyzed for pH and blood gases (Radiometer ABL505). Any respiratory acidosis was corrected by adjusting the frequency and/or tidal volume of the ventilator. Metabolic acidosis was corrected by iv infusion of 4.2% sodium bicarbonate solution. Fluid was replaced with a continuous iv drip of 0.9% saline (~20 ml/h). With the use of heating lamps beneath the operating table, core temperature was maintained at 38.7 ± 0.1°C.Protocols
Efficacy of cardiac autonomic denervation was tested by performing controlled hemorrhages before and after denervation. Withdrawal of 20 ml of arterial blood resulted in a fall in ABP (~20 mmHg), with a corresponding reflex tachycardia (>20 beats/min) before denervation. Blood was then reinfused, and protocols were undertaken once HR and ABP returned to prehemorrhage values. This reflex tachycardia in response to a similar fall in ABP was abolished after cardiac denervation (Fig. 1).
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Protocol 1: Effect of Mol on HR after cardiac denervation. In 11 animals, a bolus injection of the NO donor Mol was given (0.2-0.4 mg/kg iv) (22). HR and ABP were monitored for up to 30 min after administration. At this point, ZD-7288 (0.2 mg/kg iv bolus), a specific blocker of the If (2, 10, 15) was administered to six of these animals. This dose blocks ~75% of the HR response caused by activation of If (15). HR was allowed to stabilize for 20-30 min, after which a repeat dose of Mol was given and HR and ABP were monitored again over time.
Protocol 2: Effect of Mol on HR after cardiac denervation and
-adrenergic blockade.
A further 11 animals were pretreated with propranolol (0.3 mg/kg iv) to
block the action of circulating catecholamines, and protocol 1 was repeated. ZD-7288 was
administered to 10 of these animals.
Protocol 3: Effect on the HR response to Mol of giving
If and
-adrenergic antagonists first.
The protocol was reversed by giving ZD-7288 before Mol in a third group
of rabbits (n = 5) that had been
cardiac denervated and treated with propranolol.
Protocol 4: Effect of SNP on HR after cardiac denervation and
propranolol.
In another group of rabbits (n = 7),
protocol 2 was repeated with the use
of a different NO donor, SNP (mean dose 15 µg · kg
1 · min1
iv infusion, Fresenius Injectomat-S syringe infusion pump). SNP was
infused at a variable rate to maintain a constant reduction in ABP for
up to 30 min. The infusion of SNP was repeated after ZD-7288.
Experiments were carried out in dark conditions because SNP is
sensitive to light.
Isolated working rabbit heart protocol. Hearts were removed from male New Zealand White rabbits (1.7-2.5 kg), as previously described (9). Within 2 min of removal of the heart, the aorta was cannulated and retrograde perfusion of the coronary arteries with Tyrode solution was begun in Langendorff fashion. The mode of perfusion was later switched from retrograde to anterograde perfusion to establish a working heart preparation. A preload of 10 mmHg and an afterload of 77 mmHg were set, and the heart was enclosed in a thermal chamber to ensure that temperature and humidity remained constant. After a period of stabilization, the heart was perfused with 50 µM SNP in Tyrode solution, and the effect on HR was monitored. Hearts were perfused with either 1 µM ZD-7288 or 2 mM cesium chloride (CsCl). CsCl is also a specific inhibitor of If (10, 21); however, by having a faster action than ZD-7288, it is better suited to the isolated working heart preparation.
Statistics
Data are shown as means ± SE. Comparisons were made by using a repeated measures one-way ANOVA; i.e., all data were compared with their own control values within the protocols, and a post hoc Scheffé's test was used. In the case of paired comparisons, a Student's paired t-test was used. P < 0.05 was accepted as statistically significant.| |
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Arterial blood gases and arterial pH were well controlled throughout
the experiments (Table 1).
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Protocol 1: Effect of Mol on HR After Cardiac Denervation
Figures 2 and 3 show that a bolus administration of Mol resulted in a transient fall in mean ABP [(MABP), 
15 ± 3 mmHg, from 71 ± 4 to 56 ± 3 mmHg]. After this hypotensive effect, ABP
returned toward baseline, but HR remained elevated throughout the
follow-up period. HR increased by 28 ± 6 beats/min
(P < 0.01) with a MABP of 67 ± 3 mmHg. Administration of the blocker of the If,
ZD-7288, caused a reduction in baseline HR of 72 ± 9 beats/min
(from 303 ± 11 to 231 ± 9 beats/min; MABP, 74 ± 3 mmHg).
Mol elicited a similar transient fall in ABP after ZD-7288, but the
peak HR response was only increased by 8 ± 1 beats/min
(P < 0.05; MABP, 65 ± 3 mmHg).
The rate of increase in HR in response to Mol was also markedly
retarded by ZD-7288 (Fig. 3).
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Protocol 2: Effect of Mol on HR After Cardiac Denervation and
-Adrenergic Blockade
-adrenergic blockade
(peak HR, 14 ± 3 beats/min, P < 0.01; MABP, 63 ± 3 mmHg). After ZD-7288 (HR with ZD-7288,
33 ± 6 beats/min, from 243 ± 10 to 210 ± 6 beats/min; MABP, 67 ± 3 mmHg), the positive chronotropic effect of
Mol was virtually abolished (HR, 2 ± 3 beats/min,
P = not significant; MABP, 71 ± 5 mmHg). Importantly, there was a significant difference between peak
HR responses before and after ZD-7288 (P < 0.01). It should be noted that
the HR response did not plateau after Mol in the -blocked animals
compared with the non--blocked animals (see Fig. 3); therefore the
maximum response was not obtained. In addition, the increase in HR was
slower in the group pretreated with propranolol.
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Protocol 3: Effect on the HR Response to Mol of Giving
If and
-Adrenergic Antagonists First
MABP, 3 ± 2, from 61 ± 4 to 58 ± 5 mmHg). ZD-7288 decreased HR by 39 ± 6 beats/min (from 217 ± 8 to 178 ± 6 beats/min; MABP, 57 ± 4 mmHg). After
If blockade, the
bolus injection of the NO donor did not elicit a significant increase
in HR (HR, 6 ± 1 beats/min, P = not significant; MABP, 60 ± 7 mmHg). An example of this response is
shown in Fig. 6.
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Protocol 4: Effect of SNP on HR After Cardiac Denervation and Propranolol
The HR responses to SNP before and after ZD-7288 were quantitatively similar to the responses seen with Mol. After propranolol (HR,
14 ± 5 beats/min, from 215 ± 9 to 201 ± 10 beats/min; MABP, 11 ± 1, from 72 ± 3 to 61 ± 3 mmHg) infusion of SNP resulted in a rapid and sustained fall in ABP
(MABP, 20 ± 3 mmHg, from 61 ± 3 to 41 ± 3 mmHg).
SNP increased HR by 14 ± 4 beats/min
(P < 0.01; MABP, 47 ± 4 mmHg)
over the follow-up period. After administration of ZD-7288 (HR
32 ± 5, from 215 ± 10 to 183 ± 5 beats/min; MABP, 66 ± 3 mmHg), the second infusion of SNP produced a similar vascular effect (MABP, 19 ± 3, from 66 ± 3 to 47 ± 3 mmHg) and a smaller increase in HR (HR, 7 ± 3, P < 0.05; MABP, 55 ± 5 mmHg).
However, again there was a significant difference in peak HR
responses before and after ZD-7288 (P < 0.05).
Isolated Working Rabbit Heart Protocol
In the isolated working heart preparation with preload and afterload held constant, 50 µM SNP resulted in an increase in beating rate of 17 ± 3 beats/min (P < 0.01) and a decrease in aortic flow (26 ± 4 ml/min, from 99 ± 8 to
73 ± 9 ml/min; n = 6). The effect on heart rate took ~3 min to peak. Heart rate returned to baseline on
washoff, although this took 36 ± 3 min (Fig.
7). In an additional set of hearts, and
consistent with previous in vitro studies (21), ZD-7288 (1 mM) also
significantly attenuated the positive chronotropic response to SNP
(HR with SNP, 15 ± 2 beats/min; and HR with SNP + ZD-7288, 3 ± 2 beats/min, n = 4;
P < 0.05, Wilcoxon Sign test) and 2 mM CsCl (HR with SNP, 19 ± 4 beats/min; HR with SNP + CsCl, 3 ± 1 beats/min; n = 9;
P < 0.01).
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Table 2 summarizes the absolute HR
responses to the NO donors and shows that these donors can
significantly increase HR in the anesthetized rabbit and in the
isolated working rabbit heart. Furthermore, the HR response to the NO
donors is substantially reduced by the
If blocker
ZD-7288.
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ABSTRACT
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Our results show that 1) NO donors have a positive chronotropic effect on HR in vivo that is independent of the cardiac innervation, 2) SNP increases HR in the isolated working rabbit heart preparation, and 3) the positive chronotropic response to NO donors is markedly attentuated by ZD-7288 and 2 mM CsCl, which suggests these changes are mediated via NO stimulation of an If-dependent pathway.
Reid (24) reported that, after bilateral sinoaortic denervation, the HR
response to a 20-min infusion of SNP (~30
µg · kg1 · min1)
in conscious rabbits was abolished, although there was a trend in these
data for HR to increase (see Fig. 3 in Ref. 24). A similar
result is seen in the study by Ma and Long (14). Close inspection of
their data also shows iv SNP increased HR by ~12 beats/min (see Fig.
1 in Ref 14). Furthermore, in heart transplant recipients who showed no
evidence of autonomic reinnervation (6), inhalation of amyl nitrate (1)
or infusion of SNP (12) increased HR by 9 beats/min (11%) and 13 beats/min (15%), respectively. In addition, amyl nitrate was reported
to increase HR by 6% in healthy men who had been pretreated with
propranolol and atropine (11).
We observed a significant increase in HR following Mol (0.2-0.4
mg/kg in bolus) in anesthetized rabbits after surgical autonomic denervation of the heart. Reid (24) also showed a significant increase
in arterial plasma norepinephrine after the infusion of SNP in rabbits
before baroreceptor deafferentation. Because this could contribute to
the increase in HR seen in our experiments, we also tested the
chronotropic effect of Mol and SNP after pretreatment with propranolol.
Both NO donors still caused a significant increase in HR after
-adrenergic blockade, although the rate of increase and the
magnitude of effect were reduced (Figs. 3 and 5). This may reflect the
complete elimination of sympathetic influences or possibly the
inhibitory effect of reduction of intracellular cAMP and calcium
transients by -adrenergic blockade (19) on the activity of
If (3). However,
previous experiments in the isolated atria of the guinea pig showed
that -adrenergic blockade with nadolol (1 µM) did not affect the
chronotropic effect of the active metabolite of Mol
[3-morpholinosydnonimine (SIN-1)], in a range from nano- to
millimolar concentrations (20). Similarly, in the isolated working
rabbit heart preparation, we have observed the increase in HR due to
SNP was maintained in the presence of propranolol (unpublished observation).
The chronotropic effect of SNP that we observed in vivo in the rabbit
(~14 beats/min after propranolol) was smaller than that we reported
in the guinea pig isolated atria (21). However, we did not perform a
dose-response study in the anesthetized rabbit, and 15 µg · kg1 · min1
of SNP were within the dose range previously employed to test the
sensitivity of the arterial baroreflex in this model (29). Whereas SNP
is not a prodrug and releases NO intracellularly (28), Mol is
transformed into its active metabolite, SIN-1, in the liver (17, 23).
The long washoff of SNP is also probably related to its intracellular
action (28). Furthermore, unlike SNP, SIN-1 releases NO in the
bloodstream, where it could in part be scavenged by hemoglobin or react
with superoxide to form peroxynitrite. These factors make the HR
response to Mol in vivo difficult to compare with the chronotropic
effect of SIN-1 in vitro.
It could be speculated that the neuroendocrine response to a short period of hypotension caused by hemorrhage might have contributed to the positive chrontropic effect of NO donors in the anesthetized rabbit. However, we think this is unlikely for several reasons. First, we waited until ABP and HR returned to nearly prehemorrhage values after reinfusion of blood before measurements were taken. Second, the increase in HR with the donor was significantly reduced by the specific If blocker ZD-7288. Third, the positive chronotropic response to SNP was present in the isolated Tyrode-perfused heart that was devoid of circulating hormones.
Because it is virtually impossible to exclude all neural and circulatory factors that could modulate HR during in vivo experiments, we tested our hypothesis on the isolated Tyrode-perfused working rabbit heart (with preload and afterload fixed) and confirmed that the increase in HR caused by SNP was of a similar magnitude to the increase seen in vivo. However, the increase in HR caused by 50 µM SNP was less compared with that seen in the isolated guinea pig atrial preparation (21) at the same concentration; this may reflect a species difference in response to SNP. Nevertheless, it is clear that endogenous NO has a tonic stimulatory effect on HR. NOS inhibitors decrease basal HR in vitro (5), and a similar response is seen in conscious NOS knockout mice (27).
Assessment of Baroreflex by Using Nitrovasodilators
Nitrovasodilators have been widely used to assess the sensitivity of the baroreceptor-cardiac reflex because they were thought to be direct vasodilators with no or little extravascular effects. In recent years, however, it has become evident that they exert most of their biological effects by releasing NO and that they can directly affect cardiac and autonomic function and the activity of the arterial baroreflex itself. Indeed, NO donors have been reported to decrease the gain of the baroreceptor-cardiac reflex in conscious animals (13, 18) and to suppress baroreceptor activity independent of vascular relaxation in the isolated carotid sinus preparation of the anesthetized rabbit (16). In addition, NO donors reduce norepinephrine release (25) and the HR response to sympathetic nerve stimulation in vitro (4). Conversely, NOS inhibitors enhance norepinephrine release (25) and the HR response to sympathetic nerve stimulation (4, 26). By increasing the intracellular concentration of cGMP, NO donors can also interfere with-adrenergic signaling; this leads to an inhibition of
cAMP-dependent stimulation of Ca2+
currents in sinoatrial cells (7). Taken together, these data indicate
that NO donors may act to depress the neurally mediated HR response to
a fall in ABP. Conversely, there is evidence presented here and with in
vitro preparations that shows NO donors can increase HR directly.
What is the mechanism underlying the positive chronotropic effect of NO donors? Low concentrations (nanomolar to micromolar) of NO donors can increase the spontaneous beating rate in the isolated atrial preparation in guinea pigs (21). Musialek et al. (21, 22) observed that the increase in rate was mimicked by 8-bromo-cGMP, prevented by guanylate cyclase inhibitors, and suppressed after inhibition and depletion of the sarcoplasmatic Ca2+ stores with ryanodine and cyclopiazonic acid, respectively. In addition, the positive chronotropic effect was virtually abolished by blockers of the If, whereas it was not affected by the Ca2+ channel antagonist nifedipine. Importantly, both SNP and SIN-1 caused a time-dependent increase in If in rabbit sinoatrial node cells. Our results in the anesthetized rabbit are consistent with these data and suggest that, in addition to modulating sympathetic responses and baroreceptor activity, NO donors can exert a direct positive chronotropic effect which could bias the evaluation of baroreflex sensitivity by these agents. In vivo, however, this effect develops more slowly than the neurally mediated reflex HR response. Therefore it seems unlikely that this action will have a significant additional effect on HR unless NO donors are infused over minutes rather than injected as a bolus.
In summary, although our results establish that NO donors have a direct and baroreflex-independent effect on HR in vitro and in vivo, they also contribute to evidence that suggests that nitrovasodilators may not be ideal for the assessment of the baroreceptor cardiac reflex because these agents have significant extravascular effects (3).
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ACKNOWLEDGEMENTS |
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This work was supported by the British Heart Foundation, Garfield Weston Trust (B. Casadei) and Major Stanley's Memorial Scholarship Fund (N. Hogan).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: D. J. Paterson, University Labortory of Physiology, Parks Rd., Oxford OX1 3PT, UK (E-mail: david.paterson{at}physiol.ox.ac.uk).
Received 2 November 1998; accepted in final form 23 February 1999.
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REFERENCES |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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; n = 11),
and Mol in the presence of ZD-7288 (
;
n = 6) on HR
(top) and mean ABP (MABP;
bottom) over time. Mol alone caused
a significant increase in HR. Note that when MABP increased toward
baseline levels, HR continued to rise. When Mol was given in the
presence of ZD-7288, although a similar vascular effect occurred, the
increase in HR was markedly attenuated. After 12 min in the
post-ZD-7288 trace, n = 3. Values are means ± SE;
n, no. of animals.
