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2-adrenoceptors in
Purkinje?
Division of Cardiovascular Diseases, Department of Internal Medicine, University of Iowa College of Medicine; and Veterans Administration Medical Center, Iowa City, Iowa 52242
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Recent studies have shown the presence of postjunctional
2-adrenergic receptors on canine Purkinje fibers but not
muscle cells. Stimulation of these receptors results in prolongation of
the action potential duration and the Purkinje relative refractory period. We studied the effect of 2-adrenergic agonists
on inducible ischemic ventricular tachycardia (VT) of both
Purkinje fiber and myocardial origin. Open-chest dogs in whom VT was
induced with extrastimuli after occlusion of the anterior descending
coronary artery were studied. A mapping system, incorporating Purkinje signals, characterized the mechanisms of VT. The
2-adrenergic agonists clonidine (0.5-4.0
µg/kg) or UK 14,304 (4-5 µg/kg) versus saline were given
intravenously after reproducibility of inducible sustained monomorphic
VT had been demonstrated. Eighteen dogs were given clonidine, eleven of
which had focal Purkinje VT. Of these 11 dogs, clonidine blocked VT
induction in 9 (81.9%) and rendered VT nonsustained in 1 (9.1%), and
VT remained inducible in 1 dog (9.1%), although this was focal
midmyocardial VT only. In the seven dogs with VT of myocardial origin,
six (85.6%) remained inducible with clonidine, whereas one dog
(14.4%) had only nonsustained VT after clonidine. Of the six dogs, UK
14,304 blocked VT induction in four (66.6%) and rendered VT
nonsustained in one (16.7%), and VT remained inducible in one dog
(16.7%). In four dogs with VT of myocardial origin, VT remained
inducible. In the eight control dogs that were given saline, focal
Purkinje VT was repeatedly inducible. Pharmacological stimulation of
postjunctional 2-adrenoceptors on Purkinje fibers may
selectively prevent induction of VT of Purkinje fiber origin in the
ischemic canine ventricle.
ischemia; mapping; autonomics
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IN CONTRAST TO THE
EFFECTS of 
-adrenergic stimulation and blockade, the role of
-adrenergic receptors in the heart is less well defined, and the
postsynaptic -adrenergic receptors in the heart were thought to be
primarily of the 1-subtype (5, 8). However,
recently published studies (4, 13, 14, 22, 23) have
demonstrated the presence of postjunctional 2-adrenergic receptors in canine cardiac Purkinje fibers but not in the myocardium. Stimulation of these postjunctional 2-adrenergic
receptors results in prolongation of the Purkinje relative refractory
period (PRRP) in the intact dog (4) and in prolongation of
the action potential duration (APD) in isolated canine Purkinje fibers
in vitro (22). The presence of 2-adrenergic
receptors in canine Purkinje fibers has been confirmed by a radioligand
binding and autoradiographic study (14). The
electrophysiological effects of 2-adrenergic stimulation
in isolated Purkinje fibers are abolished after incubation with
pertussis toxin, implying that a pertussis toxin-sensitive G protein is
mediating these effects (22). In isolated Purkinje fibers,
concomitant 2- and -adrenergic stimulation prevents the induction of triggered activity previously inducible under -adrenergic stimulation alone (22). These results
suggest that the 2-adrenergic effects are mediated
through a G protein that inhibits adenylate cyclase activity, thereby
counteracting the -adrenergic effects on cAMP production, which has
been implicated to be an important mediator of arrhythmias under
conditions of ischemia and reperfusion (15).
The Purkinje system has been suspected of being a site of origin of ventricular arrhythmias occurring in the early ischemic period (10). We (1) recently reported that the Purkinje system may be importantly involved in the development of spontaneous ventricular tachycardia (VT) during acute ischemia in a canine model.
This study tested the hypothesis that 2-adrenergic
agonists could prevent the induction of previously inducible VT of
Purkinje fiber origin while not affecting VT originating from
intramyocardial sites during the first 1-3 h after coronary artery
occlusion in the dog.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Healthy adult mongrel dogs of either gender weighing 18-24 kg were used for these studies. The protocol was approved by the University of Iowa Animal Use and Care Committee and conformed to the guidelines of the American Physiological Society.
Surgical preparation.
Dogs were anesthetized with 500 mg of thiopental sodium and
100-200 mg/kg iv -chloralose as a bolus. Anesthesia was
maintained with a continuous intravenous infusion of -chloralose
dissolved in polyethylene glycol at 8 mg · kg
1 · h1. The animals
were intubated and ventilated on a ventilator (Harvard Apparatus) with
settings adjusted to achieve a physiological arterial PCO2 (25-35 Torr) and to maintain a normal
PO2 (80-150 Torr). NaHCO3 was
infused as necessary to maintain the pH within physiological range
(7.30-7.45). The serum electrolytes K+ (3.6-5.0
meq/l), Mg2+ (1.5-3.0 mg/dl), and
Ca2+ (8.5-10.5 mg/dl) were periodically measured and
were always within normal limits. Arterial pressure was continuously
monitored via a femoral arterial line, and the femoral vein was
cannulated for infusion of drugs and saline.
Electrophysiological measurements. A bipolar electrode was used to pace the right atrium at two times diastolic threshold with pulses of 2-ms duration at a cycle length (CL) of 300 ms. The region of the sinus node was permanently clamped to control the rate. Surface electrocardiographic leads II and V5R were continuously monitored. All six limb leads (I, II, III, aVR, aVL, and aVF) and lead V5R were recorded. Ventricular pacing for VT induction was performed from the innermost pole of each of the 16-pole needles placed in three locations (apical septum, anterior base, and lateral midwall) outside of the risk zone of the coronary artery occlusion. Cathodal stimuli (2-ms duration at 4 times diastolic current of threshold) were applied to the pacing electrode while the anode was located in the abdominal subcutaneous tissue. Twenty-one multipolar plunge needles were inserted into and surrounding the risk zone of the left anterior descending coronary artery occlusion as described previously in detail (1). Each needle recorded six bipolar electrograms from circumferential electrodes made from Teflon-insulated tungsten wires (1 mm apart), enabling recordings from a total of 126 sites. Details regarding the electrodes, including interelectrode and interbipole spacing, were as recently described (1).
Electrograms were recorded simultaneously on two separate computers: one for the three endocardial-most bipoles, and the other for the three epicardial-most bipoles (1). Signals from the three endocardial-most electrodes were amplified by a gain of 100, band-pass filtered between 3 and 1,300 Hz, and sampled at 3.2 kHz. The epicardial electrograms were sampled at frequency of 1 kHz per channel and band-pass filtered at 30-300 Hz. Three-dimensional activation maps were constructed from multiplexed signals. Data from both acquisition systems were incorporated for the construction of three-dimensional activation maps with a common surface electrocardiogram (lead V5R) recording pacing spikes, allowing for alignment of signals from both computers. Each needle had 16 unipoles, which were used to select the six optimal bipolar electrograms that were adjusted to maximize the capability to record Purkinje signals on the endocardial-most bipole. The adjustment was performed by sequential recordings on a storage oscilloscope for each bipole. A switching box was utilized to connect the selected bipoles to each amplifier. The length of the needles (22 mm, with circumferential electrodes covering the proximal 16 mm of the needle shaft) traversed through the left ventricular wall into the left ventricular cavity. The epicardial-most bipole recorded an electrogram from the epicardium, and subsequent bipoles recorded electrograms sequentially through the myocardial wall. The endocardial-most bipole was used to record Purkinje potentials when they could be identified. Purkinje potentials were identified at their endocardial location according to previous published criteria from this laboratory, including 0.5-mV spikes lasting 1-2 ms, preceding by 1-11 ms the larger and longer muscle spike and the surface QRS on the lead recording the earliest activity (1, 3, 4). If a Purkinje potential was not identified for a given electrode, no activation time was marked for the endocardial-most electrogram. Activation maps were constructed as described before (1). Ventricular effective refractory period (VERP) was determined by delivering extrastimuli (Bloom stimulator) after eight paced complexes, with the effective refractory period defined as the longest interval between the drive pacing (S1) and the first extrastimulus (S2) that did not capture the ventricle. The drive CL was 300 ms. VT induction utilized up to four premature stimuli as follows: the first premature stimulus (S2) was fixed at 4 ms longer than the VERP, and a second stimulus (S3) was employed at the same coupling interval. The S3 was shortened in 10-ms decrements until either VT induction or failure to capture occurred. If no VT was induced, the same procedure was followed for the third (S4) and fourth extrastimuli (S5) as required. There was a pause of 1 s before the next drive started. The PRRP was defined as the longest S1-S2 that produced a delay in the Purkinje activation but did not produce a delay of the local muscle activation of the pacing electrode (3). The PRRP were measured in subsets of five dogs for each drug used. For the experiment in which renal sympathetic nerve activity (RSNA) was recorded, the dog's flank was opened, and the hilum of the left kidney was dissected to expose the renal nerves. The distal nerve was cut and desheathed, and multifiber recordings were made utilizing a platinum electrode. The nerve and sheath were encased in silicone gel. Recordings were made with a high-impedance probe with signals filtered over 30 Hz-3 kHz with a HIPS 11J model Grass instruments recorder (16). Nerve volleys were audible through a loud speaker, and RSNA was quantified by the counting frequency of action potentials that exceeded a selected voltage set above electrical noise using a nerve traffic analyzer (16).Definitions. VT was defined as at least three or more premature ventricular complexes in a row. The CL of VTs was averaged over the first 10 complexes. VT was considered sustained if it lasted longer than 30 s or cardioversion was required because of hemodynamic collapse. Only five VTs were cardioverted; four VTs were reproduced after cardioversion, so the results were not affected.
VT was designated to have a focal origin when no electrical activity could be recorded on all adjacent sites in three-dimensions between the latest activation of one QRS complex and the earliest of the next QRS. Moreover, conduction from the site of earliest activity to adjacent electrodes could not manifest a conduction delay, which might account for a majority of the CL of the VT. Purkinje origin of VT was defined as a focal endocardial mechanism with recording of a Purkinje potential before the QRS on the lead recording the earliest activity to be considered mechanistically involved. Purkinje potentials had to be identified on electrograms during atrial pacing before and after coronary occlusion in addition to the VT recording. Mechanisms were defined as reentrant when the earliest activation site was located immediately adjacent to the site of the latest activation from the previous complex and continuous diastolic activation was recorded between complexes. Reentrant mechanisms also demonstrated unidirectional and functional block to the subsequent earliest site of activation. Ischemia was defined as a reduction in voltage of electrograms as described by Ruffy et al. (21) and previously used in this model (1).Experimental protocol. A total of 41 dogs were studied. After instrumentation of the risk zone with 21 multipolar plunge needles and before coronary artery occlusion, induction of VT was attempted with extrastimuli to exclude artifactual VT due to electrode instrumentation alone. None of the animals had inducible VT under these circumstances. The left anterior descending coronary artery was then occluded, and VT induction was attempted using serial induction protocols during the time period from 1 to 3 h after occlusion. Pacing was from one of three additional electrodes placed outside the risk zone located in locations as described above. No spontaneous sustained VT or ventricular fibrillation was observed during the period of 1-3 h after coronary artery occlusion. Although the physiological conditions during 3 h of evolving ischemia were not constant, previous studies (2, 25) using this model have demonstrated that VT is reproducibly inducible over the period of 1-3 h after coronary occlusion.
When VT was induced with extrastimuli, repeat induction was attempted from the same site to ensure reproducibility. If the dogs had morphologically similar inducible VT on at least two consecutive attempts from the same pacing site, a drug or saline was given (a schematic of the protocol is shown in Fig. 1). They were given an2-agonist, clonidine (0.5-4.0 µg/kg), or UK
14,304 (4.0-5.0 µg/kg), as an intravenous infusion over 20 min
or saline, and the induction protocol was repeated after 30 min. Five
dogs also had inferior vena caval occlusion to achieve similar changes in arterial pressure as produced by UK 14,304.
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Pharmaceutical agents.
Clonidine and -chloralose were purchased from Sigma (St. Louis, MO),
and UK 14,304 was purchased from Research Biochemicals (Natick, MA).
Data analysis.
All data are expressed as means ± SE. Fisher's exact test was
used to test differences in inducibility with pharmacological intervention between groups receiving 2-adrenergic
agonists and the control group. A Student's t-test was used
for comparison of mean arterial pressures (MAP) and refractory periods
before and after drug administration and for comparison of drug doses. A P value of <0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Of 41 dogs studied with reproducibly inducible sustained
monomorphic VT, 18 were given clonidine, 10 were given UK 14,304, and 8 dogs were given saline and served as a control group for repeated
inducibility over the period of 1-3 h after coronary artery
occlusion. An additional five dogs served as controls for hypotensive
effects of 2-adrenergic agents. The mean CL of all VTs
was 135 ± 3 ms; VT with Purkinje origin had a CL of 136 ± 3 ms, and all other VTs had a mean CL of 132 ± 2 ms
[P = not significant (NS)]. The mean number of
Purkinje signals observed in the endocardial-most layer in all
dogs was 9 ± 0.5 (range 4-15) of 21 electrodes.
Mechanisms and origin of inducible VTs.
Twenty-five of thirty-six (69.4%) VTs were of focal Purkinje origin
(Table 1). An example of the focal
Purkinje VT is shown on the electrogram in Fig.
2. A drive is followed by three
extrastimuli and induction of VT. The VT complexes are preceded by
Purkinje spikes, indicating that the earliest site of activity during
these is in the Purkinje system. Figure 3
shows an activation map for the first VT complex. The earliest activity
seen is in the Purkinje layer, and subsequent activation proceeds away
from this site in all directions without any evidence of conduction
delay, indicating a focal origin of this complex. The other 11 VTs were
of either focal epicardial or reentrant mechanisms (Table 1 and Figs.
4 and
5).
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Effect of 2-adrenergic agonists on inducible VTs.
Of the 18 dogs given clonidine, 11 had focal Purkinje VT. VT induction
was completely blocked in nine dogs (81.8%), whereas in one dog
(9.1%) only nonsustained Purkinje VT was inducible (P < 0.0005 compared with control group). The mean dose of clonidine was
1.9 ± 0.3 µg/kg. One dog (9.1%) continued to have inducible VT
after clonidine (2 µg/kg) administration but with a midmyocardial focal origin only, whereas only Purkinje VT was inducible before, but
not after, clonidine administration. Of the three dogs with intramyocardial macroreentrant VT, all continued to have inducible VT
after clonidine. Likewise, of the four dogs with epicardial focal VT,
all remained to have inducible VT on clonidine administration (mean
dose 1.9 ± 0.6 µg/kg, P = NS compared with dose
that prevented focal Purkinje VT), although in one dog only
nonsustained VT was induced after clonidine. After clonidine
administration, MAP decreased from 85 ± 4 to 80 ± 4 mmHg
(P < 0.05), although the VERP (from 137 ± 7 to
137 ± 4 ms) did not change (P = NS) (Table
2). The PRRP in a subset of the dogs
given clonidine (n = 5) prolonged from 179 ± 9 to
182 ± 6 ms (P < 0.05), indicating a specific
effect of the drug on postjunctional 2-adrenergic
receptors on Purkinje fibers.
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2-adrenergic agonist UK 14,304, 6 had inducible focal Purkinje VT before receiving the drug. VT induction was prevented in four (66.6%) of these and rendered nonsustained in one dog (16.7%) (P < 0.005 compared
with control group) after UK 14,304 (mean dose 4.4 ± 0.9 µg/kg)
administration. VT originating in the Purkinje fibers was inducible in
only one dog (16.7%) after UK 14304 administration (4 µg/kg). In two
of four dogs in which induction of Purkinje VT was prevented by UK 14,304, VTs with focal midwall origin were inducible only after UK
14,304 was given. In four dogs with VT of epicardial origin (3 reentrant and 1 focal), UK 14,304 (mean dose 4.5 ± 1.0 µg/kg, P = NS compared with dose that prevented focal Purkinje
VT) did not affect VT inducibility. After UK 14,304 administration, MAP decreased from 104 ± 10 to 65 ± 11 mmHg (P < 0.05), and VERP was unchanged (141 ± 5 to 142 ± 5 ms,
P = NS), but PRRP increased from 175 ± 6 to
181 ± 4 ms (P < 0.05), indicating an
2 -adrenergic receptor effect in Purkinje fibers (Table
2).
When the results of the effects of both 2-agonists on
inducible VT are combined, they were effective in preventing focal Purkinje VT in 13 of 17 dogs (76.4%), partially effective (sustained to nonsustained VT) in 2 dogs (11.8%), and not effective in 2 dogs
(11.8%). VTs with epicardial focal or reentrant mechanisms were not
affected by the 2-adrenergic agonists in 10 of 11 dogs (90.1%), and in 1 of 11 dogs (9.9%) nonsustained VT was inducible after the 2-adrenergic agonist was given. These combined
results provide further support that the 2-adrenergic
agonists may preferentially modulate only VTs of Purkinje fiber origin.
Neither clonidine (54 ± 4% to 56 ± 3%, P = NS) nor UK 14,304 (61 ± 4 to 62 ± 4%, P = NS) had an effect on the size of the ischemic zone, expressed as the percentage of electrodes exhibiting voltage changes consistent with ischemia.
Observations from an experiment with RSNA recordings during the use of
clonidine in doses from 0.5-8.0 µg/kg is shown in Fig. 6. With the doses of clonidine used for
arrhythmia prevention in this study, no reduction in RSNA was seen. On
the other hand, an increase in RSNA was seen with doses of 0.5 and 2.0 µg/kg. Only a mild decrease was seen in MAP with a dose increase from 0.5 to 2.0 µg/kg. With a dose of 8.0 µg/kg, a decrease in MAP was
seen and a lesser increase in the RSNA occurred, which may be
consistent with the initiation of a central sympathoinhibitory effect
of clonidine at that dose. This suggests that the doses used in this
study may not have caused significant central inhibition of sympathetic
tone.
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2-agonists on Purkinje
tissue were responsible for alterations in inducibility of VT by UK
14,304.
Control group.
Eight dogs with focal Purkinje VT were not given an
2-adrenergic agonist but served as controls for repeated
inducibility over the time course of the study. All eight dogs had
reproducible inducible VT with the same origin over time. In these
dogs, both MAP [from 109 ± 8 to 115 ± 9 mmHg
(P = NS)] and VERP [from 146 ± 6 to 143 ± 7 ms (P = NS)] were stable over the time course of repeated inducibility.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of this study indicate that inducible ischemic
VT of Purkinje fiber origin appears to be susceptible to selective modulation by pharmaceutical agents that stimulate the postjunctional 2-adrenergic receptor on Purkinje tissue. The
2-adrenergtic agonists clonidine and UK 14,304 were both
effective in preventing induction of previously inducible VT of
Purkinje fiber origin only while most of the inducible VT originating
in the ventricular myocardium was not affected by
2-adrenergic agonists. In addition, PRRP was increased,
but no change was noted in the VERP, and a decrease in RSNA was not
seen with the doses of clonidine used for VT modulation. Finally,
mechanically induced reduction of arterial pressure similar to that
produced by an 2-agonist produced no effect on Purkinje
VT. These novel findings suggest an functionally important role for the
postjunctional 2-adrenergic receptors recently described
on canine Purkinje fibers.
2-Adrenergic receptors on Purkinje fibers.
The existence of postjunctional 2-adrenergic receptors
was first suggested in a report by Mugelli et al. (19),
who demonstrated that changes in automaticity in sheep Purkinje fibers
exposed to norepinephrine under conditions of hypoxia were blocked by yohimbine but not 1- or -adrenergic blockers.
Earlier, Rosen et al. (20) reported that clonidine
decreased automaticity in isolated dog Purkinje fibers but, because
these effects were not blocked by yohimbine, they were attributed to
direct effects. Cable et al. (4) later showed in an intact
dog model that 2-adrenergic stimulation prolonged the
PRRP selectively without any effect on the VERP and that these effects
were attenuated by yohimbine. A subsequent study (22)
utilizing standard microelectrode techniques in isolated superfused
Purkinje fibers showed that 2-adrenergic stimulation,
both with norepinephrine in the presence of propranolol and prazosin
and UK 14,304, prolonged the APD. These effects were also
reversed by yohimbine, suggesting 2-adrenergic receptor specificity. Further studies have shown that the effects of
2-adrenergic agonist on APD were intact in the presence
of blockers of the ion channels of inward rectifying and slow
rectifying K+ currents, Cl current, and
Ca2+ currents but were abolished in the presence of
4-aminopyridine, a blocker of transient outward K+ current
(Ito). These results are suggestive of
Ito being a major mediator of modulation of the
APD of 2-adrenoceptor agonists (13).
2-adrenergic agonists, indicating that the 2-adrenergic effects in Purkinje fibers are
mediated through a pertussis toxin-sensitive G protein, likely
Gi (22). The 2-adrenergic
receptor coupling to Gi, which inhibits adenylate cyclase
and cAMP production, could therefore potentially counteract some of the
arrhythmogenic effects of excess -adrenergic stimulation. Sustained
triggered activity, which was inducible in isolated Purkinje fibers
under conditions of elevated extracellular calcium and unopposed
-adrenergic stimulation, could be suppressed in the presence
of concomitant - and 2-adrenergic
stimulation (22).
This constitutes the basis of the hypothesis that
2-adrenergic effects may have an antiarrhythmic effect
on those arrhythmias that originate from the His-Purkinje system and
are induced during the setting of enhanced sympathetic tone, such as in
acute ischemia/infarction.
Effects of 2-adrenergic agents on inducible VT.
The results of this study strongly suggest that
2-adrenergic agents selectively modulate VT of focal
Purkinje fiber origin, whereas focal and macroreentrant VT with origin
in the myocardium were not affected. In addition to the postjunctional
receptor mediated 2-adrenergic stimulation, clonidine is
known to have other pharmacological effects, including stimulation of
the central nervous system (CNS) imidazoline receptors
(26) and all 2-adrenergic agonists have an
effect on central or prejunctional 2-adrenergic receptors and, through these, may modulate the sympathetic nervous system output from the CNS, resulting in decreased peripheral sympathetic tone. Presynaptically, clonidine may inhibit
norepinephrine release from nerve terminals (26). We
performed an experiment in which RSNA was recorded during infusion of
clonidine in doses from 0.5 to 8.0 µg/kg. No decrease in RSNA was
seen, indicating a lack of inhibition of central sympathetic outflow by
clonidine in the doses used in this study. Hence, the modulation
of VT induction by clonidine and UK 14,304 can be attributed to their
effects on postjunctional 2-adrenergic receptors in
cardiac Purkinje tissue.
2-adrenergic agonists used in
this study resulted in a decrease in MAP. MAP fell modestly in response to clonidine and substantially in response to UK 14,304. The effects of
UK 14,304 in vivo have not been well characterized. It is a selective
2-adrenergic agonist and has predominately been used as
a tool in experimental pharmacology. In a previous study
(9) involving a similar model in our laboratory, a
decrease in MAP of up to 50 mmHg did not affect the inducibility of VT,
although transmural activation times and the rate of VT were affected. In the present study, a similar decrease in MAP, produced by inferior vena caval ligation, had no effect on VT inducibility. Kabell et al.
(11), however, reported that blood pressure may affect focal arrhythmias arising in ischemically injured hearts,
albeit >24 h later. It cannot be completely ruled out that some degree of modulation of central sympathetic outflow may have occurred with
administration of the 2-adrenergic agonists because a
direct 2-adrenergic effect on vascular smooth muscle
results in vasoconstriction. However, if inhibition of central
sympathetic outflow was a significant mechanism in suppressing
inducible VT in this study, both VT from intramyocardial sites and VT
originating from Purkinje fibers would have been expected to be
affected approximately equally, which was not the case. Our results,
showing that induction of Purkinje VT was selectively inhibited,
whereas VT from intramyocardial sites were not suppressed by UK 14,304, further indicate a lack of effect in the ventricular myocardium. VERP
was not affected by either 2-adrenergic agonist,
indicating minimal or no prejunctional effect at the doses given,
because prejunctional 2-adrenergic stimulation would be
expected to increase the VERP by inhibiting norepinephrine release
(18). Both clonidine and UK 14,304 increased the PRRP in a
nonselected subgroup of animals, consistent with a direct
postjunctional effect on 2-adrenoceptors on Purkinje fibers.
On the basis of the results of this study, we speculate that a major
function of the postjunctional 2-adrenergic receptors on
Purkinje fibers is to counterbalance the effects of -adrenergic stimulation by inhibition of cAMP production, which may be an important
mediator of arrhythmogenesis during ischemia.
VT of Purkinje fiber origin.
Previous studies (1, 17) from this laboratory have shown
that the Purkinje system may be involved in the genesis of both spontaneous and inducible VT during acute ischemia. In the
present study, we examined the effects of 2-adrenergic
modulation on inducible VT because reproducibility was important to
assess the effects of the pharmacological intervention.
Limitations.
A major limitation to these observations is that the drugs used in this
study, UK 14,304 and especially clonidine, both have a variety of
effects, although common to both are 2-adrenergic agonist effects. Effects on sites outside of Purkinje fibers likely occurred during this study as seen by the effects of the decrease in
MAP. Both drugs can cross the blood-brain barrier and influence 2-adrenergic receptors in the CNS. Clonidine can also
stimulate imidazoline receptors in the CNS. Ideally, a study like this
present one would be performed using an 2-adrenergic
agonist that does not cross the blood-brain barrier. We are, however,
not aware of an 2-adrenergic agonist with such
properties. The selective effects on Purkinje VT and increase in the
PRRP seen along with lack of effect on VERP are consistent with a drug
effect directly on the 2-adrenergic receptors on
Purkinje fibers. An experiment where RSNA was recorded with doses of
clonidine used in this study revealed no decrease in central
sympathetic outflow with the doses used in this study.
2-adrenergic antagonists to confirm
2-adrenergic selectivity of the actions of clonidine and
UK 14,304, after giving and testing for VT with an
2-adrenergic agonist, more difficult.
The mechanisms of the actions of the 2-adrenergic
agonists were not studied. However, previous studies from this group
have suggested a possible mechanism. Samson et al. (22)
suggested that the 2-adrenoceptors on Purkinje fibers
are coupled to a pertussis toxin-sensitive G protein. Another recent
study (23) investigated the effects of - and
2-adrenergic stimulation on Purkinje fiber contraction.
The strength of Purkinje fiber contraction was enhanced by
isoproterenol, forskolin, and 8-bromo-cAMP. 2-Adrenergic stimulation with UK 14,304 reversed the effects of isoproterenol and
forskolin but not 8-bromo-cAMP, further suggesting that
2-adrenoceptors on Purkinje fibers are coupled to a
pertussis toxin-sensitive G-protein, likely Gi.
As discussed previously, it is unknown whether VT of Purkinje fiber
origin occurs during acute ischemia in humans. It is also unclear at present whether 2-adrenoceptors
exist on human Purkinje fibers as they appear to on canine Purkinje
fibers. This awaits further examination. Thus although the results of
this study are intriguing and suggest a potential antiarrhythmic role
for 2-adrenoceptors in canine Purkinje fibers, these
results should not presently be extrapolated to humans.
In conclusion, the results of this study suggest that pharmacological
stimulation of 2-adrenoceptors on Purkinje fibers may selectively prevent induction of VT originating in this tissue under
ischemic conditions in a canine model. This may indicate an
important role for these 2-adrenoceptors recently
described in canine Purkinje fibers.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. Mark Chapleau for technical assistance and Linda Bang for expert secretarial assistance.
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FOOTNOTES |
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This work was supported by grants from the American Heart Association, Iowa Affiliate, and the Veterans Administration Medical Center. Dr. Arnar was supported by a Fellowship Award from the American Heart Association, Iowa Affiliate.
Address for reprint requests and other correspondence: J. B. Martins, Div. of Cardiovascular Diseases, Dept. of Internal Medicine, Univ. of Iowa College of Medicine, 200 Hawkins Dr., Iowa City, IA 52242 (E-mail: james-martins{at}uiowa.edu).
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. Section 1734 solely to indicate this fact.
Received 19 July 1999; accepted in final form 25 October 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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875-883,
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Ben-Haim, SA,
Cable DG,
Rath TE,
Carmen L,
and
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Impulse propagation in the Purkinje system and myocardium of intact dogs.
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14 m), consistent with the observations of the electrogram in
Fig. 
