Effects of A1 Adenosine Receptor Agonism Using N6-Cyclohexyl-2′-O-Methyladenosine in Patients With Left Ventricular Dysfunction
Background The role of adenosine as a neuromodulator in heart failure was studied with the use of a selective adenosine A1 receptor agonist, N6-cyclohexyl-2′-O-methyladenosine (SDZ-WAG 994).
Methods and Results Fifty patients with heart failure symptoms and moderate left ventricular systolic dysfunction had a balloon flotation catheter inserted. Patients received placebo or a single oral dose of either 1, 2, or 5 mg SDZ-WAG 994. After baseline measurements were obtained, hemodynamic and electrophysiological recordings were repeated at 30-minute intervals for the next 4 hours, then every 6 hours for the next 24 hours. Blood samples for norepinephrine, epinephrine, aldosterone, atrial natriuretic peptide, and plasma renin activity were drawn at baseline and 2 hours after drug administration. A1 adenosine receptor agonism produced no important effects on systemic, right atrial, pulmonary artery, or pulmonary capillary wedge pressures; cardiac index; respiratory rate; or heart rate. The PR interval (a reflection of A1 receptor–mediated activity) increased significantly in a stepwise fashion. At the 5-mg dose of SDZ-WAG 994, significant increases in atrial natriuretic peptide (216±137 to 407±146 pg/mL) and norepinephrine (477±243 to 618±237 pg/mL) levels were noted.
Conclusions A1 adenosine receptor agonism with SDZ-WAG 994 resulted in no significant hemodynamic changes at rest in this subset of patients with left ventricular dysfunction. An increase in the PR interval and atrial natriuretic peptide level, consistent with adenosine A1 receptor–mediated activity, was observed. In addition, an increase in the norepinephrine level was observed, suggesting a role for adenosine as a peripheral nervous system neuromodulator.
Adenosine is a naturally occurring nucleoside with potent cardiac actions that are mediated through adenosine A1 and A2 receptor subtypes.1 When stimulated, the cardiac A1 receptors slow impulse propagation through the atrioventricular (AV) node.1 The A2 adenosine receptors mediate vasodilation.1 Recent evidence also suggests that adenosine, acting via the A1 receptor, is an important endogenous neuromodulator within the brain,2 heart,3 and peripheral nervous system.4 5
An A1 adenosine receptor agonist, N6-cyclohexyl-2′-O-methyladenosine (SDZ-WAG 994), has now been developed for use in humans (Sandoz Pharmaceuticals). This compound has been demonstrated to be a potent and orally active, selective A1 adenosine receptor agonist.6 7 Binding assays denote an A1/A2 adenosine receptor selectivity ratio of 280.8 This stable form of adenosine provides an additional tool to examine the neuromodulatory effects of adenosine.
In animal studies, SDZ-WAG 994 caused a concentration-dependent slowing of the spontaneous atrial rate and prolongation of AV nodal conduction that could be completely antagonized with a specific A1 adenosine receptor antagonist.8 A frequency-dependent prolongation of AV nodal conduction was also recognized; that is, with increasing atrial rates, a greater negative dromotropic effect on AV nodal conduction occurred.8 These studies suggest a possible therapeutic use in the long-term treatment of atrial tachyarrhythmias.
Pharmacokinetic studies in human volunteers show that the peak plasma concentration of SDZ-WAG 994 occurs 1 to 2 hours after oral administration, with a terminal elimination half-life of ≈0.5 hours (unpublished data, Sandoz Pharmaceuticals, 1996). It is estimated that the oral effective bioavailability of SDZ-WAG 994 is ≈30% to 50%.7 Therefore, oral doses of 0.05 mg/kg (3 to 5 mg total dose) are expected to be effective in humans. Preliminary data from healthy male volunteers suggest that 2- and 5-mg doses of SDZ-WAG 994 are well tolerated.9
The purpose of the present study was to evaluate the role of adenosine as a neuromodulator with the use of the selective A1 adenosine receptor agonist SDZ-WAG 994. Because SDZ-WAG 994 may be used clinically for its antiarrhythmic qualities in patients with heart failure and atrial arrhythmias, we chose to study patients with mild to moderate left ventricular dysfunction to determine the potential hemodynamic and neurohumoral effects of A1 adenosine receptor agonism in this population.
The design was a multicenter, placebo-controlled, randomized, double-blind study that used four parallel study groups. Patients had to be clinically stable, in normal sinus rhythm without AV conduction delay, and have moderate left ventricular systolic dysfunction (defined as an ejection fraction of between 20% and 45% as assessed by multiple-gated acquisition or echocardiography). Prospective study patients were excluded if abnormalities in hematologic indexes, blood chemistries, urinalysis, or chest roentgenogram (other than cardiomegaly) were detected.
Patients must have been taking stable doses of digoxin, a diuretic, and an ACE inhibitor for at least 30 days and must have agreed to be placed on a caffeine-free diet 24 hours before the investigation. On the day of the study, the patients' morning medications were withheld. A balloon flotation catheter was placed through a central vein and advanced into the pulmonary artery. After a 1-hour rest period, patients were randomly assigned to receive placebo or a single oral dose of either 1, 2, or 5 mg SDZ-WAG 994.
Measurements of heart rate, PR interval, blood pressure, respiratory rate, right atrial pressure, mean pulmonary pressure, pulmonary wedge pressure, and cardiac output were obtained at baseline and then repeated after dosing at 30-minute intervals for the next 4 hours and then every 6 hours for the next 24 hours. From these measurements, cardiac index, systemic vascular resistance, and left ventricular stroke work index were calculated. Venous blood samples for norepinephrine, epinephrine, aldosterone, atrial natriuretic peptide, and plasma renin activity were drawn at baseline and 2 hours after drug administration from an indwelling catheter. The patients' usual morning medications were administered after the fourth-hour hemodynamic measurements. Seven days later, patients were reexamined and questioned for adverse effects. Vital signs, ECG, and laboratory analysis were also obtained.
All data were summarized as mean±SD from each measurement period. A two-way repeated measures ANOVA was used to analyze multiple comparisons among the control and intervention measurements. Differences between group means were considered significant at the level of P≤.05. The Mantel-Haenszel test was used as a test of significance for linear trend of PR-interval prolongation.
Fifty patients (45 men and 5 women) aged 39 to 75 years (mean, 56±9 years) served as the subjects of this study. Most (68%) were NYHA class II, and the average left ventricular ejection fraction was 30±6%. The cause of left ventricular dysfunction was documented ischemic heart disease in the majority of patients (38/50). In the remainder, ischemic heart disease was likely but undocumented. The protocol was successfully completed in all 50 patients, and no serious adverse experiences or complications of the study procedures occurred during administration of placebo or SDZ-WAG 994.
Hemodynamic, Respiratory, and ECG Changes After A1 Adenosine Receptor Stimulation
No significant hemodynamic or respiratory rate changes were detected after increasing A1 adenosine receptor stimulation by ascending single oral doses of SDZ-WAG 994 compared with placebo (Table⇓). The PR interval (a measure of the adenosine A1 receptor–mediated effect) increased significantly after the administration of SDZ-WAG 994 (Fig 1⇓).
Neurohormonal Changes After A1 Adenosine Receptor Stimulation
With increasing A1 adenosine receptor stimulation, there was a stepwise trend toward increased atrial natriuretic peptide and norepinephrine levels that achieved significance with the 5-mg oral dose. Atrial natriuretic peptide levels demonstrated a mean net change from predose levels of −21 pg/mL in the placebo group compared with +191 pg/mL observed with the 5-mg dose (P<.01). While norepinephrine levels fell (mean, 46 pg/mL) in the control group, they rose with increasing A1 adenosine receptor stimulation, reaching a mean increase of 140 pg/mL after 5 mg of SDZ-WAG 994 (P<.01) compared with baseline (Fig 2⇓). No other significant neurohormonal changes were detected.
Effect of SDZ-WAG 994 on Laboratory Indexes
SDZ-WAG 994 had no effect on the total blood count, electrolyte profile, renal function tests, liver function tests, or urinalysis from samples collected 24 hours and 7 days, respectively, after administration of this adenosine agonist compared with precatheterization (before administration of SDZ-WAG 994) laboratory values. Measurements of total urinary output before and after administration of SDZ-WAG 994 were not determined.
This investigation examined for the first time the role of adenosine as a neuromodulator in patients with heart failure. The major finding was that adenosine A1 agonism could be achieved safely with the use of a novel, selective, orally active agent in patients with moderate left ventricular systolic dysfunction. With doses found to induce significant adenosine A1–mediated effects in normal volunteers,9 no clinically important or statistically significant hemodynamic, respiratory, or ECG changes occurred other than the expected dose-dependent increase in PR interval.
The rise in atrial natriuretic peptide levels after adenosine A1 receptor stimulation represents the first report of such an increase in humans. This finding is consistent with the results of a recently reported animal study that documented an increase in atrial natriuretic peptide levels after A1 but not A2 adenosine receptor stimulation.10 Interestingly, we observed that this rise in atrial natriuretic peptide levels occurred in the absence of increases in either right or left atrial pressure or the left ventricular stroke work index. These observations suggest that the increase in atrial natriuretic peptide is a direct A1 adenosine receptor–mediated effect. The reason why this rise in atrial natriuretic peptide was not associated with a fall in blood pressure or vascular resistance is of interest and could relate to the rise in norepinephrine observed.
The increase in plasma norepinephrine levels found at the highest level (5 mg) of A1 adenosine receptor stimulation was not entirely expected. These data, however, support the hypothesis that adenosine is a ubiquitous endogenous neuromodulator. Adenosine is known to have an inhibitory effect on adrenergic neurotransmission as well as on presynaptic norepinephrine release within the heart.11 12 It is also well accepted that adenosine is one of the major inhibitory neuromodulators in the central nervous system.2 However, there is increasing evidence that adenosine may play an excitatory role within the heart3 as well as in the peripheral nervous system.4 5 13 Bertolet et al3 recently reported that the A1 adenosine receptor modulated the transmission of noxious stimuli from the heart to the brain. Costa and Biaggioni4 5 further demonstrated that brachial artery infusion of adenosine excited afferent nerve fibers and increased muscle sympathetic nerve activity by 100%, an effect that could be antagonized by the adenosine antagonist theophylline. The rise in norepinephrine levels noted in the present study provides evidence for increased sympathetic nervous system activation. The mechanism involved in the observed norepinephrine increase and the role of adenosine as an excitatory peripheral nervous system neuromodulator demand further elucidation. Specifically, was this a direct effect of A1 receptor stimulation, a secondary response to vasodilation resulting from atrial natriuretic peptide release, or a combination of these direct and indirect effects?
In conclusion, A1 adenosine activation by SDZ-WAG 994 proved to be well tolerated and caused no significant hemodynamic changes at rest in this subset of patients with left ventricular dysfunction. A1 adenosine receptor stimulation, documented by PR-interval prolongation, was associated with a rise in atrial natriuretic peptide and norepinephrine levels. This study provides pilot data for future application of selective adenosine A1 receptor agonists to further our understanding of the role of adenosine as an endogenous neuromodulator.
We would like to thank the nurse coordinators at the study sites for their efforts in making this project a reality: University of Florida—Eileen Handberg-Thurman, Kay Worley; University of Minnesota/Minneapolis VA Medical Center—Susan Ziesche, Ann Steckler; University of Nevada—Richard Wildermuth; University of California—Cindy Klinski, Debbie Lau; and Richmond VA Medical Center—Catherine Murphy.
- Received March 4, 1996.
- Revision received July 2, 1996.
- Accepted July 10, 1996.
- Copyright © 1996 by American Heart Association
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