Bamiphylline improves exercise-induced myocardial ischemia through a novel mechanism of action.

Abstract

BACKGROUND In patients with stable angina pectoris aminophylline, a nonselective antagonist of adenosine receptors, markedly improves exercise capacity. To establish the role played by A1 adenosine receptors in the anti-ischemic action of aminophylline, the effects of bamiphylline, a selective A1 antagonist, on exercise-induced ischemia were investigated in patients with stable angina pectoris. METHODS AND RESULTS In a single-blind, placebo-controlled, randomized cross-over trial in 18 patients, oral administration of 1200 mg bamiphylline increased both the time to 1-mm ST segment depression (from 524 +/- 177 to 664 +/- 192 seconds, P < .01) and the rate-pressure product at 1-mm ST segment depression (from 159 +/- 31 to 190 +/- 34 beats per minute per mm Hg/10(2) (P < .001). End-diastolic and end-systolic left ventricular volumes, left ventricular ejection fraction, and systolic septal and posterior wall thickening investigated by two-dimensional echocardiography in 12 of the 18 patients were not affected by oral administration of bamiphylline (124 +/- 22 versus 125 +/- 20 mL, P = NS; 49 +/- 12 versus 50 +/- 13 mL, P = NS; 60 +/- 8% versus 58 +/- 7%, P = NS; 35 +/- 6% versus 36 +/- 7%, P = NS; 32 +/- 6% versus 33 +/- 6%, P = NS, respectively). In 7 of the 18 patients, the intravenous infusion of bamiphylline (5 mg/kg in 15 minutes) during cardiac catheterization did not produce any significant change of heart rate (76 +/- 10 versus 75 +/- 13 beats per minute, P = NS), mean right atrial pressure (3.8 +/- 1.7 versus 3.7 +/- 1.7 mm Hg, P = NS), mean aortic pressure (102 +/- 12 versus 99 +/- 10 mm Hg, P = NS), or left ventricular end-diastolic pressure (14 +/- 3 versus 14 +/- 4 mm Hg, P = NS) compared with baseline. Furthermore, after intravenous infusion of bamiphylline, the diameter of seven proximal and distal normal segments and of seven stenotic segments were similar to those measured at baseline (3.1 +/- 0.5 versus 3.1 +/- 0.5 mm, P = NS; 1.6 +/- 0.2 versus 1.7 +/- 0.2 mm, P = NS; 1.6 +/- 0.5 versus 1.6 +/- 0.5 mm, P = NS, respectively). CONCLUSIONS In patients with stable angina pectoris, oral administration of bamiphylline improves exercise capacity. Its anti-ischemic action does not appear to be mediated by systemic hemodynamic effects or by stenosis dilation. Therefore, the improvement of myocardial ischemia caused by bamiphylline is probably due to redistribution of coronary blood flow toward the underperfused subendocardium. This novel anti-ischemic action would appear to be mediated by antagonism of A1 receptors.

Adenosine Receptors and Asthma

“…In an animal model of allergic asthma, L-97-1 blocks allergic airway responses, BHR to histamine, and airway inflammation (Nadeem et al 2006; Obiefuna et al 2005). A number of A 1 AR antagonists have been or currently are in clinical trials for a number of different medical indications and, as a class, appear to be safe and well tolerated in humans (Barrett 1996; Bertolet et al 1996; Dittrich et al 2007; Doggrell 2005; Gaspardone et al 1993; Givertz et al 2007; Gottlieb et al 2002; Greenberg et al 2007). …”

Electrical Neuromodulation and the Heart with Special Emphasis on Myocardial Ischemia

“…Furthermore, the redistribution in coronary blood flow from normally perfused to impaired perfused regions has also been observed following the administration of aminophyline, theofylline or bamiphylline and was coined "the Robin Hood phenomenon" (stealing from the "rich" non-ischemic areas and supplying the blood to the "poor" ischemic regions). 110,111 All these three drugs are affecting adenosine handling through their interaction with Xanthine metabolisme. Further, the adenosine re-uptake inhibitor dipyridamole blunts the effect of SCS 108 and the drinking of caffeine too has been reported to reduce the effects of neuromodulation through its effect on adenosine, via xanthine metabolism.…”

Adenosine receptors and asthma in humans

“…In an animal model of allergic asthma, L‐97‐1 blocks allergic airway responses, airway hyperresponsiveness to histamine, and airway inflammation ( Obiefuna et al ., 2005 ; Nadeem et al ., 2006 ). Moreover, a number of A 1 AR antagonists have been in clinical trials for a number of different indications and, as a class, seem to be safe and well tolerated in humans ( Foutillan et al ., 1983 ; Catena et al ., 1988 ; Morandini, 1988 ; Gaspardone et al ., 1993 ; Barrett, 1996 ; Bertolet et al ., 1996 ; Gottlieb et al ., 2002 ; Doggrell, 2005 ; Dittrich et al ., 2007 ; Greenberg et al ., 2007 ; Givertz et al ., 2007 ). Three A 1 AR antagonists, Adentri (BG 9928) (Biogen Idec, Cambridge, MA, USA), SLV320 (Solvay Pharmaceuticals SA, Brussels, Belgium) and rolofylline (KW 3902) (Merck & Co. Inc., Whitehouse Station, NJ, USA) are currently in phase II (SLV320) and phase III (Adentri, BG 9928 and KW 3902, rolofylline) clinical trials for the treatment of congestive heart failure with renal impairment (59–62; http://clinicaltrials.gov; Biogen press release 21 August 2008).…”