Monopoli A, Casati C, Lozza G, Forlani A, Ongini E
Schering-Plough Research Institute, San Raffaele Science Park, I-20132, Milan, Italy.
J Pharmacol Exp Ther. 1998 Apr;285(1):9-15.
We characterized the in vivo cardiovascular profile of SCH 58261, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo[1,5-c] pyrimidine, a selective A2A adenosine receptor antagonist, in conscious, freely moving rats by use of the telemetry system. In normotensive rats, SCH 58261, at 10 mg/kg i.p., significantly (P < .05) inhibited hypotension and tachycardia induced by the A2A receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (0.01 mg/kg i.p.), but not the bradycardic effect caused by the A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (0.03 mg/kg i.p.). SCH 58261, when administered alone, at 0.1 and 1 mg/kg i.p., did not induce significant hemodynamic changes, but at 10 mg/kg i.p., it slightly increased both systolic blood pressure (SBP) and diastolic blood pressure (DBP) (+19 +/- 3 and +16 +/- 2 mm Hg, respectively; P < . 01) and heart rate (HR) (+85 +/- 5 beats/min; P < .01). These effects were inhibited by adrenergic blockade with propranolol (30 mg/kg i.p.) and phentolamine (10 mg/kg i.p.): -5 +/- 3 mm Hg on DBP and -12 +/- 11 beats/min on HR (P < .01). In spontaneously hypertensive rats, SCH 58261, at 3 and 10 mg/kg i.p., increased weakly both SBP (+19 +/- 5 mm Hg and +25 +/- 4 mm Hg) and DBP (+14 +/- 4 mm Hg and +23 +/- 4 mm Hg) vs. vehicle (P < .01) and HR (+45 +/- 17 and +64 +/- 18 beats/min vs. vehicle, respectively; P < .01). The data indicate that SCH 58261 retains A2A selective receptor antagonist properties in vivo. Its effect on cardiovascular sympathetic outflow further suggests that endogenous adenosine exerts a tonic vascular regulation through A2A receptors. Therefore, SCH 58261 can be a useful pharmacological tool for clarifying A2A-mediated cardiovascular actions of adenosine.
我们利用遥测系统，在清醒、自由活动的大鼠体内，对选择性A2A腺苷受体拮抗剂SCH 58261（7-(2-苯乙基)-5-氨基-2-(2-呋喃基)-吡唑并-[4,3-e]-1,2,4-三唑并[1,5-c]嘧啶）的心血管特征进行了表征。在正常血压大鼠中，腹腔注射10 mg/kg的SCH 58261能显著（P <.05）抑制A2A受体激动剂2-己炔基-5'-N-乙基羧酰胺腺苷（腹腔注射0.01 mg/kg）诱导的低血压和心动过速，但对A1受体激动剂2-氯-N6-环戊基腺苷（腹腔注射0.03 mg/kg）引起的心动过缓效应无抑制作用。单独腹腔注射0.1和1 mg/kg的SCH 58261时，未引起显著的血流动力学变化，但腹腔注射10 mg/kg时，收缩压（SBP）和舒张压（DBP）均略有升高（分别为+19±3和+16±2 mmHg；P <.01），心率（HR）升高（+85±5次/分钟；P <.01）。普萘洛尔（腹腔注射30 mg/kg）和酚妥拉明（腹腔注射10 mg/kg）的肾上腺素能阻断可抑制这些效应：DBP降低-5±3 mmHg，HR降低-12±11次/分钟（P <.01）。在自发性高血压大鼠中，腹腔注射3和10 mg/kg的SCH 58261，与溶剂对照组相比，SBP（分别为+19±5 mmHg和+25±4 mmHg）和DBP（分别为+14±4 mmHg和+23±4 mmHg）轻度升高（P <.01），HR也升高（分别为+45±17和+64±18次/分钟，与溶剂对照组相比；P <.）。数据表明，SCH 58261在体内保留了A2A选择性受体拮抗剂的特性。其对心血管交感神经流出的影响进一步表明，内源性腺苷通过A2A受体发挥紧张性血管调节作用。因此，SCH 58261可能是阐明腺苷A2A介导的心血管作用的有用药理学工具。
