McDermott D A, Meller S T, Gebhart G F, Gutterman D D
Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City 52242-1194, USA.
Cardiovasc Res. 1995 Jul;30(1):39-46.
Epicardial application of pharmacologic agonists has been used to study nociceptive and reflex responses to agents such as bradykinin. We utilized a model where intrapericardial bradykinin was administered in a closed-chest rat. The procedure allows for reproducible administration of microliter doses of pharmacologic agonists in both conscious and anesthetized animals.
Bradykinin (BK) has been shown to produce sympathoexcitatory reflexes when applied to the heart. BK typically produced a dose-dependent (0.001-10 micrograms) decrease in arterial blood pressure and tachycardia in pentobarbital-anesthetized rats. In contrast, in alpha-chloralose-anesthetized or awake rats, pericardial administration of BK produced a dose-dependent (0.001-10 micrograms) increase in arterial blood pressure and tachycardia. Maximal cardiovascular changes were produced by 1 microgram BK. The maximum change in arterial pressure was +33.6 +/- 9% in awake, +38.9 +/- 6% in chloralose-anesthetized, and -20 +/- 7% in pentobarbital-anesthetized rats. In alpha-chloralose-anesthetized rats, tachyphylaxis to pericardial administration of 1 microgram BK occurred at 5 and 15, but not at 30 min dosing intervals. Administration of the receptor selective B2-antagonist D-Arg,[Hyp3,Thi5,8 D-Phe7]-BK (200 micrograms) or the mixed B2/B1 antagonist [Thi5,8,D-Phe7]-BK (200 micrograms), produced similar attenuation of the pressor and tachycardia responses to BK. Bilateral transection of the cervical vagus nerve, bilateral removal of the stellate ganglion or ganglion blockade (hexamethonium), but not administration of indomethacin, reduced the magnitude of the tachycardia to BK. Only ganglionic blockade significantly reduced the pressor response to BK.
These results demonstrate that pericardial administration of BK produces a tachycardia and pressor effect in awake and alpha-chloralose-anesthetized rats and a tachycardia and depressor effect in pentobarbital-anesthetized rats. These responses appear to be mediated through activation of BK (presumably B2) receptors on cardiac vagal and sympathetic afferents, and may include a direct action of BK on the heart. This model of pericardial administration of pharmacologic agonists may be useful in studies of cardiac pain and reflex responses.
心外膜应用药理学激动剂已被用于研究对缓激肽等药物的伤害性和反射反应。我们采用了一种在闭胸大鼠心包内注射缓激肽的模型。该方法可在清醒和麻醉动物中重复给予微升剂量的药理学激动剂。
缓激肽（BK）应用于心脏时已被证明会产生交感兴奋反射。在戊巴比妥麻醉的大鼠中，BK通常会产生剂量依赖性（0.001 - 10微克）的动脉血压下降和心动过速。相比之下，在α-氯醛糖麻醉或清醒的大鼠中，心包内注射BK会产生剂量依赖性（0.001 - 10微克）的动脉血压升高和心动过速。1微克BK产生最大的心血管变化。清醒大鼠的动脉压最大变化为+33.6±9%，氯醛糖麻醉大鼠为+38.9±6%，戊巴比妥麻醉大鼠为-20±7%。在α-氯醛糖麻醉的大鼠中，对心包内注射1微克BK的快速耐受性在给药间隔为5分钟和15分钟时出现，但在30分钟时未出现。给予受体选择性B2拮抗剂D-Arg，[Hyp3，Thi5，8 D-Phe7]-BK（200微克）或混合B2/B1拮抗剂[Thi5，8，D-Phe7]-BK（200微克），对BK的升压和心动过速反应产生类似的减弱作用。双侧切断颈迷走神经、双侧切除星状神经节或神经节阻断（六甲铵），但吲哚美辛的给药未减弱，可降低对BK的心动过速幅度。只有神经节阻断显著降低了对BK的升压反应。
这些结果表明，心包内注射BK在清醒和α-氯醛糖麻醉的大鼠中产生心动过速和升压作用，在戊巴比妥麻醉的大鼠中产生心动过速和降压作用。这些反应似乎是通过激活心脏迷走和交感传入神经上的BK（可能是B2）受体介导的，并且可能包括BK对心脏的直接作用。这种心包内给药药理学激动剂的模型可能对心脏疼痛和反射反应的研究有用。
