Whorlow S L, Angus J A, Wright C E
Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
J Cardiovasc Pharmacol. 1998 Dec;32(6):951-61. doi: 10.1097/00005344-199812000-00012.
The effects of N-type calcium channel inhibition with omega-conotoxin GVIA (omega-CTX) on cardiovascular parameters and vagally mediated autonomic reflexes and the role of the renin-angiotensin system were assessed in conscious rabbits. Omega-CTX (10 microg/kg, i.v.) resulted in hypotension, tachycardia, and attenuation of the sympathetic and vagal components of the baroreceptor-heart rate reflex (baroreflex). In the control group (no pretreatment), the peak decrease in mean arterial pressure (MAP) of 13 +/- 3 mm Hg from 72 +/- 2 mm Hg occurred after 33 +/- 3 min, with a corresponding tachycardia of 80 +/- 20 beats/min (n = 6). The tachycardia was due to vagal withdrawal, as a similar increase in heart rate (84 +/- 8 beats/min) after omega-CTX was observed after pretreatment with the beta-adrenoceptor antagonist, propranolol (n = 6). Angiotensin-converting enzyme (ACE) inhibition with enalaprilat revealed a larger, more rapid decrease in MAP in response to omega-CTX (-19 +/- 4 mm Hg from 65 +/- 1 mm Hg after 18 +/- 2 min; n = 6) compared with the control group. Similar larger decreases in MAP were also observed in the presence of the AT1-receptor antagonist, losartan, or the bradykinin B2 receptor antagonist, HOE-140 (n = 5-6). Pretreatment with enalaprilat, losartan, or HOE-140 caused a 50% decrease in the reflex tachycardia after omega-CTX compared with that observed in the control group, and omega-CTX caused a greater attenuation of the vagal component of the baroreflex and a decrease in the bradycardia evoked by the Bezold-Jarisch-like reflex. Also, there was a significant decrease in the bradycardia induced by the nasopharyngeal reflex after omega-CTX in the presence of ACE inhibition and HOE-140. Thus in the conscious rabbit, angiotensin II and bradykinin have a role in attenuating and slowing the hypotensive effect of N-type calcium channel inhibition. Vagolytic effects of omega-CTX on the baroreflex are augmented, and on other vagal reflexes are unmasked, via inhibition of the renin-angiotensin system. The complexity and mechanism of the interaction between N-type calcium channels and the renin-angiotensin system remain to be elucidated.
在清醒兔中评估了ω-芋螺毒素GVIA（ω-CTX）抑制N型钙通道对心血管参数、迷走神经介导的自主反射的影响以及肾素-血管紧张素系统的作用。静脉注射ω-CTX（10μg/kg）导致低血压、心动过速，并减弱压力感受器-心率反射（压力反射）的交感和迷走神经成分。在对照组（未预处理）中，平均动脉压（MAP）从72±2mmHg峰值下降13±3mmHg发生在33±3分钟后，相应的心动过速为80±20次/分钟（n = 6）。心动过速是由于迷走神经撤离，因为在用β-肾上腺素能受体拮抗剂普萘洛尔预处理后，观察到ω-CTX后心率有类似的增加（84±8次/分钟）（n = 6）。用依那普利拉抑制血管紧张素转换酶（ACE）显示，与对照组相比，ω-CTX引起的MAP下降更大、更迅速（18±2分钟后从65±1mmHg下降至-19±4mmHg；n = 6）。在存在AT1受体拮抗剂氯沙坦或缓激肽B2受体拮抗剂HOE-140的情况下，也观察到MAP有类似的更大下降（n = 5 - 6）。与对照组相比，用依那普利拉、氯沙坦或HOE-140预处理导致ω-CTX后反射性心动过速降低50%，并且ω-CTX导致压力反射的迷走神经成分有更大程度的减弱以及贝佐尔德-雅里什样反射诱发的心动过缓减少。此外，在存在ACE抑制和HOE-140的情况下，ω-CTX后由鼻咽反射诱发的心动过缓也显著降低。因此，在清醒兔中，血管紧张素II和缓激肽在减弱和减缓N型钙通道抑制的降压作用中起作用。通过抑制肾素-血管紧张素系统，ω-CTX对压力反射的迷走神经解迷走作用增强，对其他迷走神经反射的作用被揭示。N型钙通道与肾素-血管紧张素系统之间相互作用的复杂性和机制仍有待阐明。
