Hayashi Koichi, Wakino Shu, Ozawa Yuri, Homma Koichiro, Kanda Takeshi, Okubo Ken, Takamatsu Ichiro, Tatematsu Satoru, Kumagai Hiroo, Saruta Takao
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Keio J Med. 2005 Jun;54(2):102-8. doi: 10.2302/kjm.54.102.
The present study examined the role of L-/T-type Ca channels and the interaction between these channels and protein kinase C (PKC) in hypertension. The isolated perfused hydronephrotic rat kidney model was used to visualize directly the renal microvascular effects of L-/T-type Ca channel blockers (nifedipine and mibefradil, respectively). Nifedipine reversed the angiotensin II-induced constriction of afferent, but not efferent, arterioles in kidneys from Wistar-Kyoto rats (WKY), and similar magnitude in dilation was observed in spontaneously hypertensive rats (SHR). Although mibefradil elicited dilation of both arterioles, the afferent arteriolar dilation was less in SHR than in WKY (57+/-5% vs. 80+/-4% reversal at 1 micrommol/L). The pretreatment with staurosporine did not alter the angiotensin II-induced afferent arteriolar constriction in WKY, but attenuated this response in SHR. Furthermore, staurosporine enhanced the nifedipine-induced afferent arteriolar dilation (62+/-3% vs. 50+/-3% reversal at 10 nmol/L), and restored the attenuated afferent arteriolar response to mibefradil in SHR. The pretreatment with thapsigargin (a blocker of IP3-mediated intracellular calcium release) prevented the angiotensin II-induced afferent arteriolar constriction in WKY, but caused a significant constriction of afferent arterioles in SHR and efferent arterioles in WKY and SHR; in this setting, mibefradil did not alter efferent arteriolar tone. In conclusion, although both L-type (nifedipine) and T-type Ca channel blockers (mibefradil) exerted potent vasodilation of rat renal microvessels, these actions were modified by PKC, which determined the afferent arteriolar sensitivity to these blockers in SHR. Furthermore, the enhancement in nifedipine-induced afferent arteriolar dilation by staurosporine in SHR suggests that L-type Ca channel activity is augmented in hypertensive animals.
本研究探讨了L型/T型钙通道在高血压中的作用以及这些通道与蛋白激酶C（PKC）之间的相互作用。采用离体灌注肾积水大鼠肾脏模型，直接观察L型/T型钙通道阻滞剂（分别为硝苯地平和米贝地尔）对肾微血管的影响。硝苯地平可逆转血管紧张素II诱导的Wistar-Kyoto大鼠（WKY）肾脏入球小动脉而非出球小动脉的收缩，在自发性高血压大鼠（SHR）中观察到类似程度的扩张。虽然米贝地尔可引起两种小动脉的扩张，但SHR中入球小动脉的扩张程度低于WKY（1 μmol/L时的逆转率分别为57±5%和80±4%）。用星形孢菌素预处理不会改变WKY中血管紧张素II诱导的入球小动脉收缩，但会减弱SHR中的这种反应。此外，星形孢菌素增强了硝苯地平诱导的入球小动脉扩张（10 nmol/L时的逆转率分别为62±3%和50±3%），并恢复了SHR中对米贝地尔减弱的入球小动脉反应。用毒胡萝卜素（一种IP3介导的细胞内钙释放阻滞剂）预处理可防止WKY中血管紧张素II诱导的入球小动脉收缩，但会导致SHR中入球小动脉和WKY及SHR中出球小动脉的显著收缩；在这种情况下，米贝地尔不会改变出球小动脉张力。总之，虽然L型（硝苯地平）和T型钙通道阻滞剂（米贝地尔）均可使大鼠肾微血管产生强效血管舒张作用，但这些作用受到PKC的调节，PKC决定了SHR中入球小动脉对这些阻滞剂的敏感性。此外，SHR中星形孢菌素增强硝苯地平诱导的入球小动脉扩张表明，高血压动物中L型钙通道活性增强。
