|Budget Amount *help
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
The present project was designed to determine the role of gap junctions in endothelium-derived hyperpolarizing factor (EDHF)-mediated vascular hyperpolarization, the types of connexins composing gap junctions, and the pathophysiological roles of vascular gap junctions.
In the rat arteries, inhibitors of gap junctions markedly inhibited EDHF-mediated hyperpolarization, suggesting that gap junctions play an important role in EDHF-mediated hyperpolarization. Furthermore, immunohistochemical analysis revealed that, although connexins 37, 40 and 43 are expressed in the vascular wall, connexin 37 and 40 are the two major connexins expressed between endothelial cells, suggesting that these connexins may play a pivotal in the EDHF-mediated hyperpolarization.
We have previously shown that EDHF-mediated hyperpolarization was impaired in arteries from aged rats. In this study, we demonstrated that antihypertensive treatment with angiotensin II receptor antagonist candesartan cillexetil prevented the age-related impairment of EDHF-mediated hyperpolarization.
EDHF-mediated hyperpolarization was also impaired by hypertension, and anthihypertensive treatments corrected this abnormality. The present study evaluated the effects of hypertension and antihypertensive treatments on the expressions of connexins. We found that the expressions of connexin 37 and 40 in endothelial cells were significantly decreased in hypertension, and the antihypertensive treatment with candesartan cilexetil normalized the expressions of these connexins, findings consistent with those of EDHF-mediated hyperpolarization.
These findings suggest that gap junctions (connexins 37 and 40) play an important role in the EDHF-mediated hyperpolarization, and the alterations of gap junction may be associated with changes of EDHF-mediated hyperpolarization under pathophysiological conditions, such as hypertension.