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¥2,400,000 (Direct Cost : ¥2,400,000)
Fiscal Year 1996 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Fiscal Year 1995 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide which was first identified from ovine hypothalamic tissues, based upon its ability to elevate cyclic AMP in rat pituitary cell cultures. PACAP is struucturally a member of secretin/glucagon family, presenting 68% homology with vasoactive intestinal polypeptide (VIP). PACAP exerts a potent positive intropic effect on isolated perfused rat heart and exhibits hypotensive effect due to vasodilation, and stimulation of catecholamine release from adrenal medulla, suggesting the implication of PACAP in cardiovascular control. In this project, we have studied the pathophysiological role of PACAP in the cardiovascular system.
The radioimmunoassay established for PACAP has demonstrated that PACAP is widely distributed in several tissues of rats including adrenal gland, testis, thymus, besides of brain. PACAP-like immunoreactivity and its transcripts were also found in the pancreas. Interestingly it was demonstrated that
PACAP as low as 10^<-13> M potentiated glucose-induced insulin secretion from rat islets, indicating the involvement of PACAP in the regulation of insulin secretion. In order to clarify the pathophysiological implication of PACAP in streptozotocin-diabetic rats, male Sprague-Dawley rats (6 weeks) were injected intravenously with streptozotocin (50mg/kg). Four weeks later, the plasma glucose levels of teh treated rats were increased 4-fold compared to those of the controls. In the pancreas and hypothalamus of treated rats, PACAP immunoreactivity was increased significantly 30%, 10%, respectively. In contrast, PACAP immunoreacivity in the lung ans adrenal gland did not changes. These observations suggest that PACAP might be implicated in the pathophysiology of diabetes mellitus.
We have characterized PACAP/VIP receptors expressed in the cardiovascular system. In rat vascular smooth muscle (VSMC), PACAP and VIP shower the same potency to increase intracellular cyclic AMP.On the other hand, in the cultured rat endothelial cells 'EC), PACAP exhibited the 1000 times more potency than VIP.By using RT-PCR method, it was revealed that three types of PACAP/VIP receptor genes (PACAP receptor, VIP receptor type 1 and VIP receptor type 2) are expressed in rat heart and aortic tissues. In the EC,PACAP receptor and VIP type 2 receptor are expressed. In the VSMC,only VIP receptor type 2 gene is expressed. Gene expression levels of PACAP in VSMC and EC were examined by using RT-PCR.PACAP gene transcript was observed significantly in both cells. VIP,however, gene expression was observed only in EC.
The present study indicates the possible local regulatory system of VIP/PACAP as an autocrine or paracrine in the cardiovascular system. Less