Abstract
Age-related vascular diseases are induced by vascular dysfunction, which involves changes in the vasomotor response. The voltage-dependent L-type calcium channel (VDCC) protein is involved in the regulation of vessel function (contraction/relaxation action). In the present study, we evaluated age-related vasomotor function and expression of the signal-related target proteins, including VDCC, using thoracic aorta from both 8- and 40-week old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). In contraction experiments using aortic rings, vasomotor responses of both phenylephrine-induced contraction and acetylcholine-induced relaxation were significantly attenuated with age in SHR, whereas WKY did not lose activity with age. Contraction induced by angiotensin II was impaired only for the 40-week old SHR among all the rat groups tested, although enhanced AT1R/reduced AT2R expression with age was observed for both WKY and SHR. In contrast, a vasomotor responsiveness to Bay K 8644 (a VDCC agonist) at the initial contraction phase was significantly attenuated in both 40-week WKY and SHR with significant reduction of VDCC protein expression. The reduced VDCC expression in 40-week old rats significantly lowered the relaxation activity of VDCC blockers, such as verapamil and Trp-His, but did not affect that of nifedipine. Taken together, we provided the first evidence that aging caused a reduction of VDCC expression in rat aorta, irrespective of the rat strain, along with diminishment of the therapeutic potential of VDCC blockers.
Highlights
It has been reported that aging greatly affects vessel tone and arterial stiffness [1], causing the onset of vascular-related diseases such as hypertension, diabetes mellitus and atherosclerosis, by arterial dysfunction of receptors, ion channels, and signal transduction pathways [2,3]
We found a similar spectrum for ACh-induced relaxation (Figure 1C) with the contraction spectrum obtained in Figure 1B; a significant reduction in the relaxation response by 10 mM ACh was observed only for the 40-week spontaneously hypertensive rats (SHR), while no significant changes in the relaxation response were observed among the other groups
We investigated whether aging in rats influences vasomotor tone using thoracic aortic rings from both young (8week) and aged (40-week) WKY and SHR
Summary
It has been reported that aging greatly affects vessel tone and arterial stiffness [1], causing the onset of vascular-related diseases such as hypertension, diabetes mellitus and atherosclerosis, by arterial dysfunction of receptors, ion channels, and signal transduction pathways [2,3]. No studies have been reported regarding the relationship between age and expression of the voltage-dependent L-type Ca2+ channel (VDCC) in aorta. Ishii et al [8] reported an alternative therapeutic effect of blocking the cascade, in which a 10-week oral administration of nifedipine (10 mg/kg/day, a VDCC blocker) markedly suppressed the onset of atherosclerosis in apo E-deficient mice. In this study, we primarily investigated the effect of aging and/or hypertension on the vasomotor response (contraction/ relaxation) using thoracic aorta from both 8- and 40-week old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) as a function of vasomotor-related receptor and channel expression. We clarified whether compounds having VDCC blocking activity retained their relaxation potential in aged rat vessels
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