Abstract
To understand the changes in physiological responses due to aging, a number of bioactive probes based on different signal transduction pathways are necessary. In this study, we comprehensively and systematically investigated changes in blood vessel function with age using a 336-dipeptide library.In the early stage of hypertension, the most potent vasorelaxant dipeptide was Ser-Tyr (SY) in the mesenteric artery isolated from spontaneously hypertensive rats (SHR). SY-induced vasorelaxation and anti-hypertensive effects were blocked by L-NAME, an inhibitor of nitric oxide synthase (NOS), suggesting that SY activates the NO system. On the other hand, the patterns of dipeptides with vasorelaxation activity in early and advanced stages of hypertension were different. In the advanced stage, the most potent vasorelaxing dipeptide was Asn-Ala (NA). Orally administered NA (1.5 mg/kg) reduced the blood pressure in the advanced stage, at which drugs were sometimes less effective, and the anti-hypertensive effects lasted for 6 hr. The NA-induced vasorelaxation and anti-hypertensive activity was blocked by lorglumide, an antagonist of the cholecystokinin CCK1 receptor, suggesting that NA activated the CCK system.Taken together, in the early and advanced stages of hypertension, SY and NA exhibited vasorelaxing and anti-hypertensive effects via the NO and CCK systems, respectively.
Highlights
Aging attenuates many physiological functions and is a major risk factor for many diseases
The profile of vasorelaxation activity of dipeptides was markedly different between spontaneously hypertensive rats (SHR) with early and advanced hypertension
We found that SY exhibited the most potent vasorelaxation activity and orally administered SY reduced the blood pressure in SHR with early hypertension, which was mediated through the nitric oxide (NO) pathway
Summary
Aging attenuates many physiological functions and is a major risk factor for many diseases. The mechanism of aging-induced physiological alteration has not yet been investigated in details. To increase the healthy life expectancy, the mechanisms of aging must be clarified. The Canadian physician William Osler said that “A man is as old as his arteries”. Aging is closely associated with functional changes in arteries, and the prevalence of hypertension increases with age [1]. The purpose of this study was to understand the changes in arterial function with age by comparing the vasorelaxation activity in SHR with early (15–18 weeks) and advanced hypertension (over 27 weeks old)
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