Attenuation of L-type Ca²⁺ channel expression and vasomotor response in the aorta with age in both Wistar-Kyoto and spontaneously hypertensive rats

PLoS One. 2014 Feb 12;9(2):e88975. doi: 10.1371/journal.pone.0088975. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology
  • Aging / metabolism
  • Aging / physiology*
  • Angiotensin II / pharmacology
  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / physiology*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / metabolism*
  • Gene Expression Regulation* / drug effects
  • Male
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Vasoconstriction* / drug effects
  • Vasodilation* / drug effects

Substances

  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Angiotensin II
  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester

Grants and funding

This study was supported by a grand-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (No. 22248014) to TM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.