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Assessment of Vascular Tone Responsiveness using Isolated Mesenteric Arteries with a Focus on Modulation by Perivascular Adipose Tissues
Published on: June 3, 2019
Aging Reduces L-Type Calcium Channel Current and the Vasodilatory Response of Small Mesenteric Arteries to Calcium
Sulayma A Albarwani1, Fathi Mansour1, Abdul Aleem Khan1
1Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University Muscat, Oman.
Insights
Aging reduces the effectiveness of calcium channel blockers (CCBs) in mesenteric arteries. This decreased sensitivity is linked to lower L-type voltage-gated calcium channel (LTCC) current density in older rats.
Area of Science:
- Cardiovascular Physiology
- Aging Research
- Pharmacology
Background:
- Calcium channel blockers (CCBs) are crucial for managing cardiovascular diseases (CVD), with usage increasing in aging populations.
- Aging is an independent risk factor for CVD, necessitating an understanding of its impact on drug efficacy.
Purpose of the Study:
- To investigate how aging affects the sensitivity of small mesenteric arteries to L-type voltage-gated calcium channel (LTCC) blockers.
- To determine if aging alters calcium current density in these arteries.
Main Methods:
- Isometric tension measurements of third-order mesenteric arteries from young (2.5-3 months) and old (22-26 months) male F344 rats.
- Cumulative concentration-response curves for nifedipine, verapamil, and diltiazem to assess artery relaxation.
- Electrophysiological assessment of LTCC current density and Western blot analysis for Cav1.2 protein expression.
Main Results:
- Older rats exhibited significantly reduced sensitivity (right-shifted IC50 values) to CCBs compared to younger rats.
- Bay K 8644-induced increases in resting tension were diminished in arteries from old rats.
- LTCC current density and Cav1.2 protein expression were significantly lower in arteries from old rats.
Conclusions:
- Aging diminishes the vasodilatory response of small mesenteric arteries to CCBs.
- Reduced LTCC current density, associated with decreased Cav1.2 protein expression, is a key factor contributing to this age-related decrease in CCB sensitivity.
Abstract:
Calcium channel blockers (CCBs) are widely used to treat cardiovascular disease (CVD) including hypertension. As aging is an independent risk factor for CVD, the use of CCBs increases with increasing age. Hence, this study was designed to evaluate the effect of aging on the sensitivity of small mesenteric arteries to L-type voltage-gated calcium channel (LTCC) blockers and also to investigate whether there was a concomitant change in calcium current density. Third order mesenteric arteries from male F344 rats, aged 2.5-3 months (young) and 22-26 months (old) were mounted on wire myograph to measure the tension during isometric contraction. Arteries were contracted with 100 mM KCl and were then relaxed in a cumulative concentration-response dependent manner with nifedipine (0.1 nM-1 μM), verapamil (0.1 nM-10 μM), or diltiazem (0.1 nM-10 μM). Relaxation-concentration response curves produced by cumulative concentrations of three different CCBs in arteries of old rats were shifted to the right with statistically significant IC50s. pIC50 ± s.e.m: (8.37 ± 0.06 vs. 8.04 ± 0.05, 7.40 ± 0.07 vs. 6.81 ± 0.04, and 6.58 ± 0.07 vs. 6.34 ± 0.06) in young vs. old. It was observed that the maximal contractions induced by phenylephrine and reversed by sodium nitroprusside were not different between young and old groups. However, Bay K 8644 (1 μM) increased resting tension by 23 ± 4.8% in young arteries and 4.7 ± 1.6% in old arteries. LTCC current density were also significantly lower in old arteries (-2.77 ± 0.45 pA/pF) compared to young arteries (-4.5 ± 0.40 pA/pF); with similar steady-state activation and inactivation curves. Parallel to this reduction, the expression of Cav1.2 protein was reduced by 57 ± 5% in arteries from old rats compared to those from young rats. In conclusion, our results suggest that aging reduces the response of small mesenteric arteries to the vasodilatory effect of the CCBs and this may be due to, at least in part, reduced current density of LTCC.
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