Aging Down Regulates L‐Type Voltage‐gated Calcium Channels in Resistance Coronary Arteries
Authors: Mansour Fathi A , Hassan Mohammed O , Khan Abdul Aleem , Albarwani Sulayma 
Published: November 2023

Introduction

Aging is a well‐established independent risk factor for the development of cardiovascular disease. Myogenic tone (MT) refers to the ability of resistance arteriolar vascular smooth muscle (VSMC) to alter its tone in response to changes in transmural pressure. L‐type voltage‐gated calcium channels (VGCC) represent the main pathway for calcium (Ca2+) influx into VSMC. The aim of this study was to investigate the role of VGCC in maintenance of myogenic tone of small coronary arteries in old age.

Methods

Fischer 344 male rats, aged 22 – 26 (old) months and 3–4 months (young) were sacrificed and branches with an outer diameter, 70–110 μm of left anterior descending artery were dissected. Changes in the outer diameter in response to alterations of intravascular pressure with 20 mmHg increments from 0–100 mmHg under no flow condition were recorded. Intracellular calcium [Ca2+]i was estimated using fluorescence ratio of 340/380 of Fura‐2 in pressurized arteries. Whole‐cell L‐VGCC currents were recorded from isolated VSMC using 10 mM Ba2+ as charge carrier. RNA was isolated and real time PCR was performed to measure the expression level of mRNA encoding pore forming VGCC α1‐subunit. Values were expressed as means ± SEM and were compared using unpaired t‐test. A P value of <0.05 was considered as significant.

Results

MT at 80 mmHg of arteries from old was significantly reduced by 21.85 ± 3.0% (n = 31) (p < 0.0001) compared to that of young 41.7 ± 2.95% (n = 27). Simultaneous measurement of [Ca2+]i with MT, showed that, at 80 mmHg arteries from old had significantly (p < 0.01) lower calcium ratio (0.24 ± 0.02) compared to that from young (0.31 ± 0.02). Both, increases in myogenic tone and [Ca2+]i were fully abolished by the VGCC blocker nifedipine and slightly increased by VGCC agonist Bay K 8644 in arteries from old and young (n = 8–12), indicating that myogenic tone was brought about mainly by influx of Ca2+ through VGCC. Peak inward VGCC current densities (pA/pF) recorded from cells isolated from arteries of old were significantly lower (‐3.66 ± 0.41, n= 36) than those from young (− 8.8 ± 0.88, n= 27), with a reduction of approximately 58%. The half voltages (V0.5) of activation and inactivation were similar between the two groups. These results suggest reduced availability of functional VGCC in membranes of coronary VSMC of old rats. Finally, the expression level of mRNA encoding the pore‐forming α1 subunit of the VGCC in arteries of old was also reduced by 47% compared to young (P < 0.05) giving a relative quantity of expression values of 0.49 ± 0.10 and 0.93 ± 0.14 for old and young respectively (n =5 each).

Conclusion

Our functional, electrophysiological and molecular results showed for the first time, that resistance coronary arteries from old animals exhibited significantly reduced MT, [Ca2+]i, VGCC currents and their gene expression compared to arteries from young animals, suggesting a down regulation of VGCC with aging.

Support or Funding Information

Sultan Qaboos University and The Research Council of Oman