Altered sodium-calcium exchange in afferent arterioles of the spontaneously hypertensive rat
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L D Nelson1, N A Mashburn, P D Bell
1Department of Medicine, University of Alabama at Birmingham, USA.
Insights
In spontaneously hypertensive rats, impaired sodium-calcium exchange in afferent arterioles contributes to elevated intracellular calcium. This dysfunction is age-dependent and suggests a potential mechanism for hypertension development.
Area of Science:
- Cardiovascular Physiology
- Renal Physiology
- Hypertension Research
Background:
- Hypertension involves altered vascular smooth muscle function.
- Sodium-calcium exchange (NCX) plays a critical role in regulating intracellular calcium in vascular cells.
- Dysfunctional NCX may contribute to the elevated blood pressure observed in spontaneously hypertensive rats (SHR).
Purpose of the Study:
- To investigate potential derangements in Na-Ca exchange activity in afferent (AA) and efferent (EA) arterioles of spontaneously hypertensive rats (SHR) compared to Wistar-Kyoto (WKY) rats.
- To assess the impact of age (3 and 9 weeks) on Na-Ca exchange function in these arterioles.
- To determine if altered calcium handling contributes to hypertension in SHR.
Main Methods:
- Cytosolic calcium concentration ([Ca2+]i) was measured using fura-2 photometry in isolated AA and EA from 3- and 9-week-old WKY and SHR.
- Changes in [Ca2+]i were assessed during alterations in extracellular sodium concentration ([Na+]e) to probe Na-Ca exchange activity.
- Intracellular sodium ([Na+]i) was manipulated using ouabain to further investigate NCX function.
Main Results:
- Baseline [Ca2+]i was similar in AA of WKY and SHR at both ages.
- In AA, the increase in [Ca2+]i upon sodium reduction was attenuated in 9-week-old SHR compared to younger SHR and WKY rats of both ages.
- The rate of Ca2+ removal (sequestration/extrusion) was significantly reduced in AA of 9-week-old SHR, and ouabain-induced increases in [Na+]i did not fully restore NCX function in these arterioles.
- No significant differences in Na-dependent or Na-independent [Ca2+]i changes were observed in EA segments between WKY and SHR at either age.
Conclusions:
- Diminished Na-Ca exchange activity and impaired Na-independent Ca2+ handling mechanisms in afferent arterioles may contribute to elevated cytosolic calcium in spontaneously hypertensive rats.
- These alterations in calcium regulation are age-dependent and specific to the afferent arteriole, suggesting a potential role in the development and maintenance of hypertension.
- Na-Ca exchange regulation differs between afferent and efferent arterioles in spontaneously hypertensive rats.
Abstract:
Studies were performed to determine if there is a derangement in Na-Ca exchange activity in afferent (AA) and efferent (EA) arterioles from 3- and 9-week-old spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Cytosolic calcium concentration ([Ca2+]i) was assessed using microscope-based photometry in fura-2 loaded arterioles bathed in a Ringer's solution. Baseline [Ca2+]i was similar in the AA of 3- and 9-week-old WKY and SHR. In AA from 3-week-old rats, [Ca2+]i increased by 89 +/- 15 nM in WKY and by 73 +/- 13 nM in SHR during decreases in bath sodium concentration ([Na+]e) from 150 to 2 mM (Na+ replaced with n-methyl-D-glucamine). In 9-week-old hypertensive SHR (SBP = 150 mm Hg), increases in [Ca2+]i were attenuated (24 +/- 3 nM) relative to 3-week-old WKY and SHR, and 9-week-old WKY (90 +/- 9 nM; P < 0.05). Likewise, the rate of removal of Ca2+ in the continued presence of 2 mM Nae (Ca2+ sequestration and/or extrusion) was markedly reduced in AA of 9-week-old SHR (-0.15 +/- 0.03 nM/second) versus 3-week-old SHR (-0.72 +/- 0.12 nM/second) and 3- and 9-week-old WKY (-0.49 +/- 0.10 and -0.67 +/- 0.14 nM/second). In other experiments, AAs were preincubated in 1 mM ouabain to increase intracellular [Na+]. This maneuver augmented the increase in [Ca2+]i obtained with removal of Na+e; however, the responses obtained in 9-week-old SHR arterioles were still attenuated compared to those obtained in arterioles for 3- and 9-week-old WKY and 3-week-old SHR. These results suggest that exchanger number and/or sensitivity to the transmembrane Na gradient was reduced in the SHR AA. In EA, baseline [Ca2+]i was similar in 3- and 9-week-old WKY and SHR. In contrast to AA, the magnitude of Na-dependent and Na-independent changes in [Ca2+]i was not different in the EA of 3- and 9-week-old WKY and SHR. These results indicate that regulation of Na-Ca exchange activity may differ between AA and EA segments. Furthermore, diminished Na-Ca exchange and Na-independent Ca2+ sequestering/extrusion mechanisms could contribute to altered AA [Ca2+]i in the SHR.