Recycling and buffering of intracellular calcium in vascular smooth muscle from genetically hypertensive rats

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ObjectiveTo test the hypothesis that impaired Ca2+ recycling by the sarcoplasmic reticulum Ca-ATPase contributes to augmented force development in arteries from stroke-prone spontaneously hypertensive rats (SHRSP).MethodsForce development to caffeine (0.3–30 mmol/l) in the absence of extracellular Ca2+ was compared in aortic strips from SHRSP and Wistar-Kyoto (WKY) rats. In another protocol the strips were rinsed at the peak of contraction to caffeine (20 mmol/l) and subsequently restimulated with the alkaloid. The second response, dependent on recycled Ca2+, was used as a measure of sarcoplasmic reticulum function. A third protocol evaluated caffeine-induced contractions after Ca2+ depletion and reloading. In these latter experiments the effects of thapsigargin, an inhibitor of the sarcoplasmic reticulum Ca-ATPase, and ryanodine, an activator of sarcoplasmic reticulum Ca2+ release channels, were used to evaluate Ca2+ buffering. Finally, unidirectional 45Ca2+ influx was measured.ResultsContractions to caffeine (0.3–30 mmol/l) were larger in SHRSP aortic strips than in WKY rat strips. After a rinse at the peak of the initial response to caffeine, SHRSP segments contracted more when challenged a second time. Thapsigargin (0.3–10 μmol/l) caused a concentration-dependent contraction during Ca2+ loading that was greater in SHRSP than in WKY rat strips, and a concentration-dependent inhibition of caffeine-induced contraction with similar median inhibitory concentrations in the two groups. Ryanodine did not cause contraction during Ca2+ loading, but caffeine-induced contractions were reduced after ryanodine treatment in both groups. 45Ca2+ influx was increased in SHRSP aortic segments.ConclusionsThe greater force development to caffeine in SHRSP aortic strips probably reflects a greater storage of activator Ca2+ in the sarcoplasmic reticulum. On the basis of the pharmacological properties of thapsigargin and ryanodine, it appears that the larger store is caused by enhanced Ca2+ influx across the sarcolemma rather than by recycling of Ca2+ by sarcoplasmic reticulum Ca-ATPase. Experiments evaluating the secondary response to caffeine also support the interpretation that recycling of activator Ca2+ into the sarcoplasmic reticulum does not explain the augmented force development in SHRSP aortic segments.

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