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Platelet membrane calmodulin-stimulated calcium-adenosine triphosphatase. Altered activity in essential hypertension
Insights
Essential hypertension is linked to elevated platelet calcium levels. A defective calcium efflux pump in hypertensive individuals may contribute to this, potentially as a protective mechanism against calcium overload.
Area of Science:
- Biochemistry
- Cardiovascular Physiology
- Cell Biology
Background:
- Elevated platelet free calcium (Ca2+) concentration is observed in essential hypertension and correlates with blood pressure.
- Free cytoplasmic calcium levels are regulated by calcium influx, pooling, and efflux mechanisms.
Purpose of the Study:
- To investigate the characteristics of platelet membrane Ca2+-ATPase in normotensive and hypertensive subjects.
- To determine the role of calmodulin-stimulated Ca2+-ATPase activity in essential hypertension.
Main Methods:
- Characterization of platelet membrane Ca2+-ATPase kinetics (affinity for Ca2+, orthovanadate inhibition, calmodulin stimulation).
- Comparison of basal and calmodulin-stimulated Ca2+-ATPase activity between normotensive and hypertensive individuals.
- Assessment of calmodulin and Ca2+ affinities in platelet membranes from both groups.
Main Results:
- Platelet membranes possess a high-affinity Ca2+-ATPase inhibited by orthovanadate and stimulated by calmodulin.
- While absolute increases in calmodulin-stimulated activity were similar, the *degree* of stimulation was significantly reduced in hypertensive subjects (40% vs. 135%).
- Hypertensive subjects showed markedly greater basal and calmodulin-stimulated Ca2+-ATPase *capacity* (1.5- to 1.8-fold).
Conclusions:
- Defective calcium efflux pump activity, indicated by reduced calmodulin stimulation, may contribute to elevated cytoplasmic calcium in essential hypertension.
- This defect might be an adaptive mechanism to prevent cellular Ca2+ overload.
- Differences in Ca2+-ATPase capacity and calmodulin responsiveness highlight potential dysregulation in platelet calcium handling in hypertension.
Abstract:
Platelet free Ca2+ concentration has been found to be elevated in essential hypertension and to correlate with blood pressure level. Free cytoplasmic calcium concentration is determined by calcium influx, pooling, and efflux. The present study found a Ca2+-ATPase in platelet membranes that has a high affinity for Ca2+ (Km approximately 1 microM), is inhibited by low concentrations of orthovanadate (Ki approximately 1 microM), and can be stimulated by calmodulin (Km approximately 5 nM). The absolute increase in calmodulin-stimulated Ca2+-ATPase activity was not different between normotensive and hypertensive subjects; however, the degree of stimulation of Ca2+-ATPase activity at saturating calmodulin concentrations apparently was diminished in calmodulin-deficient membranes from subjects with established essential hypertension (40%) as compared to that in normotensive subjects of similar age (135%; p less than 0.001). Affinities for calmodulin and Ca2+ were comparable between the two groups, while the capacity for Ca2+-ATPase activity (basal and calmodulin-stimulated) was markedly greater (1.5- to 1.8-fold) in both native and calmodulin-deficient membranes from hypertensive subjects. On the other hand, the defective calcium efflux pump activity, as assessed by a decreased degree of calmodulin stimulation, may have contributed to elevated cytoplasmic calcium concentrations and the associated enhanced hormone sensitivity in platelets from essential hypertensive subjects. This may represent an adaptive negative feedback control mechanism to protect the cell against Ca2+ overload.