Gender differences in vascular smooth muscle reactivity to increases in extracellular sodium salt

Hypertension is more common in men and postmenopausal women than in premenopausal women, and gender differences in sensitivity to high dietary Na+ salt have been suggested; however, the vascular mechanisms involved are unclear. We investigated whether increases in the extracellular concentration of Na+ ([Na+](e)) enhance the mechanisms of vascular smooth muscle contraction and whether the vascular effects of [Na+](e) exhibit gender differences. Isometric contraction and Ca-45(2+) influx were measured in endothelium-denuded aortic strips that were isolated from intact male, intact female, castrated male, and ovariectornized (OVX) female Sprague-Dawley rats and incubated in Krebs' solution (2.5 mmoI/L Ca2+) containing increasing [Na+](e) by the addition of 1, 3, 6, 10, 20, and 30 mmol/L NaCl. Increasing [Na+](e) for 30 minutes did not increase the resting tone or Ca-45(2+) influx in any group of rats. Phenylephrine (Phe) caused concentration-dependent increases in contraction and Ca-45(2+) influx. In vascular strips from intact males, increasing [Na+](e) by the addition of 1 to 6 mmol/L NaCl significantly increased the magnitude of Phe contraction and Ca-45(2+) influx. Further increases in [Na+](e) by the addition of 10, 20, and 30 mmol/L NaCl increased Phe-induced Ca-45(2+) influx but inhibited Phe contraction, possibly because of excessive increases in ionic strength. Preincubation with 2,4-dichlorobenzamil (10(-5) mol/L), inhibitor of the Na+-Ca2+ exchanger, or KB-R7943 (10(-5) mol/L), selective inhibitor of the reverse mode of the Na+-Ca2+ exchanger, abolished the increases in Phe contraction and Ca-45(2+) influx at increasing [Na+](e) obtained by the addition of 1 to 6 mmol/L NaCl. Preincubation in Krebs' solution containing control [Na+](e) plus 1 to 6 mmol/L LiCl or N-methyl-D-glucamine did not increase Phe contraction. In intact females, the Phe contraction and Ca-45(2+) influx were less than those in intact males and were not enhanced with increases in [Na+],. The enhancement of Phe contraction and Ca-45(2+) influx with increases in [Na+], were not significantly different between castrated male rats and intact male rats but were greater in OVX female rats than intact female rats. In OVX female rats or castrated male rats treated with 17beta-estradiol (but not 17alpha-estradiol) subcutaneous implants, no significant changes in Phe contraction or Ca-45(2+) influx with increases in [Na+](e) were observed. In OVX female or castrated male rats simultaneously treated with 17beta-estradiol plus the estrogen receptor antagonist ICI 182,780, the Phe contraction and Ca2+ influx were enhanced with increases in [Na+](e). Thus, in intact male rats, small physiological increases in [Na+](e) enhance smooth muscle contraction 2 1 21 to Phe by a mechanism involving Ca2+ entry, possibly via the reverse mode of the Na+-Ca2+ exchanger. This mechanism appears to be reduced in the presence of endogenous or exogenous estrogen and thereby protects female rats against excessive increases in vascular reactivity during high dietary Na+ intake.