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(Hypertension. 2002;39:425.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Gender Differences in Vascular Smooth Muscle Reactivity to Increases in Extracellular Sodium Salt

Laura A. Barron; GaChavis M. Green; Raouf A. Khalil

From the Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson.

Reprint requests to Raouf A. Khalil, MD, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216. E-mail rkhalil{at}physiology.umsmed.edu

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 ⁴⁵Ca²⁺ influx were measured in endothelium-denuded aortic strips that were isolated from intact male, intact female, castrated male, and ovariectomized (OVX) female Sprague-Dawley rats and incubated in Krebs’ solution (2.5 mmol/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 ⁴⁵Ca²⁺ influx in any group of rats. Phenylephrine (Phe) caused concentration-dependent increases in contraction and ⁴⁵Ca²⁺ 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 ⁴⁵Ca²⁺ influx. Further increases in [Na⁺]_e by the addition of 10, 20, and 30 mmol/L NaCl increased Phe-induced ⁴⁵Ca²⁺ 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 ⁴⁵Ca²⁺ 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 Ca²⁺ influx were less than those in intact males and were not enhanced with increases in [Na⁺]_e. The enhancement of Phe contraction and Ca²⁺ influx with increases in [Na⁺]_e 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 17ß-estradiol (but not 17-estradiol) subcutaneous implants, no significant changes in Phe contraction or Ca²⁺ influx with increases in [Na⁺]_e were observed. In OVX female or castrated male rats simultaneously treated with 17ß-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 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.

Key Words: arterial pressure • muscle, smooth, vascular • calcium • sodium • gender

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