Prenatal cocaine exposure differentially causes vascular dysfunction in adult offspring.
Epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of cardiovascular diseases and hypertension in adult life. The present study tested the hypothesis that prenatal cocaine exposure causes reprogramming of vascular reactivity, leading to an increased risk of hypertension in adult offspring. Pregnant rats received cocaine (30 mg kg(-1) day(-1)) or saline from days 15 to 21 of gestational age, and experiments were conducted in 3-month-old offspring. Cocaine had no effect on the baseline blood pressure but significantly increased norepinephrine-stimulated blood pressure and decreased the baroreflex sensitivity in male but not female offspring. The cocaine treatment significantly increased norepinephrine-induced contractions in pressurized resistance-sized mesenteric arteries but not in aortas, which was primarily because of a loss of endothelial NO synthase-mediated inhibition and an enhanced Ca(2+) sensitivity in mesenteric arteries. In addition, the cocaine treatment significantly attenuated the endothelium-dependent relaxation in mesenteric arteries in male but not female offspring. Endothelial NO synthase protein levels in aortas but not mesenteric arteries were significantly increased in the cocaine-treated animals. However, cocaine significantly decreased phosphorylation levels of endothelial NO synthase in both aortas and mesenteric arteries. The results suggest that prenatal cocaine exposure programs vascular contractility via changes in endothelial NO synthase-regulated Ca(2+) sensitivity of myofilaments in the sex- and tissue-dependent manners in resistance arteries leading to an increased risk of hypertension in male offspring.
Xiao
Daliao
D
Department of Pharmacology and Physiology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Huang
Xiaohui
X
Xu
Zhice
Z
Yang
Shumei
S
Zhang
Lubo
L
D000818:Animals; D005260:Female; D008297:Male; D011247:Pregnancy; D051381:Rats; D000367:Age Factors; D001011:Aorta / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000175:diagnosis; D003042:Cocaine / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000175:diagnosis / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D018811:Maternal Exposure; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D011270:Pregnancy, Animal; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012737:Sex Factors; D014661:Vasoconstriction / Q000187:drug effects
D003042:Cocaine; D009569:Nitric Oxide