Sex-specific programming of hypertension in offspring of late-gestation diabetic rats.
BACKGROUND
The intrauterine environment strongly influences adult disease susceptibility. We used a rat model of third-trimester maternal diabetes to test the hypothesis that adult offspring exposed to hyperglycemia in utero display increased blood pressure and alterations in vascular responsiveness.


METHODS
Diabetes was induced by streptozotocin injection to pregnant rats on gestation day 13 (term 21 d) and partially controlled with insulin injections. Hemodynamic function was evaluated in 6-12-mo-old offspring.


RESULTS
Male but not female offspring of diabetic mothers (ODM) had significantly increased blood pressure as compared with controls; heart rate (HR) was similar. For both sexes, HR baroreflex responses were similar as were in vivo hemodynamic responses to angiotensin II, nitric oxide synthase inhibition, and ganglionic blockade. Aortic contractility to angiotensin II was similar in the two groups. Nitric oxide synthase inhibition and the Cu/Zn superoxide dismutase inhibitor diethyldithiocarbamate, but not the superoxide dismutase-mimetic Tempol, significantly increased contractile responses to angiotensin II in controls but not ODM. Reduced nicotinamide adenine dinucleotide phosphate-stimulated superoxide production was greater in male ODM than in controls (P < 0.05).


CONCLUSIONS
Exposure to hyperglycemia in utero results in sex-specific cardiovascular changes in adult offspring. Impaired nitric oxide-reactive oxygen species signaling may play a significant role in the hemodynamic phenotype of ODM.
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Ragheed
R
Katkhuda
Emily S
ES
Peterson
Robert D
RD
Roghair
Andrew W
AW
Norris
Thomas D
TD
Scholz
Jeffrey L
JL
Segar
D000367:Age Factors; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017704:Baroreflex; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D016640:Diabetes, Gestational / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology; D005865:Gestational Age; D006339:Heart Rate; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D015398:Signal Transduction; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005730:Ganglionic Blockers; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D013311:Streptozocin; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase