title: Effects of nitric oxide synthase inhibition on angiotensin receptors and metabolism in the pregnant hypertensive rat.
abstract: Endothelial dysfunction and a consequent decrease in nitric oxide production have been implicated in the pathogenesis of pre-eclampsia. A prominent feature of the pre-eclamptic syndrome is a loss of the pregnancy-induced refractoriness to infused pressor agents, such as angiotensin. In this study, we sought to determine whether a decrease in nitric oxide production might be linked via changes in angiotensin II receptors and angiotensin II metabolism to changes in pressor sensitivity to infused angiotensin II. Pregnant and non-pregnant spontaneously hypertensive rats (SHRs) were randomly allocated to receive 5 mg x kg(-1) x day(-1) N(G)-nitro-L-arginine methyl ester (L-NAME) in the drinking water or drinking water alone from days 7 to 14 of gestation. Steady-state metabolic clearance studies of angiotensin II were then performed, or tissues were harvested for angiotensin II receptor studies. Treatment with L-NAME caused an increase in systolic pressure (P<0.001) in both pregnant and non-pregnant rats, while urinary protein excretion increased only in the pregnant SHRs (P<0.001). Plasma angiotensin II levels were significantly increased in the L-NAME-treated SHRs compared with controls (non-pregnant, P<0.0005; pregnant, P<0.01). The metabolic clearance rate of angiotensin II was decreased by L-NAME treatment in non-pregnant SHRs (P<0.05), but was increased by L-NAME treatment in the pregnant rats (P<0.01). In the aorta, the angiotensin II receptor number increased after treatment with L-NAME in both non-pregnant (P<0.0005) and pregnant (P<0.05) SHRs, and the dissociation constant increased in the non-pregnant SHRs (P<0.005). Thus treatment of SHRs with L-NAME increased blood pressure, as well as the circulating angiotensin II concentration and vascular angiotensin II receptor expression. However, treatment with L-NAME did not affect pressor sensitivity to infused angiotensin II. We conclude, therefore, that although a decrease in nitric oxide production is associated with changes in angiotensin II concentrations and receptor numbers, it does not induce changes in pressor sensitivity to infused angiotensin II in the SHR.
authors.affiliation: University Department of Medicine, Prince Henry Hospital, Sydney, NSW 2034, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: G J
authors.initials: GJ
authors.lastname: Macdonald
authors.forename: K A
authors.initials: KA
authors.lastname: Duggan
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006973:Hypertension / Q000201:enzymology; D008657:Metabolic Clearance Rate; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000201:enzymology; D011507:Proteinuria / Q000139:chemically induced; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011945:Receptors, Angiotensin / Q000502:physiology*
chemical_list: D011945:Receptors, Angiotensin; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester