ABSTRACT
The aim of this study was to investigate the effects of adrenomedullin [ADM] on plasma renin activity and the release of vasoregulatory peptides as endothelin-1 [ET-1], nitric oxide [NO] and norepinephrine in nitric oxide synthase [NOSG] deprived pregnant rats as an animal model of preeclampsia using N -nitro-L-arginine methyl ester [L-NAME], a NOS inhibitor. Also the aim was to elucidate the possible beneficial effects of ADM on regulation of renal function, blood pressure, blood supply to uteroplacental unit and consequently on fetal growth. The current study was carried out on 60 female Wistar rats. Their average weight was 250-300 g. They were 13-18 weeks old. Two or three cycling female rats were housed with a male for 24 hours. The presence of sperms in vaginal smears was considered as day 1 of pregnancy. Rats were divided into four groups [15 rats each] according to the following experimental design: group I included virgin non-pregnant rats, group II included pregnant rats that received saline solution starting from day 7 to day 20 of gestation, group III included pregnant rats that were treated with L-NAME daily starting from the same day of gestation and for the same duration as for group II, to make an animal model of preeclampsia, group IV included pregnant rats that were treated by both L-NAME [the same dose and for the same duration as for group III] and recombinant rat ADM, 3 times a day starting from day 14 to day 20 of gestation. The following parameters were measured in the control and all pregnant rats on day 13 of gestation and also on day 20 of gestation: - mean arterial blood pressure [MAP], some renal function tests [including urine volume, urinary Na[+] and K[+], creatinine clearance as a measure of glomerular filtration rate [GFR], 24 h urinary albumin excretion], pup weight, plasma levels of ADM, endothelin-1 [ET-I], norepinephrin, total nitric oxide [NO] products and plasma renin activity [PRA]. L-NAME treatment of pregnant rats [group III] starting from day 7 to day 20 of gestation produced significant reduction of urine volume, creatinine clearance and total plasma NO as compared to control and normal pregnant rats [group II]. Moreover, their pup weight on day 20 of gestation was significantly reduced as compared to that of normal pregnant rats [P< 0.0001]. On contrast L-NAME treated rats on days 13 and 20 of gestation had significant increase of MAP, 24 h urinary Na and albumin excretion, plasma levels of ADM, ET-1, norepinephrin and PRA as compared to controls and group II on corresponding days of gestation where P<0.0001. ADM treatment of pregnant rats for 7 days starting from day 14 to day 20 of gestation significantly increased urine volume, urinary Na[+] excretion, creatinine clearance, plasma levels of ADM and total plasma NO products as compared to the same group on day 13 of gestation and L-NAME treated rats on days 13 and 20 of gestation. Moreover, their pup weight was significantly increased as compared to that of L-NAME treated rats on day 20 of gestation. However, no significant changes were detected as regard urinary K[+] excretion and PRA when comparing them to the same group on day 13 of gestation and L-NAME treated rats on days 13 and 20 of gestation. Also no significant change in plasma norepinephrin was detected between ADM and L-NAME treated rats on day 20 of gestation. On the other hand, MAP, 24 h urinary albumin excretion and plasma ET-1 level were significantly decreased in ADM treated rats on day 20 of gestation as compared to the same group on day 13 and L-NAME treated rats on days 13 and 20 of gestation. Comparing ADM treated pregnant rats on day 20 of gestation with control and normal pregnant rats on days 13 and 20 of gestation, we observed significant increase of urine volume, 24 h urinary Na excretion, plasma levels of ADM, norepinephrin and PRA and significant decrease of total plasma NO [P<0.0001] and pup weight [P<0.05], while no significant changes were found as regard MAP, 24 h urinary albumin excretion, creatinine clearance and plasma ET-1 level. The current data suggest that the increased ADM concentration seen in L-NAME induced preeclampsia plays a compensatory role and may be necessary to maintain placental vascular resistance and/or fetal circulation, growth and response to a compromised intrauterine environment. ADM administration [which achieved plasma levels of this peptide in the pathophysiological range] to NOS deprived pregnant rats as an animal model of preeclampsia has powerful vasodilator/hypotensive actions and renoprotective effect. Moreover, this study confirms the interaction of ADM with other vasoactive factors that are involved in the pathogenesis of preeclampsia by producing difference in vasoconstrictors/vasodilators balance. Clarification of this possibility must await additional studies and, in particular, the development of specific blackers of ADM secretion or action. Therefore, ADM might be a new target of therapeutic approach to preeclampsia. Manipulations that augment production of this peptide or inhibit its breakdown might find a place in the management of pregnant women with preeclampsia