An L-arginine–nitric oxide–cyclic guanosine monophosphate system exists in the uterus and inhibits contractility during pregnancy

doi:10.1016/S0002-9378(94)70405-8

American Journal of Obstetrics and Gynecology

Volume 170, Issue 1, January 1994, Pages 175-185

https://doi.org/10.1016/S0002-9378(94)70405-8 Get rights and content

Abstract

OBJECTIVE: Nitric oxide is synthesized from L -arginine and it causes relaxation of smooth muscle by elevating cyclic guanosine monophosphate levels. We hypothesized that an L -arginine–nitric oxide–cGMP system is present in the uterus and modulates contractility. STUDY DESIGN: Isometric tension of the uterus was measured in vitro from pregnant rats in response to various agents that modulate nitric oxide–cyclic guanosine monophosphate production or action. RESULTS: Major findings are as follows: (1) The substrate and a donor of nitric oxide produced uterine relaxation; (2) inhibitors of the nitric oxide–cyclic guanosine monophosphate pathway blocked the relaxation responses; (3) nitric oxide synthase was localized to several uterine cell types; (4) nitric oxide was produced by the uterus during periods when L-arginine was consumed and citrulline levels increased; (5) effects of nitric oxide substrate on relaxation were mimicked by cyclic guanosine monophosphate; (6) nitric oxide–cyclic guanosine monophosphate responses were decreased during delivery; (7) L -arginine responses were increased by progesterone, and antiprogesterone treatment decreased cyclic guanosine monophosphate – induced relaxations. CONCLUSION: An L -arginine–nitric oxide–cyclic guanosine monophosphate system is present in the uterus and it may regulate relaxation during pregnancy. The inhibitory action of L -arginine and 8-bromo-cyclic guanosine monophosphate was considerably lower during delivery and post partum, indicating that the nitric oxide system may contribute to the maintenance of uterine quiescence during pregnancy, when progesterone levels are elevated, but not during delivery. (AM J OBSTET GYNECOL 1993;170:175-85.)

Section snippets

Animals

Nonpregnant (female cycling, 180 to 200 gm body weight) and pregnant Sprague-Dawley rats on day 13 to 15 of gestation (Harlan - Sprague-Dawley, Houston) were received in our animal care facility. Animals were maintained on a regimen of animal chow and water as desired. Pregnant rats were put to death on days 17, 18, 19, and 22 of gestation before labor, at the time of spontaneous delivery (one to three pups delivered) at term, or on days 1 and 2 post partum. Nonpregnant rats were ovariectomized

Effects of L-arginine and L-NAME on uterine contractility

Application of 3 mmol/L L-arginine to muscle strips caused immediate relaxation of the spontaneous contractile activity of uterine tissue strips obtained from 18-day-pregnant rats (Fig. 1), and these relaxation responses were repeatedly inducible in each strip without washout. These results indicate that an L-arginine- nitric oxide system may exist in the uterus and induce relaxation of uterine muscle activity. The specificity of the nitric oxide–generating system was examined by using a

COMMENT

In the current study we demonstrated that an L-arginine–nitric oxide–cGMP system is present in the uterus and that it modulates uterine contractility. The major findings from this study are as follows: (1) that the substrate (L-arginine, Fig. 1) and a donor (sodium nitroprusside, Fig. 2) of nitric oxide produce substantial relaxation of the pregnant rat uterus, (2) that inhibitors of nitric oxide synthase (L-NAME, Fig. 1) and soluble guanylate cyclase (methylene blue) block the effects of L

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Nonetheless, it is well recognized that nitric oxide (NO) participates to the regulation of uterine homeostasis. Soluble guanylyl cyclase is an NO-specific target in the myometrium, generating 3⿲5⿲cyclic guanosine monophosphate (cGMP) [4,5]. Several evidence report the importance of NO/cGMP pathway in the modulation of uterine motility [6,7].
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Citation Excerpt :
In healthy humans, l-arginine supplementation increases blood lymphocyte proliferation induced by mitogen (Barbul et al., 1981). Some studies in animal models show that the l-arginine-NO system is upregulated during pregnancy and hypertension, proteinuria, glomerular damage and fetal growth retardation could be induced by blockade of NO synthesis (Aydin et al., 2004; Yallampalli et al., 1994). Mechanisms of congenital transmission of Chagas’ disease still remain unknown.
Chagas disease induces a strong immune response and l-arginine is an essential amino acid which plays an important role in homeostasis of the immune system. The aims of this study were to evaluate parasitemia, corticosterone levels, production of nitric oxide (NO), fetal morphological measurements, and histology of heart and placenta. Twenty pregnant Wistar rats (180–220 g) were grouped in: pregnant control (PC), pregnant control and l-arginine supplied (PCA), pregnant infected (PI), pregnant infected and l-arginine supplied (PIA). Females were infected with 1 × 10⁵ trypomastigotes of the Y strain (3rd day of pregnancy). Animals were supplied with 21 mg of l-arginine/kg/day during 14 days. PIA showed significant decreased levels of corticosterone and parasitemia. For control groups, any alteration in NO production was found with l-arginine supplementation; for PIA, enhanced nitrite concentrations were observed as compared to PI. Weights and lengths of fetuses were higher in l-arginine treated and infected pregnant rats as compared to untreated ones. Placental weight from the PIA group was significantly increased when compared to PI. In l-arginine treated animals, cardiac tissue showed reduced amastigote burdens. PIA and PI displayed similar placental parasitism. Based on these results, l-arginine supplementation may be potentially useful for the protection against Trypanosoma cruzi during pregnancy.
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The L-Arginine-Nitric Oxide Synthase-Nitric Oxide (L-Arg-NOS-NO) system exerts a pivotal role in the maintenance of uterine quiescence during pregnancy, whereas Homocysteine (Hcy) promotes uterine contractility. The aim of this study was to test the in vitro effects of L-Arg on spontaneous and Hcy-induced contractions of uteri excised from pregnant bitches. 104 strips cut from pregnant uteri were mounted in an organ bath. 40 out of 104 strips (16 from mid-gestation uteri and 24 from close to term uteri, respectively) were exposed to cumulative doses of L-Arg; 40 strips (16 from mid-gestation-uteri and 24 from close to term-uteri, respectively) were exposed to N-nitro-L-arginine methyl ester (L-NAME), a NOS antagonist; the remaining 24 strips (from close-to-term uteri) were first exposed to a single dose of Hcy and then to increasing doses of L-Arg. L-Arg showed no effects on spontaneous contractility both in mid-gestation- and close to term-uterine strips, whereas it promoted a relaxant effect on Hcy-induced contractility. On the contrary, L-NAME increased amplitude of contraction both in mid-gestation and close to term strips. These findings suggest that the L-Arg-NO system is present in the uterus of pregnant bitches and that Hcy is able to modulate its actions. Further investigation of this system may provide the basis of future obstetrical therapies in bitches.

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^☆: From Reproductive Sciences, Department of Obstetrics and Gynecology, The University of Texas Medical Branch.

^☆☆: Supported by the Department of Obstetrics and Gynecology.

^*: Reprint requests: Chandrasekhar Yallampalli, DVM, PhD, Department of Obstetrics and Gynecology, 301 University Blvd. Rt. J-62, Medical Research Building Room 2.143, Galveston, TX 77555-1062.

^★★: 0002-9378/94 $1.00 +.20 6/1/50813

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An L-arginine–nitric oxide–cyclic guanosine monophosphate system exists in the uterus and inhibits contractility during pregnancy☆,☆☆,*,★★

Abstract

Section snippets

Animals

Effects of L-arginine and L-NAME on uterine contractility

COMMENT

J Cardiovasc Pharmacol

Eur J Pharmacol

Nitric oxide: physiology, pathophysiology and pharmacology

Pharmacol Rev

Spontaneous release of nitric oxide inhibits electrical, Ca+ and mechanical transients in canine gastric smooth muscle

J Physiol

Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme

Proc Natl Acad Sci U S A

Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein

Proc Natal Acad Sci U S A

Role of endothelium-derived nitric oxide in the regulation of blood pressure

Proc Natal Acad Sci U S A

Elevated guanosine 3':5'-cyclic monophosphate mediates the depression of nitrovasodilator reactivity in endothelium-intact blood vessels

Arch Pharmacol

Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo

Proc Natal Acad Sci U S A

Progesterone and modulation of endothelium-dependent responses in canine coronary arteries

Am J Physiol

Force of labor

Evidence that part of the NANC relaxant response of guinea-pig trachea to electrical field stimulation is mediated by nitric oxide

Br J Pharmacol

The effect of inhibitors of nitric oxide biosynthesis and cyclic GMP formation on nerve-evoked relaxation of human cavernosal smooth muscle

Br J Pharmacol

Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo

Br J Pharmacol

Spontaneous release of nitric oxide inhibits electrical, Ca⁺ and mechanical transients in canine gastric smooth muscle