The effect of a single oxytocin or carbetocin treatment on uterine contractility in early postpartum dairy cows
Introduction
During the bovine puerperal stage, involution of the uterus has an important role in a cow to becoming pregnant again. During involution, beside the morphological changes of the endometrium, the size of the uterus also markedly decreases. The greatest size reduction in normal cows occurs during the first few days after parturition [1]. Regression processes accelerate between days 10 and 14, resulting in that by day 25, uterine diameter almost reaches its final size [2]. This can be judged from the size measured after involution is completed. However, the time of complete involution can vary within wide ranges; 25–50 days after parturition in cows [1], [2], [3].
Uterine muscle activity is important in the process of involution. A contractile uterus is advantageous in removing excessive fluid and debris from the uterine lumen early postpartum. Our previous observations on cows without fetal membrane retention showed us, that while there was a high variability among individual animals, uterine contractions generally diminished rapidly, with a major decline between 12 and 24 h after calving, and with very little spontaneous contractility left at 48 h [4].
Treatment protocols, in which uterotonic drugs are administered during the puerperal phase in cows to evacuate the uterus by increasing its contractility, aim to accelerate the process of involution. Natural prostaglandin F2α, or its synthetic analogues [5], [6], [7], [8], [9] and oxytocin (OT) [5], [10], [11], [12], are frequently used for this purpose. However, the efficiency of prostaglandin treatments in evacuating the puerperal uterus, by promoting its contractility, is questionable. Because both an induced [13] and a failing uterotonic effect [5], [9], [14], [15] have been reported for such treatments, and because OT did not show such contradictory results, the use of OT-like drugs seems to be preferred during the puerperal phase. However, only a few studies [5], [10], [11], [12] have quantified the uterotonic effects of OT if administered shortly (within 12 h) after calving [10], [11]. It can therefore be anticipated that this effect would be short lasting, as the half-life of OT has been reported to be short in cows (mean rapid T1/2 = 3.87 ± 0.1 min; and mean slow T1/2 = 25.53 ± 1 min) [16].
The biological effect of OT and its analogues depends on two factors: on how quickly it is removed from the circulation by excretion and through metabolism, and on whether there are enough specific receptors available, which are capable of binding the drug. Numerous attempts have been made to achieve a longer uterotonic effect by using oxytocin. A continuous, slow-rate intravenous drip infusion, as is often used in humans, is difficult to perform with cows under farm conditions. The increased plasma oestrogen levels in the cow around calving could enhance the effect of oxytocin in a very early postpartum uterus, possibly by stimulating the synthesis of endometrial OT-receptors, but not affecting or even prohibiting that of myometrial OT-receptors, as it was shown in mid-pregnant, parturient and non-pregnant cows [17], [18]. Because the effects of oestrogens with respect to expression of oestrogen receptors in the uterine wall are still unclear, and because of their human food safety implications, the possibility as to enhance uterotonic activity by external oestrogen treatment, should be rejected.
An alternative way to produce a prolonged uterotonic effect is to use OT-analogues with a longer biological activity, such as carbetocin (CB) [6], [8], which appeared to have a prolonged uterotonic activity in swine [19] and cows [20]. The short plasma half-life of the native OT molecule can be partly explained by its chemical structure. The circulating hormone is sensitive to the effects of aminopeptidase and disulfidase enzymes; the aminopeptidase can cleave the CN bond at position 1–2 of the molecule, while the disulfidase affects the S–S bridge at position 1–6 [21]. It has been shown that desamination of the N-terminus and replacement of the sulphur bridge with a CH2S group [21], protects the structure of the molecule and results in a prolonged oxytocin effect in rats [22], [23], [24]. The OT-analogue carbetocin (CB; 1-deamino-1-monocarba-[2-O-methyltyrosine]-OT) also produced uterotonic activity in rats [25], in sows during oestrus [19], [26] and in parturient cows [27], although its uterotonic activity, measured in vivo or in vitro, was 10 [27], more than 25 [25] or even 30 [28] times weaker than that of OT. The prolonged uterotonic effect of CB is associated with a biphasic half-life [26]. Side-effects, such as uterine tetany or tachyprophylaxis, did not occur in vivo or in vitro after CB treatment in swine [19], but did more often occur with the use of higher dose rates of OT in cows [27].
The aim of the present study was to evaluate to what extent a single treatment with either OT or CB, 14–16 h after normal parturition, influences uterine contractility on days 1 and 2 postpartum in dairy cows. Therefore, this field study addressed the following questions:
- 1.
What is the short-term intrauterine pressure response to a single treatment with OT or CB, when injected intramuscularly between 14 and 16 h postpartum?
- 2.
Do the long-term (12–36 h post-treatment) characteristics of uterine contractility, induced by OT or CB given between 14 and 16 h postpartum, differ from that recorded in untreated control animals?
- 3.
Are there any differences between the OT and CB induced contractility characteristics in terms of their short-term and long-term effects?
Section snippets
Cows and treatment
Twenty seven Holstein–Friesian dairy cows, kept at a large-scale dairy cattle farm in Hungary, were used in this study during the autumn of 2001. All the cows had shed their fetal membranes within 12 h of normal calving. If necessary, light assistance only, the aid of one or two persons, was provided during calving. Cows with lacerations or ruptures of the soft birth canal were excluded from the study. For 2–3 weeks preceding the expected calving, the cows were housed in a calving barn with two
Results
Fig. 2a and b present typical examples of 90-min recordings around the single intramuscular treatment at 14–16 h postpartum, with either 50 IU OT or 0.35 mg CB, showing their effect on IUP changes.
Table 1 summarizes the mean values (±S.E.M.) of the IUP parameters for each 1-h IUP recording, in each experimental group—for the statistical analysis of both the short- and the long-term effects.
Fig. 3a–d illustrate the changes in the FREQ, AMP, AUC and TAUC values for the two treated groups and the
Discussion
The uterotonic effects caused by the administration of a single intramuscular treatment of either oxytocin (50 IU), or its long-acting analogue, carbetocin (0.35 mg), were compared in this field study on early postpartum dairy cows, after normal parturition. It turned out that both drugs significantly increased the FREQ and TAUC values of the pressure cycles, mainly during the first post-treatment hour. The uterotonic effects of the two drugs were almost equal, and a prolonged uterotonic effect
Acknowledgements
This study was carried out within the framework of the International PhD Programme of Utrecht University, The Netherlands, and was partly supported by the Hungarian Scientific Research Fund, Grant No. OTKA T 043505, the Hungarian State Eötvös Scholarship and the Bolyai János Research Scholarship of the Hungarian Academy of Science.
References (37)
- et al.
Effects of estradiol cypionate and natural and synthetic prostaglandins on myometrial activity in early postpartum cows
Theriogenology
(1989) - et al.
Effects of oestradiol cypionate on spontaneous and oxytocin-stimulated postpartum myometrial activity in the cow
Br Vet J
(1990) - et al.
Half-life, clearance and production rate for oxytocin in cattle during lactation and mammary involution
Domest Anim Endocrinol
(1984) - et al.
Prolonged action of deamino-carba analogues of oxytocin in the rat uterus in vivo
Eur J Pharmacol
(1974) - et al.
Pharmacology of cyclic analogues of deamino-oxytocin not containing a disulphide bond (carba analogues)
Eur J Pharmacol
(1973) - et al.
The control of myometrial functions during parturition with a ß2-mimetic compound, Planipart®
Theriogenology
(1980) - et al.
Uterus of the cow after parturition: involutional changes
Am J Vet Res
(1968) - et al.
Postpartum ovarian activity and uterine involution in dairy cattle
J Am Vet Med Assoc
(1966) - et al.
A review of postpartum ovarian activity and involution of the uterus and cervix in cattle
Cornell Vet
(1969) - et al.
Characteristics of bovine early puerperal uterine contractility recorded under farm conditions.
(2005)
Uterotonic effect of prostaglandin F2α and oxytocin on the postpartum cow
Am J Vet Res
Einfluß verschiedener Uterotonika auf den Nachgeburtsabgang bei Rindern nach konservativen und operativen geburtshilflichen Eingriffen
Tierärztl Umsch
Die Uterusmotorik des Rindes während Spätgravidität, Geburt und Puerperium. II. Medikamentelle Beeinflussung
Schweiz Arch Tierheilkd
Uterotonika im Puerperium des Rindes
Monatsh Veterinärmed
Untersuchungen zur postpartalen Uterusmotilität des Rindes. 2. Mitt.: Uterusmotilität im Frühpuerperium des Rindes nach Oxytozinapplikation
Monatsh Veterinärmed
Die Uterusbewegungen bei Kühen während der Geburt und der Nachgeburtsphase
Schweiz Arch Tierheilkd
Exogenous prostaglandin F2α promotes uterine involution in the cow
Acta Vet Scand
Prostaglandin F2α metabolite levels in normal and uterine-infected postpartum cows
Vet Res Commun
Cited by (37)
Effects of oxytocin and PGF2α on uterine contractility in cows with and without metritis—An in-vitro study
2018, Animal Reproduction ScienceCitation Excerpt :Oxytocin caused significant shortening of one distance in Group M− and of two distances in Group M+. This confirms that oxytocin enhances uterine contractility in the puerperal period in cows and is consistent with results of in-vivo studies in postpartum cows without metritis, in which oxytocin had a positive effect on uterine contractility (Kündig et al., 1990a; Gajewski et al., 1999; Bajcsy et al., 2006). A lesser effect of oxytocin after day 4–5 postpartum described previously in cows in in vivo studies (Kündig et al., 1990a) did not occur in the present study, and days postpartum had no effect on contractility pattern after stimulation with oxytocin.
Effect of oxytocin and PGF2α on chlortetracycline absorption from the uterus of early postpartum camels (Camelus dromedarius)
2015, TheriogenologyCitation Excerpt :Understanding the interaction between prophylactic treatments in the postpartum uterus is essential for developing effective therapeutic strategies. One of the motivations for injecting oxytocin during the postpartum period is its uterotonic effect [19,40,41]. Our study showed that oxytocin had no significant effect on the serum concentration of CTC in early postpartum dromedary camels.
Modulatory effect of three antibiotics on uterus bovine contractility invitro and likely therapeutic approaches in reproduction
2014, TheriogenologyCitation Excerpt :Several researches have been conducted on diseases that affect the uterus during delicate process of uterine involution [4–6]. In this period, the natural antibacterial mechanisms of the uterus (local production of antibodies, the phagocytic action of neutrophils and macrophages), the mechanical action of the secretions, and the contractile activity of myometrium [7–11] perform an action of self-cleaning by allowing, in most cases, to limit the duration and spread of infection [12]. However, sometimes the defense mechanisms are not able to counteract the action of bacteria [13,14], resulting in the development of pathologies, such as retained placenta and metritis, that affect the genital tract and the fertility of the subject [15,16].
Circulatory level of interleukin-1 in periparturient cows with or without postpartum reproductive diseases
2013, Asian Pacific Journal of ReproductionEx vivo influence of carbetocin on equine myometrial muscles and comparison with oxytocin
2012, TheriogenologyCitation Excerpt :A drug without side effects and a long half-life stimulating a prolonged tocolytic effect might improve uterine clearance. The use of carbetocin, a long acting analogue of oxytocin, has been investigated as a beneficial form of treatment on uterine involution in bovines [9], as well as in humans for the treatment of postpartum hemorrhage [10–12]. In adult, nonlactating anestrous mares carbetocin has been shown to have a half-life of approximately 17 min, which is 2.5-fold longer than that of oxytocin, and not associated with any side effects [7].
Oxytocin treatment immediately after calving does not reduce the incidence of retained fetal membranes or improve reproductive performance in crossbred Zebu cows
2010, TheriogenologyCitation Excerpt :Frazer [5] summarized that a single dose of oxytocin (40 IU) may cause increased frequency of rapid uterine contractions or initial tetanic spasm (duration of response, 6 to 10 min), but would not maintain sustained myometrial activity [5]. Bajcsy et al [17] working with Holstein cows, reported a significant short term effect of oxytocin treatment (50 IU) on intrauterine pressure, indicating that a single dose of oxytocin can provoke a rapid, but not prolonged uterotonic effect, making it necessary to give frequent treatments to achieve this effect [17]. Most studies regarding uterine response to oxytocin treatment have been conducted with Bos taurus dairy and beef cattle in temperate climates.