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Chronic Guanethidine Treatment of Female Rats Including Effects on the Fetus

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Chronic Guanethidine Treatment of Female Rats Including Effects on the Fetus Chronic guanethidine treatment of female rats including effects on the fetus Barbara K. Evans and G. Burnstock Department ofZoology, University ofMelbourne, Parkville, Victoria, 3052, Australia Summary. Adult virgin female rats were injected daily with low doses (5 or 10 mg/kg) or a high dose (30 mg/kg) of guanethidine for 12 or 8 weeks respectively. 'Short' and 'long' noradrenergic neurones were unaffected by low doses. This contrasts markedly to earlier findings in male rats in which long-term damage of 'short' noradrenergic neurones occurred, and indicates a basic difference between 'short' noradrenergic neurones in male and female rats. Widespread degeneration of both types of neurones followed treatment with high doses and little reinnervation was observed 8 weeks after cessation of treatment. Fertility, pregnancy and litter size were apparently unaffected. Some teratogenic effects were observed in the offspring of female rats treated with guanethidine (10 or 25 mg/kg/day) before and throughout pregnancy. However, these effects had largely disappeared by the time the offspring were 10 weeks old. Since noradrenergic neurones of newborn rats are particularly sensitive to damage by guanethidine it would appear that either very little guanethidine crosses the placental barrier or that noradrenergic neurones are not susceptible during prenatal development to the cytotoxic effects of guanethidine. Introduction Particular interest has been shown in 'short' noradrenergic neurones (Owman & Sjöstrand, 1965; Sjöstrand, 1965) since they apparently share a number of properties, apart from the length of their aeon, which differ considerably from those of ordinary 'long' noradrenergic neurones (see Owman, Sjöberg & Sjöstrand, 1974). For example, they are more resistant to damage by 6- hydroxydopamine (Malmfors & Sachs, 1968), depletion of noradrenaline stores after reserpine (Sjöstrand & Swedin, 1968) or a-methyl-p-tyrosine (Swedin, 1970) and inhibition of development by anti-nerve growth factor (Hamberger, Levi-Montalcini, Norberg & Sjöqvist, 1965). On the basis of such results it has been suggested that 'short' noradrenergic neurones constitute a distinct neuronal type. However, most of these studies were carried out using male animals and the 'short' noradrenergic neurones which innervate the male, and part of the female internal genitaUa have been shown to differ. Whereas oestrogen and progesterone markedly influence the noradrenaline content of female 'short' noradrenergic neurones (Sjöberg, 1968a, b; Falck, Owman, Rosengren & Sjöberg, 1969a, b), they have no effect on the noradrenaline content of male 'short' noradrenergic neurones (Owman, Sjöberg, Sjöstrand & Swedin, 1970). In male rats and mice the 'short' noradrenergic innervation has been shown to be considerably more sensitive to damage by chronic guanethidine treatment than 'long' noradrenergic neurones (Gannon, Iwayama, Burnstock, Gerkens & Mashford, 1971; Evans, Gannon, Heath & Burnstock, 1972; Evans, Iwayama & Burnstock, 1973; Evans, Heath & Burnstock, 1979a). The purpose of this study was to investigate the effects of chronic treatment * Present address: Department of Anatomy and Embryology, University College London, Gower Street, London WC1E6BT, England. Downloaded from Bioscientifica.com at 10/03/2021 08:17:59PM via free access with low and high doses of guanethidine, a drug used widely in the treatment of hypertension, on the peripheral noradrenergic neurones of the female rat and particularly to see whether the 'short' noradrenergic neurones are affected earlier or with lower doses. The possibihty of damage to fetal noradrenergic neurones as a result of maternally administered guanethidine was also investigated. Materials and Methods Thirty-five (35) adult virgin female rats were injected with guanethidine sulphate (Ismelin: CIBA) at low doses (5 or 10 mg/kg/day) for 12 weeks or a high dose (30 mg/kg/body weight/day) for 8 weeks. The rats were küled by bleeding under light ether anaesthesia at selected intervals during treatment and up to 8 weeks following cessation of treatment. A second group of age-matched untreated female rats served as controls and in all cases control tissue was processed together with the guanethidine-treated tissue. The formaldehyde-induced fluorescence method for the histochemical demonstration of tissue monoamines (Falck & Owman, 1965), as described in detaü elsewhere (Evans et al., 1973), was carried out on the following tissues: right atrium, superior cervical ganghon, iris, coeliac ganglion, ovary, oviduct, uterus, vagina, paracervical ganglion, urethra and ureter. Using light-field iUumination it is possible to identify the presence of intact non-fluorescent nerve cell bodies in sympathetic ganglia. The absence of such cells and the continued lack of fluorescence many weeks after cessation of treatment were taken to indicate that degeneration of the noradrenergic neurones had taken place. The validity of this belief has been shown in other studies (Burnstock et al., 1971; Heath et al, 1972; Evans et al., 1979b) using Ught and electron microscopy. Another group of 9 virgin female rats were injected with 25, 10 or 1 mg guanethidine/kg/day for 2 weeks before mating with normal males. The injections were continued without interruption until the end of pregnancy. The male offspring were killed 1, 2 and 10 weeks after birth and tissue from the right atrium, superior cervical gangUon, ileum, vas deferens, epididymis and pelvic plexus was prepared for fluorescence histochemistry. Male offspring were examined since the 'short' noradrenergic neurones supplying the male reproductive tract have been shown to be particularly sensitive to low doses of guanethidine (Gannon et al, 1971; Evans et al, 1972, 1973). One vas deferens from the 10-week-old males was reserved for organ bath experiments where the response to stimulation of intramural nerves and sensitivity to noradrenaline were determined. The conditions and experimental procedure were as described elsewhere (Evans et al, 1973). After weaning, the mothers were killed and selected tissues processed for fluorescence histochemistry. Results Low doses Treatment with low doses (5 or 10 mg/kg/day) of guanethidine caused no change in the fluorescent appearance of the noradrenergic innervation to the right atrium, ureter, iris or of the noradrenergic cell bodies in the superior cervical or coeliac ganglia either during or following treatment. The noradrenergic nerves supplying the female reproductive tract were also unaffected by low doses of guanethidine. Fluorescent nerve fibres were still clearly visible in the ovary (PI. 1, Fig. 2), oviduct (PL 1, Fig 6), uterus (PL 2, Fig. 10) and vagina (PL 2, Fig. 14); the pattern and density of this innervation were comparable to that of control tissue (PL 1, Figs 1 and 5; PL 2, Figs 9 and 13). The general appearance of the paracervical ganglion (PL 3, Fig. 21) and the noradrenergic innervation of the urethra was also normal. Downloaded from Bioscientifica.com at 10/03/2021 08:17:59PM via free access High dose The effect of a high dose (30 mg/kg/day) of guanethidine on the fluorescence of the nora¬ drenergic innervation of the atrium, iris and on the cells of the superior cervical and coeliac (PL 3, Figs 17, 18 and 19) ganglia supported the results of an earner study (Burnstock, Evans, Gannon, Heath & James, 1971) in which similar treatment produced a widespread sympa- thectomy involving the degeneration of over 95% of peripheral noradrenergic neurones in both male and female rats. The reinnervation of these tissues after cessation of treatment was the same as seen in male rats and is described in detail elsewhere (Evans et al, 1979b). The normal paracervical gangUon is a diffuse ganglion in which only a small proportion (between 20 and 30%) of the nerve ceU bodies show weak to moderate fluorescence (PL 3, Fig. 20). The remainder are non-fluorescent presumably cholinergic ceUs (see also Adham & Schenk, 1969; Kanerva, 1972a, b). A large number of small intensely fluorescent cells in groups of various sizes are scattered throughout the ganglion. After 1 week of treatment with the high dose of guanethidine there was a decrease in the number of fluorescent ganglion cells and after 4 weeks only occasional fluorescent cell bodies were seen. Some perivascular fibres were still present. After treatment for 8 weeks no fluorescent nerve cell bodies or fibres were seen in the ganglion (PL 3, Fig. 21). Non-fluorescent gangUon cells were still evident and a few of these appeared vacuolated. There was very little increase in autofluorescent material in the ganglion. The appearance of the ganglion showed little change 8 weeks after cessation of treatment. Only isolated fluorescent gangUon cells were seen and, apart from a partial return of perivascular innervation within the ganglion, very few fluorescent fibres were seen. Non-fluorescent nerve cell bodies and small intensely fluorescent cells in the ganglion appeared normal throughout treatment and recovery. The fluorescent innervation to the reproductive organs and urethra had decreased greatly after treatment for 1 week. A few fibres were seen in the isthmus of the oviduct (PL 1, Fig. 7) and in the vagina (PL 2, Fig. 15) but virtually no fibres were seen in the uterus (PL 2, Fig. 11), uterotubal junction or ovary. Occasional perivascular fibres were visible throughout the reproductive tract. No fluorescent fibres were present in these organs after treatment for 4 or 8 weeks (PL 1, Fig. 3). The very small noradrenergic
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