C Pharmacology & Toxicology 2003, 92, 189–194. Copyright C Printed in Denmark . All rights reserved ISSN 0901-9928 Blunted Central Bromocriptine-Induced Tachycardia in Conscious, Malnourished Rats Saad Lahlou, Paula F. Arau ´jo Lima, Leylliane F. L. Interaminense and Gloria Pinto Duarte Department of Physiology and Pharmacology, Center of Biological Sciences, Federal University of Pernambuco, 50670–901, Recife, PE, Brazil (Received April 29, 2002; Accepted September 26, 2002) Abstract: Bromocriptine-induced tachycardia, persisting after adrenalectomy, is mediated by central dopamine D 2 receptor stimulation through activation of the sympathetic outflow to the heart. The present study investigated the effects of malnutrition during pregnancy on bromocriptine-induced tachycardia in adult conscious rats. Malnourished rats were obtained by feeding dams a multideficient diet (providing 8% protein) during mating and pregnancy. Birth weight was significantly reduced in malnourished rats when compared to control rats born to dams fed standard commercially diet (23% protein) during mating and pregnancy. Baseline mean aortic pressure and heart rate in malnourished rats were comparable to those of well-nourished rats. Tachycardia (33∫9 beats/min.), but not the hypotensive response to intra- venous bromocriptine (150 mg/kg) was significantly reduced in malnourished rats, compared with control rats (70∫10 beats/min.). In malnourished rats, pretreatment with intravenous domperidone (500 mg/kg) blocked the bromocriptine- induced hypotension, without affecting the tachycardia. Neither cardiac vagal (40∫6 beats/min.) nor sympathetic tone (76∫6 beats/min.) was significantly altered by multideficient diet-induced malnutrition (51∫6 and 67∫10 beats/min., respectively). In isolated perfused heart preparations from malnourished rats, positive inotropic response to isoproterenol (10 ª8 to 10 ª4 M) was not significantly different compared to that in control rats. In summary, malnutrition during foetal life blunted the bromocriptine-induced tachycardia, an effect that could be related to central dopamine D 2 receptor desensitization rather than to impairment of autonomic regulation of the heart or cardiac b-adrenoceptor desensitization. Intravenous treatment with bromocriptine, a dopamine D 2 receptor agonist, induces dose-dependent decreases in mean aortic pressure and increases in heart rate in conscious rats (Lahlou & Demenge 1991). Reduction of bromocriptine-in- duced hypotension by either intravenous or intrathecal domperidone, a dopamine D 2 receptor antagonist that does not cross the blood-brain barrier (Laduron & Leysen 1979), suggests that this effect is mediated partly by peripheral and partly by spinal dopamine D 2 receptor stimulation (Lah- lou & Demenge 1991; Lahlou & Pinto Duarte 1998b). This partial spinal mediation was further corroborated by studies in conscious, spinal cord-transected rats (Lahlou & Demenge 1992). Bromocriptine-induced tachycardia does not seem to be related to motor stimulation (Creese & Iversen 1973) as it also occurs with a similar order of magnitude in anaesthet- ized rats (Lahlou & Demenge 1991). It also appears unre- lated to peripheral and/or spinal dopaminergic mechanisms since intravenous or intrathecal domperidone did not affect it (Lahlou & Demenge 1991). It might be tempting to sug- gest that this tachycardia is simply a reflexogenic response to the blood pressure decrease, even though its maximum occurred later than the peak hypotensive effect. However, previous findings preclude such a hypothesis and point to Author for correspondence: Saad Lahlou, Department of Physi- ology and Pharmacology, Center of Biological Sciences, Federal University of Pernambuco, 50670–901, Recife, PE Brazil (fax π55 81 3271 8976, e-mail lahlou/npd.ufpe.br). independent mechanisms for bromocriptine-induced hypo- tensive and tachycardiac effects (Lahlou & Demenge 1991; Lahlou et al. 1993; Lahlou & Pinto Duarte 1998a & b; Lah- lou et al. 2000). Tachycardia elicited by bromocriptine was shown to be elicited by central dopamine D 2 receptor acti- vation, since it was antagonized by intravenous pretreat- ment with neuroleptics that cross the blood-brain barrier and was also inhibited by domperidone given into a lateral cerebral ventricle (Lahlou et al. 1993). Because it is also completely abolished by pretreatment with intravenous pro- pranolol (Lahlou & Demenge 1991), the tachycardia may be mediated by b-adrenoceptors stimulated by bromocriptine- induced epinephrine release from adrenal medulla (Hamil- ton 1981). However, bromocriptine-induced tachycardia was unaffected by adrenalectomy (Lahlou et al. 1993). Thus, stimulation of central dopamine D 2 receptors could increase heart rate via activation of central sympathetic out- flow to the heart. This hypothesis was further corroborated by the finding that 5-day pretreatment with isoproterenol, a model of compensatory hypertrophy associated with car- diac b-adrenoceptor desensitization (Nanoff et al. 1989) re- duced bromocriptine-induced tachycardia (Lahlou & Pinto Duarte 1998a). Malnutrition is a worldwide health problem and experi- mental studies have shown that pre- or postnatal nutritional manipulations may program adult size, metabolism, blood lipids, diabetes, obesity, blood pressure, glomerular hyper- trophy, atherosclerosis, behavior and learning (Lucas et al. 1997; Lucas 1998). Catecholamine concentrations in the