Clinical and Experimental Pharmacology and Physiology (2003) 30, 555–557 SHORT COMMUNCIATION EFFECTS OF PREWEANING DOXAZOSIN TREATMENT ON ADULT PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT Erika I Boesen, Tamara V Lewis, Michelle M Kett and Warwick P Anderson Department of Physiology Monash University, Melbourne, Victoria, Australia SUMMARY 1. The neonatal/preweaning period appears to represent a critical period of involvement of the sympathetic nervous system in the development of hypertension in spontaneously hypertensive rats (SHR). 2. We tested whether 1-adrenoceptor-mediated effects during the preweaning period are involved in the development of hypertension in the adult SHR. 3. Male SHR were treated with the 1-adrenoceptor antag- onist doxazosin (10 mg/kg per day, s.c.) from postnatal day 1 to 21 inclusive. Direct conscious blood pressure and heart rate were measured via the caudal artery at 12 weeks of age. 4. Preweaning treatment with doxazosin had no significant effect on mean arterial blood pressure or heart rate in male SHR at 12 weeks of age. 5. These findings do not support the involvement of 1- adrenoceptor-mediated effects during the preweaning period in the development of hypertension in adult SHR. Key words: 1-adrenoceptor, hypertension, spontaneously hypertensive rats, sympathetic nervous system. INTRODUCTION The neonatal (preweaning) period appears to represent a critical period of involvement of the sympathetic nervous system in the development of hypertension in spontaneously hypertensive rats (SHR). When initiated during this period, treatments targeted against the sympathetic nervous system can attenuate (1-adreno- ceptor antagonist 1 ) or abolish hypertension in SHR (neonatal sympathectomy 2,3 ). However, when such treatment protocols are initiated later than 3 weeks of age (i.e. post-weaning), they have little (-adrenoceptor antagonists, 4 renal denervation 5 ) or no effect on adult SHR blood pressure (1- or 2-adrenoceptor antagonists 6 ). McCarty and Lee 1 reported that administration of the 1-adreno- ceptor antagonist terazosin to SHR from postnatal day 1 to 21 attenuated hypertension as measured at 100 days of age. These investigators postulated that this reduction in adult blood pressure by preweaning 1-adrenoceptor blockade could be due to a reduction in vascular smooth muscle hypertrophy and hyperplasia. 1 However, terazosin also demonstrates significant binding at the 2-adrenoceptor. 7,8 Accordingly, we have used doxazosin, a selec- tive 1-adrenoceptor antagonist, from postnatal day 1 to 21 to further determine the specific role of the receptor in the develop- ment of hypertension and cardiovascular hypertrophy in the SHR. METHODS This study was approved in advance by the Monash University Physiology Animal Ethics Committee and conducted in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. Spontaneously hypertensive rats were housed at 22–24°C, with a 12 h light–dark cycle. Rat chow and water were supplied ad libitum. Pregnant SHR were obtained from the Baker Medical Research Institute (Prahran, Victoria, Australia) and caged individually. The date of birth (postnatal day 0) was designated as the day the entire litter was first present by 09.00 h. On postnatal day 1, pups were assigned randomly to receive either vehicle (3% dimethyl sulphoxide, 97% peanut oil, s.c.) or doxazosin (10 mg/kg per day s.c.; Pfizer, Sandwich, UK) once daily from postnatal day 1 to 21 inclusive. This dose of doxazosin was chosen from a pilot study in which it caused a significant (P = 0.005) right shift of the phenyle- phrine–mean arterial pressure dose–response relationship in 3–4-week-old rats, with responses to 5, 10 and 20 g/kg phenylephrine reduced by more than 50% 24 h following doxazosin treatment (i.e. at the time at which the next dose of doxazosin would normally be given; data not shown). At 12 weeks of age, male SHR were briefly anaesthetized (metho- hexitone sodium; 50 mg/kg, i.p.; Eli Lily, West Ryde, NSW, Australia) and the caudal artery cannulated for direct arterial blood pressure measurement, as described previously. 9,10 At least 1 h following recovery, resting con- scious mean arterial pressure and heart rate were measured over a period of 20–30 min. An arterial blood sample was then collected for measurement of plasma renin activity. 11 Animals were killed humanely with an overdose of pentobarbitone (Rhone Merieux, Pinkemba, NSW, Australia) and the left ventricle dissected out and weighed. Data were analysed using Student’s t-test. RESULTS At 12 weeks of age, conscious mean arterial pressure was almost identical in rats treated with doxazosin or vehicle from 1 to 21 days (Table 1). Thus, preweaning doxazosin treatment did not attenuate the subsequent development of hypertension in the SHR. There were also no significant effects on heart rate, left ventricle to bodyweight ratio or plasma renin activity (Table 1). There was no significant difference in bodyweight between vehicle- and Correspondence: Erika Boesen, Department of Physiology, PO Box 13F, Monash University, Victoria 3800, Australia. Email: Erika.Boesen@med.monash.edu.au The peer review of this paper was administered by the Editor– Pharmacology. Received 18 October 2002; revision 16 April 2003; accepted 18 April 2003.