Br. J. c/lin. Pharmac. (1986), 21, 45S-54S Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise P. LUND-JOHANSEN, P. OMVIK & H. HAUGLAND Section of Cardiology, Medical Department, University of Bergen, School of Medicine, Bergen, Norway 1 The acute and chronic haemodynamic effects of doxazosin were studied in 14 patients (10 males, four females) with essential hypertension, at rest supine and sitting and during 100 W bicycling exercise. 2 Blood pressure (BP) was recorded intra-arterially in the brachial artery, cardiac output (CO) was measured by Cardiogreen and heart rate (HR) by ECG. 3 One hour after injection of doxazosin 0.5-1.0 mg i.v., mean arterial pressure (MAP) was reduced by 8% at rest supine, 12% at rest sitting and 10% at 100 W (all changes statistically significant), associated with a reduction in total peripheral resistance index (TPRI) of 5% at rest supine, 9% at rest sitting (P < 0.01) and 14% at 100 W (P < 0.001). HR was slightly increased (5%, NS) and cardiac index (CI) was unchanged during rest and slightly increased during exercise (4%, P < 0.05). 4 Patients were then given doxazosin capsules (2-16 mg once daily), aiming at a casual BP of < 140/90 mmHg without side-effects. Central haemodynamics were restudied after 1 year. 5 After 1 year of doxazosin treatment, MAP was reduced by 13% at rest supine, 16% at rest sitting and 17% at 100 W (all P-values < 0.001). TPRI was reduced by 19% at rest supine, 20% at rest sitting and 18% at 100 W (all changes statistically significant). CI was increased by 8% at rest supine (P < 0.05) but was unchanged sitting and at 100 W. 6 It is concluded that doxazosin lowers BP through a reduction in TPRI acutely as well as chronically, without reductions in CO. BP control was maintained over 1 year without side- effects. Thus, doxazosin normalizes central haemodynamics in patients with mild to moderate essential hypertension, both at rest and during exercise. Keywords cardiac output doxazosin exercise haemodynamics total peripheral resistance Introduction hypertension, and then to study the changes induced by 8-12 months of chronic treatment with Doxazosin is a new postsynaptic a,-adrenoceptor doxazosin orally. blocker; it is related to prazosin but has a longer half-life (Timmermans et al., 1980; Singleton et al., 1982; Vincent et al., 1983). Its Methods antihypertensive effect has been demonstrated in Patients animals and in man (Beckett & Finch, 1982; Elliott et al., 1982; de Leeuw et al., 1982). So far, no The study protocol was approved by the Norwegian acute and chronic studies on the haemodynamic State Drug Control and informed consent was effects at rest and during exercise in man have been obtained from all patients. The 14 patients (10 reported. males and four females), aged 22-59 (mean 42.4) The purpose of the present study was to investi- years, all had sitting diastolic blood pressure, gate the first-dose effect of doxazosin intravenously between 100 and 120 mmHg on three out-patient at rest and during exercise in patients with essential control visits. Serum creatinine was within normal 45S 46S P. Lund-Johansen et al. limits and in all patients secondary hypertension versation was not allowed in the 10 min before the was excluded by usual routine procedures. All were next haemodynamic recordings. in WHO stage I or II, without other diseases (including obesity), and were actively working. Assessment 2 After 1 h of supine rest, central Twelve patients were previously untreated and two haemodynamics were recorded (assessment 2) and had been on a- or P-adrenoceptor antagonists for immediately thereafter during the next 3 min less than 1 year. In both of these patients the doxazosin 0.5-1.0 mg was injected intravenously washout period without drugs was 2 months. through the catheter in the superior vena cava. The The mean body weight was 72.7 ± 14.9 kg and patients were not aware of the injection. Blood the mean body surface area (BSA) was 1.86 ± 0.22 pressure was recorded continuously for 1 h while mi. the patients rested supine. Haemodynamic methods Assessment 3 After 1 h the haemodynamic study was repeated at rest supine and sitting and then Blood pressure was recorded continuously through during 100 W exercise (assessment 3) (see section a catheter in the brachial artery. Cardiac output was on hypotensive episodes, where the protocol was measured by Cardiogreen injected through a modified). catheter in the superior vena cava. Double determinations were performed in all situations. Chronic study The heart rate was determined from ECG record- ings. Cardiac index (CI), stroke index (SI) and total After the acute study had been completed the peripheral resistance index (TPRI) were calculated patients started oral doxazosin treatment. by standard formulae (Lund-Johansen, 1967). Doxazosin was given in capsules once daily in the Studies were performed at rest supine and sitting morning, at a starting dose of 2 mg. and during ergometer bicycling in steady state. The dose of doxazosin was increased gradually Plasma volume (PV) was determined by using every second week, aiming at a casual blood radio-iodinated (125I) human serum albumin (4 ,Ci; pressure of < 140/90 mmHg without side-effects. Radiochemical Centre, Amersham, England) with a The maximal dose was set (by Pfizer Central 10 min equilibration period. Total blood volume Research) at 16 mg. (BV) was calculated from PV and the simul- After 8-12 months the daily doses were 2 mg in taneously determined corrected packed cell three patients, 4 mg in three, 8 mg in four and 12 volume. The extracellular fluid volume (ECF) Was and 16 mg in two. The mean dose ofdoxazosin was measured as the sulphate space: 100 mCi radio- 6.5 mg. sulphate (35SO4) was injected intravenously and During the chronic study there were two drop- plasma samples were collected 30, 45, 60 and 75 outs. One patient had a myocardial infarction after min after injection. The samples were counted in 2 months (male patient, blood pressure 130/90 duplicate in a Nuclear Enterprise beta-gamma mmHg) when taking doxazosin 4 mg. After the counter (NE 8312) and zero time concentration of infarction the patient received timolol as the sole radiosulphate was calculated from the disappear- drug. One female moved to another area (her blood ance curve (Omvik et al., 1979; Omvik & Lund- pressure had fallen from 190/120 to 155/105 mmHg Johansen, 1983). on 8 mg). Statistical methods Acute study The results are presented as mean values + s.d. Assessment I Assessments were performed on Differences between means were statistically tested out-patients in the morning 2 h after a light meal. by Student's t-test for paired samples. Data from all After introduction of the catheters the patients 14 patients in the acute study were analysed and data rested supine for 30 min and central haemo- from the 12 patients fulfilling the whole protocol in dynamics were then measured at rest supine, then the chronic study were analysed. sitting, and thereafter during 6-8 min of exercise on an ergometer bicycle at 100 W (pre-test, assess- ment 1). After the exercise test the patients rested Results supine for 1 h. During this period the patients were Acute effects ofdoxazosin not allowed to sleep but they were allowed to read. The atmosphere in the laboratory was quiet. Con- The results are shown in Table 1 and Figure 1. Haemodynamic effects ofdoxazosin 47S Table 1 Central haemodynamics at rest supine, sitting and during 100 W at pre-test (1), immediately before doxazosin injection (2) and 1 h after doxazosin i.v.(3) (n = 14). Supine Sitting 10o W 1 2 3 3-1(%) 1 3 3-1(%) 1 3 3-1(%) SAP (mmHg) mean 164.8 156.5 147.9 -10.3 178.7 150.9 -15.4 214.4 199.5 -6.9 s.d. 17.2 12.4 15.6 21.0 15.1 17.7 20.3 P <0.001 <0.001 <0.001 DAP (mmHg) mean 97.9 96.0 89.5 -8.6 108.9 95.8 -12.0 116.2 105.4 -9.3 s.d. 8.5 8.4 9.8 8.7 10.9 12.5 11.0 P <0.01 <0.001 <0.001 MAP (mmHg) mean 122.9 118.0 112.8 -8.2 133.7 117.5 -12.1 156.4 141.6 -9.5 s.d. 10.7 9.9 12.3 11.2 13.7 15.1 15.1 P <0.01 <0.001 <0.001 TPRI (dyn s cm-5m2) mean 3139 3254 2974 -5.3 3824 3493 -8.6 1734 1500 -13.5 s.d. 546 588 467 702 665 283 233 P NS <0.01 <0.001 HR (beats minm-) mean 69.1 72.2 73.6 +6.5 75.8 79.4 +4.7 139.1 143.4 +3.1 s.d. 7.3 10.5 11.8 9.9 12.5 21.8 20.5 P NS NS NS CI (1 min-lm-2) mean 3.18 3.00 3.09 -2.8 2.92 2.84 -2.7 7.35 7.65 +4.1 s.d. 0.59 0.57 0.49 0.64 0.55 1.09 1.18 P NS NS <0.05 SI (ml stroke 'iM-2) mean 46.4 41.7 42.4 -8.6 38.2 35.8 -6.3 53.6 54.1 +0.9 s.d. 7.6 6.5 6.8 6.8 7.0 9.0 9.3 P <0.05 <0.05 NS P values refer to differences between assessments 1 and 3 Pre-drug results In assessment 1, the intra- rested supine for 1 h and were then restudied in the arterially recorded resting sitting blood pressure supine position immediately before the injection of was 178.4 ± 21.0/108.9 ± 8.7 mmHg, CI was 2.92 doxazosin.