Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise

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1 Br. J. c/lin. Pharmac. (1986), 21, 45S-54S Acute and chronic haemodynamic effects of doxazosin in hyertension at rest and during exercise P. LUND-JOHAEN, P. OMVIK & H. HAUGLAND Section of Cardiology, Medical Deartment, University of Bergen, School of Medicine, Bergen, Norway 1 The acute and chronic haemodynamic effects of doxazosin were studied in 14 atients (10 males, four females) with essential hyertension, at rest suine and sitting and during 100 W bicycling exercise. 2 Blood ressure (BP) was recorded intra-arterially in the brachial artery, cardiac outut (CO) was measured by Cardiogreen and heart rate (HR) by ECG. 3 One hour after injection of doxazosin mg i.v., arterial ressure (MAP) was reduced by 8% at rest suine, 12% at rest sitting and 10% at 100 W (all changes statistically significant), associated with a reduction in total eriheral resistance index (TPRI) of 5% at rest suine, 9% at rest sitting (P < 0.01) and 14% at 100 W (P < 0.001). HR was slightly increased (5%, ) and cardiac index (CI) was unchanged during rest and slightly increased during exercise (4%, P < 0.05). 4 Patients were then given doxazosin casules (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 suine, 16% at rest sitting and 17% at 100 W (all P-values < 0.001). TPRI was reduced by 19% at rest suine, 20% at rest sitting and 18% at 100 W (all changes statistically significant). CI was increased by 8% at rest suine (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 sideeffects. Thus, doxazosin normalizes central haemodynamics in atients with mild to moderate essential hyertension, both at rest and during exercise. Keywords cardiac outut doxazosin exercise haemodynamics total eriheral resistance Introduction Doxazosin is a new ostsynatic a,-adrenocetor blocker; it is related to razosin but has a longer half-life (Timmermans et al., 1980; Singleton et al., 1982; Vincent et al., 1983). Its antihyertensive effect has been demonstrated in animals and in man (Beckett & Finch, 1982; Elliott et al., 1982; de Leeuw et al., 1982). So far, no acute and chronic studies on the haemodynamic effects at rest and during exercise in man have been reorted. The urose of the resent study was to investigate the first-dose effect of doxazosin intravenously at rest and during exercise in atients with essential 45S hyertension, and then to study the changes induced by 8-12 months of chronic treatment with doxazosin orally. Methods Patients The study rotocol was aroved by the Norwegian State Drug Control and informed consent was obtained from all atients. The 14 atients (10 males and four females), aged ( 42.4) years, all had sitting diastolic blood ressure, between 100 and 120 mmhg on three out-atient control visits. Serum creatinine was within normal

2 46S P. Lund-Johansen et al. limits and in all atients secondary hyertension was excluded by usual routine rocedures. All were in WHO stage I or II, without other diseases (including obesity), and were actively working. Twelve atients were reviously untreated and two had been on a- or P-adrenocetor antagonists for less than 1 year. In both of these atients the washout eriod without drugs was 2 months. The body weight was 72.7 ± 14.9 kg and the body surface area (BSA) was 1.86 ± 0.22 mi. Haemodynamic methods Blood ressure was recorded continuously through a catheter in the brachial artery. Cardiac outut was measured by Cardiogreen injected through a catheter in the suerior vena cava. Double determinations were erformed in all situations. The heart rate was determined from ECG recordings. Cardiac index (CI), stroke index (SI) and total eriheral resistance index (TPRI) were calculated by standard formulae (Lund-Johansen, 1967). Studies were erformed at rest suine and sitting and during ergometer bicycling in steady state. Plasma volume (PV) was determined by using radio-iodinated (125I) human serum albumin (4,Ci; Radiochemical Centre, Amersham, England) with a 10 min equilibration eriod. Total blood volume (BV) was calculated from PV and the simultaneously determined corrected acked cell volume. The extracellular fluid volume (ECF) Was measured as the sulhate sace: 100 mci radiosulhate (35SO4) was injected intravenously and lasma samles were collected 30, 45, 60 and 75 min after injection. The samles were counted in dulicate in a Nuclear Enterrise beta-gamma counter (NE 8312) and zero time concentration of radiosulhate was calculated from the disaearance curve (Omvik et al., 1979; Omvik & Lund- Johansen, 1983). Acute study Assessment I Assessments were erformed on out-atients in the morning 2 h after a light meal. After introduction of the catheters the atients rested suine for 30 min and central haemodynamics were then measured at rest suine, then sitting, and thereafter during 6-8 min of exercise on an ergometer bicycle at 100 W (re-test, assessment 1). After the exercise test the atients rested suine for 1 h. During this eriod the atients were not allowed to slee but they were allowed to read. The atmoshere in the laboratory was quiet. Conversation was not allowed in the 10 min before the next haemodynamic recordings. Assessment 2 After 1 h of suine rest, central haemodynamics were recorded (assessment 2) and immediately thereafter during the next 3 min doxazosin mg was injected intravenously through the catheter in the suerior vena cava. The atients were not aware of the injection. Blood ressure was recorded continuously for 1 h while the atients rested suine. Assessment 3 After 1 h the haemodynamic study was reeated at rest suine and sitting and then during 100 W exercise (assessment 3) (see section on hyotensive eisodes, where the rotocol was modified). Chronic study After the acute study had been comleted the atients started oral doxazosin treatment. Doxazosin was given in casules once daily in the morning, at a starting dose of 2 mg. The dose of doxazosin was increased gradually every second week, aiming at a casual blood ressure of < 140/90 mmhg without side-effects. The maximal dose was set (by Pfizer Central Research) at 16 mg. After 8-12 months the daily doses were 2 mg in three atients, 4 mg in three, 8 mg in four and 12 and 16 mg in two. The dose of doxazosin was 6.5 mg. During the chronic study there were two droouts. One atient had a myocardial infarction after 2 months (male atient, blood ressure 130/90 mmhg) when taking doxazosin 4 mg. After the infarction the atient received timolol as the sole drug. One female moved to another area (her blood ressure had fallen from 190/120 to 155/105 mmhg on 8 mg). Statistical methods The results are resented as values + Differences between s were statistically tested by Student's t-test for aired samles. Data from all 14 atients in the acute study were analysed and data from the 12 atients fulfilling the whole rotocol in the chronic study were analysed. Results Acute effects ofdoxazosin The results are shown in Table 1 and Figure 1.

3 Haemodynamic effects ofdoxazosin Table 1 Central haemodynamics at rest suine, sitting and during 100 W at re-test (1), immediately before doxazosin injection (2) and 1 h after doxazosin i.v.(3) (n = 14). 47S Suine Sitting 10o W (%) (%) (%) SAP (mmhg) P DAP (mmhg) P <0.01 MAP (mmhg) P <0.01 TPRI (dyn s cm-5m2) P <0.01 HR (beats minm-) P CI (1 min-lm-2) P <0.05 SI (ml stroke 'im-2) P <0.05 <0.05 P values refer to differences between assessments 1 and 3 Pre-drug results In assessment 1, the intraarterially recorded resting sitting blood ressure was ± 21.0/108.9 ± 8.7 mmhg, CI was min-' m-2, HR 75.8 ± 9.9 beats min-, SI 38.2 ± 6.8 ml stroke-' m-2 and TPRI 3824 ± 702 dyn s cm-5m2. These results comare well with results in similar grous of atients studied in our laboratory with the same methods (Lund-Johansen, 1983; Lund- Johansen & Omvik, 1983). There is also good agreement between the intra-arterially recorded sitting blood ressure and the casual sitting blood ressure at the last control before the haemodynamic study (174/107 mmhg vs 178/109 mmhg intra-arterially). Stability of the haemodynamics before drug injection After the first recordings the atients rested suine for 1 h and were then restudied in the suine osition immediately before the injection of doxazosin. Comared with assessment 1 in the suine osition, some minor changes were seen in assessment 2. In most males arterial ressure (MAP) showed only small changes and the value was mmhg (vs at assessment 1), a difference of -3 % (). In the females the variations were greater. For the whole grou MAP was versus mmhg (a difference of -4.9 mmhg). In the males HR was almost back to re-exercise suine values: 68.9 vs 67.9 beats min', a slight increase of + 1 %. In the females the heart rate was slightly increased comared with reexercise suine values. For the whole grou the heart rate was 72.2 beats min'-i (vs reexercise). The slight fall in MAP was associated with an increase in TPRI from 3139 to 3254 dyn s cm-5 m2 (+3.7%, ).

4 48S P. Lund-Johansen et al Rest suine 10 I L I 0L -10 * -20- * 20- Rest sitting 10 0~~~~~~~~ : L -10 * -20 * ** W exercise 10. nat F6 Ej 11" -20 ** R*** MAP TPRI Ci HR Si Figure 1 arterial ressure (MAP), total eriheral resistance index (TPRI), cardiac index (CI), heart rate (HR) and stroke index (SI) after doxazosin at rest suine, at rest sitting and at 100 W. *P < 0.05, **P < 0.01, ***P < Acute (D) and chronic (M) changes in Hyotensive reactions after doxazosin injection In the first three atients studied, doxazosin 1 mg was injected over 3 min and hyotensive reactions were seen after min. In the first atient, BP fell from 149/97 to 93/53 mmhg. The atient was ale and sweating but, after the legs had been raised for 5-10 min, BP increased to 116/62 mmhg. A haemodynamic study 30 min after injection showed a fall in TPRI from 3288 to 1934 dyn s cm-5 m2, a decrease of - 40%. CI had increased from 2.77 to min-' m-2 and SI had increased from 47.8 to 57.2 ml stroke -1 m-2. HR was ractically unchanged, 58 beats min'-i at re-injection and 60 beats min-i during the hyotensive hase. In the second atient, re-injection BP was 163/98 mmhg and after 15 min BP was only 93/57 mmhg. The atient was ale and sweating. After the legs had been elevated the ressure rose to 143/89 mmhg. HR showed a small increase from 65 to 72 beats min '. The third atient demonstrated a fall in BP from 156/98 mmhg to 70/40. After the legs had been raised the ressure rose gradually to 113/63 mmhg. After 30 min the blood ressure was 120/74. TPRI had fallen from 3241 to 2589 dyn s cm-5 m2 (-20%). HR was ractically unchanged, 74 vs 72 beats min-', and CI showed no changes (2.89 vs min-' m-2). After- these hyotensive reactions, the dose was reduced to 0.5 mg in atients weighing less than 70 kg and 0.7 mg in atients over 70 kg. No further hyotensive reactions were seen. The reactions to doxazosin 1 mg i. v. are clearly not the same as those of doxazosin 1 mg orally, due to differences in bioavailability. Haemodynamic changes at rest suine Systolic arterial ressure (SAP) fell in all but one atient. This atient had a low retreatment SAP of only 137 mmhg. One hour after the injection SAP was mmhg vs at assessment 1, a difference of -10% (P < 0.001). Diastolic arterial ressure (DAP) fell in all but two atients, both of whom had low initial values. After 1 h DAP was 89.5 mmhg vs 97.8 mmhg at assessment 1, a difference of -8.6% (P < 0.01). MAP fell in all but two atients, who both had low initial values. After 1 h MAP was mmhg vs at assessment 1, a difference of -8.2% (P < 0.01). In site of these acute reductions in BP, HR showed only small insignificant changes. After 1 h HR was 73.6 beats min-i (vs 69.1 at assessment 1 and 72.2 immediately before the injection, assessment 2). Thus no reflex tachycardia was seen 1 h after the injection in site of a 10 mmhg reduction in BP. No clear reflex tachycardia was seen even in the atients who had the rather severe hyotensive reactions with SAP reductions of mmhg. TPRI fell in all but two atients, who both had low initial values. TPRI fell to 2974 dyn s cm-5m2 from 3139 at assessment 1 (a difference of -5.3%, ). However, when comared with TPRI recorded immediately before the injection, the fall was greater (-8.6%). Comared with re-injection levels CI showed only minor changes, an increase from 3.00 to min-' m-2 (+ 3%, ). Comared with assessment I there was a fall of 3 % (). SI showed only minor changes. One hour after the injection SI was 40.4 ml stroke-' m 2 vs 41.7 immediately before the injection. Haemodynamic changes at rest sitting The reductions in BP were greater at rest sitting than at rest suine. Thus, 1 h after the doxazosin injection SAP was 27.5 mmhg lower than at the re-test assessment 1 (-15.4 %, P < 0.001), DAP was mmhg lower (-12.0%, P < 0.001) and MAP was 16.2 mmhg lower (-12.1 %, P < 0.001). MAP was lower in all atients, the differences ranging from -1 mmhg to -42 mmhg.

5 Comared with assessment 1, HR was slightly higher, 79.4 beats min-' vs 75.8 (+4.7%, ). Only in two atients (females) was the increase in HR greater than 1-2 beats minm- '. Thus no marked reflex tachycardia was seen even in the uright osition. TPRI fell in all but three atients and the fall was greater than at rest suine (-8.6%, P < 0.01). CI showed ractically no changes (as at rest suine). One hour after doxazosin injection, CI was min-m m-2 vs 2.92 at assessment 1 (a difference of -2.7%, ). SI tended to be lower than at assessment 1, 35.8 versus 38.2 ml strokem-2, a difference of -6.3% (P < 0.05). Haemodynamic changes during 100 W exercise The reductions in SAP, DAP and MAP were less than during rest sitting. The differences Haemodynamic effects of doxazosin 49S (highly significant) between assessment I and 1 h after doxazosin injection were -6.9%, -9.3% and -9.5 % for SAP, DAP and MAP, resectively. One hour after the injection HR was slightly higher than at assessment 1, beats min- vs , a difference of % (). TPRI fell in all atients. The fall was more ronounced than at rest. The difference between assessment 1 and I h after doxazosin infusion was -13.5% (P < 0.001). CI was higher than at assessment I in 10 atients. In the others only small changes were seen. The value increased from 7.35 to min-im-2, a difference of 4.1% (P < 0.05). The stroke index showed ractically no changes, a difference of 0.9% (). Thus the increase in CI was mainly due to the increase in HR. Table 2 Central haemodynamics at rest suine, sitting and during 100 W at re-test (1) and at 1 year (4) following doxazosin orally (n = 12) SAP (mmhg) DAP (mmhg) MAP (mmhg) TPRI (dyn s cm-5m2) HR (beats min- ) CI (1 min-im-2) SI (ml stroke-, m -2) Suine Sitting 100 W I 4 4-1(%) (%) I(%) <0.O <0.01 < < < P values refer to differences between assessments 1 and 4

6 50S P. Lund-Johansen et al. Chronic effects ofdoxazosin The results are shown in Tables 2, 3 and 4. m E C- cn ^ 160U 0 4~~~ ~~ 0, _ ob 8 *o 9:0 a after 2 months, 145/88 mmhg after 6 months and 141/87 mmhg after 1 year. One atient felt 'restless' and had high HR values (84-88 beats min ') at the follow-u controls. He was restudied after 8 months. Thereafter, atenolol 25 mg was added and the atient's comlaints disaeared. His HR droed to 60 beats min' and he became normotensive. In the other atients no side-effects were seen. (One atient had a non-fatal myocardial infarction after 4 months as already stated, but this was regarded as a coincidence. The atient was a smoker. His recovery was uneventful, with a BP of 120/80 mmhg on timolol monotheray.) 10C_ DAP (mmi 180F I. Haemodynamics at rest suine SAP, DAP and MAP were reduced in all but one atient. Mean SAP fell from to mmhg (-12.4%, P < Ig) 0.001), DAP fell from 96.3 to 83.7 mmhg (-13.1%, P < 0.001) and MAP fell from Figure 2 Intra-arterially measured bllood ressures at to mmhg (-12.9%, P < 0.001). The rest sitting before ( H,) and during ((0, D) chronic changes in MAP ranged from +6 to -26 mmhg. theray (individual results). 0, 0 maale atients, U, O HR showed ractically no changes, the female atients. values being almost identical at assessment 1 and after 1 year. Thus no tendency to tachycardia was Casual blood ressure and side-ejtects Casual BP seen. The HR ranged from 56 to 82 beats min'-'. at rest sitting fell from 174/107 nnmhg before the TPRI fell in all but one atient the reduction haemodynamic study to 156/97 mmhg after 2 being 18.6% (P < 0.01), a greater fall than during weeks, 153/96 mmhg after 4 weekzs, 148/92 mmhg the acute study. CI was increased in eight atients, fell in two and was unchanged in two. The value increased from 3.18 to min-] m-2 (+8.1%, P < 0.05). Stroke index tended to be SAP increased (by 5.8%) but the difference was not statistically significant. Rest sitting SAP, DAP and MAP fell in all 1601 atients, the reductions in SAP, DAP and MAP I E being about the same: 17.6, 16.3 and 16.4%, 140- resectively. Thus the BP fall was more a. ronounced at rest sitting than suine. One atient 1201 had a ressure of only 108/72 mmhg at the reassessment, but in the others SAP was DAP mmhg and DAP mmhg (Figure 2) **d* HR was ractically unchanged in most atients. Only one subject had an increase of more than 8 80J beats min-'. The values were ractically I11 I O-i lo w unchanged: 75.8 vs 75.9 beats min-'. TPRI was lower than at the re-study in all Exercise level atients, the reduction being -19.7% (P < Figure 3 Systolic (SAP) and diastoli4ic (DAP) blood 0.001). CI was ractically unchanged, from 2.84 to ressures before ( ) and during (------) chronic min-' m-2 (+3.9%, ). Stroke index was theray: at rest suine (o0-); at rest siitting(q,); slightly increased from 37.3 to 39.1 ml stroke-' (1OOW), during 100 W exercise. m-2 (+4.8%, ).

7 Haemodynamic effects ofdoxazosin 51S F E c a o2-1 OOW I E 130 E 0- < 120 F _ I-_ N E,0 co /,** I? C I o---i % 1 OOW _ 3000h ** ) -ji I 0*** 0_-- 1 OOw h E 50 c 2 40 C- * 30 Fn o-- 1 OOW E 0) - I 10oo- 60T o ~ 21s 1 10 OOW Exercise level Figure 4 Haemodynamic rofile of doxazosin after 1 year of treatment. Mean values s.e.. MAP, arterial ressure; TPRI, total eriheral resistance index; CI, cardiac index; HR, heart rate; SI, stroke index; ( ), before theray; (------), during theray; (o-j), at rest; (Q), at rest sitting; (100 W), during 100 W exercise. Exercise 100 W Blood ressure control was maintained during exercise, the reductions in DAP and MAP being about the same as during rest sitting (Figure 3). The relative fall in SAP was slightly less. SAP, DAP and MAP were lower in all atients. The reductions in MAP ranged from -11 to -33 mmhg, the reduction being 26.3 mmhg or -16.8%. Very small changes aeared in HR. The values were about the same, vs beats min'-'. As at rest sitting, TPRI fell in all atients. The reduction was %, thus about the same as during rest. Also as at rest sitting, CI was ractically unchanged (7.30 vs min-' m-2). SI also showed only a negligible change, +1.7% (). Bodyfluid volumes The results are shown in Table 3. During doxazosin treatment there was a consistent rise in PV and in BV. On average PV increased by 305 ml (9.8%) and BV by 408 ml (8.2%). Changes in ECF ranged from +2.6 to and changes in body weight from +6 to -8 kg. The increase in body weight of 0.7 kg was not statistically significant. Similarly the ECF remained virtually unchanged. The PV/IF ratio showed a significant increase from 0.31 to Relation between acute and chronic changes The haemodynamic alterations seen 1 h after the injection of mg doxazosin resemble largely those seen after 1 year. The fall in TPRI was the most dominant haemodynamic change. However, the changes were more ronounced after 1 after 1 h. Since the doses are not the same, it is imossible to make a direct comarison between the acute and chronic resonses, but there seemed to be year than no clear relationshi between the fall in MAP in the acute study comared with the change after 1 year.

8 52S P. Lund-Johansen et al. Table 3 Body weight and volumes of extracellular fluid (ECF), interstitial fluid (IF), lasma (PV) and blood (BV) and the ratio before (B) and after (A) chronic doxazosin treatment (n = 12) Bodv weight ECF PV BV PV/IF (kg) (1) (ml) (ml) ratio B A B A B A B A B A Mean A-B(%) a P <0.01 <0.01 <0.05 'For PV/IF A-B is exressed as a ratio not a ercentage Discussion This study has shown that doxazosin, both intravenously and orally, reduces BP in the majority of atients with mild and moderately severe essential hyertension and that the effect is maintained over 1 year of chronic theray. In the acute study, doxazosin mg injected intravenously over 3 min did not induce hyotensive reactions, although 1.0 mg induced severe hyotension while the atients rested in the suine osition. The acute fall in BP was associated with a reduction in TPRI. In the atients with a severe blood ressure reduction of -56 to -86 mmhg, TPRI was greatly reduced, by aroximately 40%. CI did not show any significant changes at rest suine. In site of the sudden fall in BP, HR was ractically unchanged. In other words, no marked reflex tachycardia was seen. These acute haemodynamic changes resembled those seen with other ostsynatic a,-adrenorecetor antagonists such as razosin and trimazosin (Chrysant et al., 1981; Constantine et al., 1973; Falch etal., 1979; de Leeuw etal., 1980; Pool et al., 1983; Stanaszek et al., 1983). The observations in the sitting osition showed that the falls in blood ressure and TPRI were more marked than at rest suine. In the sitting osition there was a slight increase in HR. This has also been reorted for razosin (Stanaszek et al., 1983). The exercise recordings show that doxazosin maintained blood ressure control during work. The relative fall in TPRI was greater than at rest and CI was actually increased by 4%, owing to increased HR and no change in SI. During the chronic study it was shown that a suitable maintenance dose ranged between 2 and 16 mg with a of 6.5 mg daily. At the haemodynamic re-assessment the blood ressure reduction was greater than in the acute study in all situations (suine, sitting and 100 W). In all these situations the fall in TPRI was greater than during the acute study. At rest suine, CI increased by 8% (P < 0.05). At rest sitting and during exercise there was a slight insignificant trend toward an increase in CI. At rest suine there was an increase in SI of aroximately 8%, but the change was not statistically significant. At rest sitting and during exercise there was a slight trend toward an increase. These chronic effects resemble those seen in a 1 year study on razosin. However, comared with the retreatment level, in the razosin study both SI and CI were significantly increased after 1 year (Lund-Johansen, 1975). In site of the vasodilating effect, no significant fluid retention was noticed and in no atient was oedema seen. There was, however; a significant increase in lasma volume of 10% and in blood volume of 8%, and an increase in the PV/IF ratio. These changes in body fluid volumes are similar to those seen during chronic razosin treatment (Stanaszek et al., 1983) and are consistent with vasodilation and eriheral fluid retention. However, in contrast to razosin, doxazosin maintained good control of BP in site of significant intravascular fluid exansion. The acute and chronic haemodynamic effects of doxazosin (and other al-adrenocetor antagonists) in hyertension are basically similar. The blood ressure is reduced exclusively through a fall in TPRI. This is in contrast to the blood ressure reduction by P-adrenocetor blockade, where the immediate effect is a reduction in HR and CI and a marked increase in TPRI. After a certain time-lag the increased TPRI falls and this brings down the blood ressure. During chronic P-adrenocetor blocker theray CI remains reduced, usually in the order of 15 to 25% (Tarazi & Dustan, 1972; Lund- Johansen, 1983).

9 Haernodlvnanic effects of doxazosinl 53S The haemodynamic changes induced by chronic doxazosin treatment are comarable with those seen after other vasodilator drugs such as converting enzyme inhibitors and calcium channel blockers (Lund-Johansen & Omvik, 1983, 1984). The sontaneously occurring haemodynamic changes in essential hyertension are characterized by a gradual increase in TPRI and a fall in CI (Lund- Johansen, 1978; Messerli et al., 1981). Doxazosin treatment oosed these changes and tended to normalize total eriheral resistance at rest as well as during exercise. At rest suine there was an increase in cardiac index due to the increase in stroke volume. It is ossible that this normalization of the heart um function and of the arteriolar resistance could artly be due to regression of the structural changes in the heart and in the resistance vessels seen in established hyertension. 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