Br. J. clin. Pharmac. (1987), 24, 571-580

An assessment of the partial agonist activity of Ro 31-1118, flusoxolol and pindolol in man

P. M. McCAFFREY, J. G. RIDDELL & R. G. SHANKS Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Belfast

1 The effects of single oral doses of three ,-adrenoceptor partial agonists (Ro 31-1118, flusoxolol and pindolol), two P-adrenoceptor antagonists (propranolol and atenolol), two 3-adrenoceptor agonists (salbutamol and prenalterol) and placebo on sleeping heart rate, quality of sleep, supine heart rate, exercise heart rate, blood pressure, forearm blood flow and finger tremor were studied in eight healthy male volunteers. 2 Sleeping heart rate was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol and decreased by propranolol and atenolol. 3 None of the drugs studied affected quality of sleep. 4 Supine heart rate was increased by flusoxolol, prenalterol and salbutamol, unaffected by Ro 31-1118 and pindolol and reduced by propranolol and atenolol. 5 Exercise heart rate was reduced by both 3-adrenoceptor antagonists and the three partial agonists and unaffected by salbutamol and prenalterol. 6 Systolic blood pressure was increased by Ro 31-1118, flusoxolol, salbutamol and prenalterol, unaffected by pindolol and reduced by propranolol and atenolol. Diastolic blood pressure was reduced by salbutamol and prenalterol. 7 Forearm blood flow was increased by Ro 31-1118, salbutamol and prenalterol, unchanged by pindolol and flusoxolol and decreased by atenolol and propranolol. 8 Finger tremor was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol. 9 ,3-adrenoceptor partial agonists have different effects on the cardiovascular system and finger tremor to ,-adrenoceptor antagonists. 10 While Ro 31-1118 and flusoxolol are antagonists mainly at the P,-adrenoceptor they have agonist activity at both 13l- and 132 adrenoceptors. 11 While pindolol is a non-selective antagonist its agonist activity is mainly at the 132- adrenoceptor. Keywords partial agonist activity pindolol flusoxolol Ro 31-1118 13-adrenoceptor antagonist

Introduction 13-adrenoceptor antagonists have a number of and partial agonist activity (Fitzgerald, 1984). additional properties including cardioselectivity, To demonstrate partial agonist activity ,B-adreno- lipid solubility, membrane stabilising activity ceptor antagonists must be shown to cause both

Correspondence to: Dr J. G. Riddell, Department of Therapeutics and Pharmacology, The Queen's University of Belfast, The Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL 571 572 P. M. McCaffrey, J. G. Riddell & R. G. Shanks measurable agonist and antagonist responses. Methods By definition the agonist activity should never cause as great a biological effect as that pro- Observations were made in 16 healthy male duced by a full agonist, such as isoprenaline, no subjects who gave informed consent after the matter how high the dose given. The observed procedures involved had been fully explained to effects of 1-adrenoceptor agonist and antago- them. The studies were approved by the Research nist activity depend on the degree ofsympathetic Ethical Committee of the Queen's University of drive. Agonist effects are most easily seen when Belfast. the level of sympathetic tone is low such as during sleep and antagonist activity predomi- Study 1 nates when the level of sympathetic tone is high Eight healthy male volunteers (mean age 23 ± 4 such as during exercise. years, mean weight 77 ± 7 kg) took part in the The classical studies of partial agonist activity study. At weekly intervals, double-blind and have been performed in experimental animals in following a randomised Latin Square design each which the effects of reflex sympathetic stimu- received on separate occasions, single oral doses lation and endogenous catecholamines have of Ro 31-1118 160 mg, flusoxolol 80 mg, pindolol been removed (Barrett & Carter, 1970; Bilski et 10 mg, atenolol 50 mg, propranolol 80mg, salbu- al., 1979). Demonstration of partial agonist tamol 8 mg, prenalterol 50 mg and placebo. activity in man has been more difficult because In the late afternoon on each study day elec- reflexes are intact and it is not possible to trodes were attached to the anterior chest wall of remove endogenous catecholamines. However a the volunteer in a modified lead II position and number of studies in man have shown that ,B- to an Oxford Medilog 4-24 miniature tape adrenoceptor partial agonists differ from 1- recorder worn in a leather case at the waist. The adrenoceptor antagonists by causing less reduc- drugs were administered orally between 23.00 h tion in supine heart rate and cardiac output and 24.00 h. Volunteers retired to bed within 30 (Svendsen et al., 1979; 1981; Taylor et al., 1982) min of drug administration. They were asked to and having flatter dose-response curves for press the event button when they went to bed, reduction of exercise tachycardia (McDevitt et when they awoke in the morning and if they al., 1977). awoke during the night. The tape recorder was Ro 31-1118 (1 - (4 - [2 - (4 - fluorophenethy- removed the following morning. The volunteer loxy) - ethoxy] phenoxy) - 3 - isopropylamino completed a St Mary's Hospital sleep question- - 2 - propanol hydrochloride is a long acting naire (Ellis et al., 1981) and a visual analogue cardioselective 3-adrenoceptor partial agonist scale for assessing the quality ofsleep. The visual (Blaber et al., 1983; O'Connor et al., 1985) and analogue scale was 10 cm long, with 'the best flusoxolol is its S-enantiomer. Pindolol is a non night's sleep ever' written at one and 'the worst cardioselective partial agonist though it has been night's sleep ever' written at the other end. The suggested that its agonist activity is mainly at the same verbal instructions were given each day: 132-adrenoceptor (Clark, 1984). Atenolol and 'Regarding how you slept last night please mark propranolol are 3-adrenoceptor antagonists, the line between the best night's sleep and the with and without cardioselectivity respectively. worst night's sleep ever. Your normal night's Salbutamol is a 132-adrenoceptor agonist sleep would be in the middle'. The tape was (Hartley et al., 1968) and prenalterol is a pre- analysed using the Oxford Instruments ECG dominately 131-adrenoceptor agonist but has Analysis system. Side effects were elicited by the been shown to have some activity at the 12- written question 'Did you notice anything adrenoceptor (Mattsson et al., 1982a,b). unusual?' The present studies were undertaken to Hourly mean heart rates for the 8 h after demonstrate the partial agonist activity of Ro treatment were compared using the SPSS para- 31-1118, flusoxolol and pindolol in man and to metric analysis of variance and Duncan's mul- compare their effects on the cardiovascular test. The results of the system and finger tremor to those of proprano- tiple range sleep question- lol, atenolol, salbutamol, prenalterol and naire and visual analogue scale were analysed placebo. Fixed oral doses were used and no using Friedman's two way analysis of variance. formal dose-response observations were made Statistically significant differences were con- because of the number of drugs studied. The sidered to exist when P was < 0.05. Results are doses of those drugs with 13-adrenoceptor expressed as the mean ± the s.d.. antagonist activity were those which have been shown to have approximately equal 13-adreno- Study 2 ceptor blocking activity. Eight healthy male volunteers (mean age 22 + Partial agonist activity ofRo 31-1118, flusoxolol and pindolol 573

0.5 years, mean weight 74 ± 11 kg) took part in the study. At weekly intervals, double-blind and following a randomised Latin Square design each received on separate occasions, single oral doses 160 mg, flusoxolol 80 mg, pindolol * of Ro 31-1118 * * FF-* * *4F* * 10 mg, propranolol 80 mg, atenolol 50 mg, salbu- +4+4+4+04+ en 00 00 00 00 00 _, tamol 8 mg, prenalterol 50 mg and placebo. All +1 +1 +1 +1 +1 +1 +1 +1 studies were carried out in the morning in a mmtn££0 £F a1~ll~ m0 \0 \0 temperature controlled room (24-25' C). On the

morning of the study the volunteer had a light * * * 4+ breakfast without caffeine. After 30 min of supine 41+4+i4+ 4+4+i 4+0-C 0N 00 O ON C., N- rest, heart rate, blood pressure, finger tremor +l +1 +1 +1 +1 +1 +1 +1 00 t ce and forearm blood flow were measured. Heart n v) tn r011 - rate was measured from a direct writing electro- cardiogram and blood pressure using a Hawksley * * random zero sphygmomanometer. The Korot- CO koff fourth sound was used for the diastolic +1 +1 +1+1+1+1+1+1 ** blood pressure. Finger tremor was measured tn t n 10 to using a piezo electric accelerometer attached to the dorsum of the middle finger of the left hand a)

CO 4+* (Arnold & McDevitt, 1983; Riddell et al., 1986). 44+ot- c- Forearm blood flow was measured using venous +l +1 +1 +1 +1 +1 +1 +1 .0CO occlusion plethysmography (Riddell et al., 1986). CZ was .0 oo oo oo N Forearm vascular resistance calculated by 00 .0

dividing mean arterial blood pressure by fore- CO U4 o C.0 twn tw)£ tb arm blood flow. 0 4+0C>4+ (N 41+4+* '-400 O ON ON 00 The measurements were repeated after a +l +1 +1 +1 +1 +1 +1 +1 4- further 15 min. The drugs were then administered c) a..C; orally with 30 ml of water. The above measure- v) ments were repeated at 30 min intervals for 3 h. ra .0 tDn tn 11 'I to An exercise step test was then performed which 4+ 0'e cm involves stepping on and off a box 46 high, 32 +1 +1** +1 +1 +1 +1+l +1 times min- for 3 min. Heart rate was measured CZ within 5 s of completing exercise. Spontaneously ,4O_ +l a) reported side effects were documented. C.) 4+\0 4+1o 4+4-+4-+4-+E b N CO The results for supine heart rate, exercise CO heart rate and percentage change in finger tremor C-,. 0^ en +l +l +l +l+l +l4 +l 'I **) oo I' 'IoO r- 00*| were log transformed. The results for systolic N- W'IO 0 N- 00 v blood pressure and diastolic blood pressure were 6

subjected to a square root transformation. As 4+ rq0o 4+o=b eq Oo c ITo-tC ,-4 ,4 some of the values for percentage change in ,r-4 O 1, e V- finger tremor were negative 100 was added to +1 +1+1 +1+1 +1 +1+1 N- c 00 't 'IO 00 NtO each. The results were compared using a para- * N N~ ND metric analysis of variance and Duncan's multiple *C; range test. A P value of < 0.05 was considered 6L .0 significant. Percentage change in forearm blood 0 +1 +1+1 +1+1 +1+1 +1 0~ Nl ~0 r-4 N- '-4 00 CZ) flow was analysed using Friedman's analysis of N- 00 N- 00 N- variance and Wilcoxon's signed rank test because C of significant differences in the variances. A CO P value of < 0.02 was considered significant. 011V

* Results Study 1

Hourly mean heart rates for the 8 h post dosing for each treatment are shown in Table 1. Hourly 574 P. M. McCaffrey, J. G. Riddell & R. G. Shanks mean heart rate at baseline was not significantly pindolol, 49 ± 19 after prenalterol, 48 ± 18 after different from placebo for any of the treatments. salbutamol, 48 ± 17 after flusoxolol, 49 ± 14 When the effects of the different treatments after Ro 31-1118, 44 ± 17 after propranolol and were compared with placebo, propranolol and 40 ± 16 after atenolol. These results did not atenolol reduced hourly mean heart rate. Pin- differ significantly. dolol reduced mean hourly heart rate in the early part of the night but caused a rise in heart rate in Study 2 the latter half of the night. There was in increase in hourly mean heart rate after Ro 31-1118, Supine heart rate Supine heart rate for each flusoxolol, salbutamol and prenalterol. treatment over the 3 h period is shown in Table Hourly mean heart rates after pindolol, Ro 2. Baseline heart rate was not significantly dif- 31-1118 and flusoxolol were significantly higher ferent for any drug. When the different treat- than those after propranolol and atenolol over ments were compared to placebo, Ro 31-1118 the majority of hourly intervals. Hourly mean and pindolol caused no change, atenolol and heart rate after prenalterol was significantly propranolol reduced heart rate and flusoxolol, higher than after all other drugs over most hourly salbutamol and prenalterol increased heart rate. intervals. When different treatments were compared to each other prenalterol produced a significantly Quality ofsleep Quality of sleep as assessed by greater increase in heart rate than all other treat- St Mary's Hospital Sleep Questionnaire was un- ments over the 3 h period. Heart rate after Ro affected by any of the drugs. There was no 31-1118, flusoxolol and pindolol was significantly difference between drugs and placebo in the higher than that after atenolol and propranolol. number of awakenings recorded on the tape. The mean distance in mm (± s.d.) from 'the Systolic blood pressure Mean systolic blood best night's sleep ever', on the visual analogue pressure for each treatment over the 3 h period is scale was 40 ± 18 after placebo, 44 ± 18 after shown in Table 3. Baseline systolic blood pressure

Table 2 Mean heart rate in beats min1 (± s.d.) before and at 0.5 h intervals for 3 h after each treatment Time (h) Drugs 0 0.5 1 1.5 2 2.5 3 Placebo 60 ± 6 59 ± 6 60 ± 7 61 ± 7 62 ± 8 60 ± 8 60 ± 9 Propranolol 60 ± 8 58 ± 8 57 ± 10 56 ± 11* 53 ± 9t** 53 ± 7t** 53 ± 9t** Atenolol 59 ± 7 57 ± 7 55 ± 10t* 53 ± 9t** 54 ± 8t** 53 ± 7t** 53 ± 9i** Pindolol 62 ± 9 62 ± 10 61 ± 10 61 ± 9 60 ± 8 60 ± 7 61 ± 8 Ro 31-1118 58 ± 6 58 ± 7 58 ± 7 59 ±6 60 ± 7 60 ± 8 63 ± 8 Flusoxolol 62 ± 9 61 ± 10 61 ± 10 64 ± 12 64 ± 11 65 ± 10 67 ± 11* Salbutamol 61 ± 6 60 ±3 66 ± 11* 71 ± 14t** 74 ± l0i** 75 ± 17t** 74 ± 10t** Prenalterol 62 ± 8 68 ± llt** 81 ± 17t** 89 ± 17t** 86 ± 17t** 90 ± 23t** 89 ± 21t** * P < 0.05 vs placebo, ** P < 0.01 vs placebo, t P < 0.05 vs baseline, t P < 0.01 vs baseline.

Table 3 Mean systolic blood pressure in mm Hg (± s.d.) before and at 0.5 h intervals for 3 h, after each treatment Time (h) Drugs 0 0.5 1 1.5 2 2.5 3 Placebo 100 ± 10 100 ± 12 99 ± 11 100 ± 12 101 ± 9 101 ± 11 101 ± 11 Propranolol 101 ± 6 98 ± 6 95 ± 5t 94 ± 7t* 94 ± 4t** 95 ± 7j:** 93 ± 8t** Atenolol 101 ± 8 98 ± 8 94 ± 10f* 94 ± 9t* 92 ± 8t** 92 ± 8t** 93 ± 10O** Pindolol 102 ± 8 101 ± 8 99 ± 6 99 ± 9 100 ± 9 99 ± 8 101 ± 12 Ro 31-1118 99 ± 6 98 ± 5 101 ± 4 101 ± 7 104 ± 8t 104 ± 6t 104 ± 8t Flusoxolol 103 ± 8 102 ± 8 102 ± 11 105 ± 10** 106 ± 9** 108 ± lOt** 107 ± 10** Salbutamol 100 ± 10 101 ± 12 104 ± 12* 110 ± 11t** 108 ± 12t** 108 ± 11t** 109 ± 14t** Prenalterol 99 ± 12 114 ± 24t** 122 ± 17f** 122± 11t** 121 ± 15t** 121 ± 16t** 119 ± 15i** * P < 0.05 vs placebo, ** P < 0.01 vs placebo, t P < 0.05 vs baseline, t P < 0.01 vs baseline Partial agonist activity ofRo 31-1118, flusoxolol and pindolol 575 was not different for any drug. When the different a percentage increase at 2.5 and 3 h to a maximum treatments were compared with placebo, Ro 31- of 74 ± 70%. 1118 and pindolol caused no change. Systolic When the different treatments were compared, blood pressure was reduced by propranolol and the percentage increases in forearm blood flow atenolol to minimum values of 93 ± 8 mm Hg after Ro 31-1118 and pindolol were significantly and 92 ± 8 mm Hg respectively. Compared with greater than after atenolol and propranolol. placebo (101 ± 11 mm Hg), flusoxolol increased systolic blood pressure to a maximum of 108 ± Forearm vascular resistance Percentage change 10 mm Hg and after salbutamol systolic blood in forearm vascular resistance was calculated pressure rose to a maximum of 109 ± 14 mm Hg. because of small differences in baseline forearm Prenalterol caused a significant increase in sys- blood flow. Compared with placebo, pindolol tolic blood pressure compared to placebo (100 ± and flusoxolol caused no change in forearm 12 mm Hg) to a maximum of 122 ± 11 mm Hg. vascular resistance. Propranolol (11 ± 24%) and When the different treatments were compared, atenolol (5 ± 14%) caused a significant increase systolic blood pressure was higher after prenal- in forearm vascular resistance at 2 h compared terol than after all other treatments. with placebo (-1 ± 10%). Forearm vascular resistance fell after Ro 31-1118 (-18 ± 13%) at Forearm blood flow There were small but sig- 3 h. Salbutamol caused a fall at 1.5 and 3 h to a nificant differences in baseline forearm blood minimum of -22 + 6% and prenalterol caused flow values; therefore percentage change was falls at 2.5 and 3 h to a minimum of -27 ± 28% calculated. Percentage change in forearm blood compared with placebo (-2 + 9%). flow for all treatments over the 3 h period is Finger tremor There was significant baseline shown in Figure 1. Compared with placebo, variation, therefore percentage change in finger pindolol and flusoxolol tended to increase forearm tremor was calculated. Percentage change in blood flow but the increase was not significant. finger tremor over the 3 h period is shown in The percentage reductions in forearm blood Figure 2. Placebo was associated with a small flow after propranolol (-16 ± 13%) and atenolol but significant increase in finger tremor to a (-10 + 9%) were significant at 2 h. Ro 31-1118 maximum of 77 ± 96%. Compared with placebo, caused a significant increase at 3 h (28 ± 20%). propranolol produced a reduction at 3 h (0.5 ± Salbutamol produced an increase at 1.5 and 3 h 60%). Similarly atenolol reduced finger tremor to a maximum of 30 ± 25%. Prenalterol produced compared to placebo at 3 h (-9 + 68%). Pindolol

75

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-25

I I I. I I 0 0.5 1 1.5 2 2.5 3 Time post dosing (h) Figure 1 Mean percentage change in forearm blood flow at each time measured for the 3 h after each treatment. 0 placebo, o salbutamol 8 mg, 0 prenalterol 50 mg, * Ro 31-1118 160 mg, v atenolol 50 mg, v propranolol 80 mg, A pindolol 10 mg and * flusoxolol. * P < 0.02 vs placebo 576 P. M. McCaffrey, J. G. Riddell & R. G. Shanks

900

0 E 500 CD

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0 0.5 1 1.5 2 2.5 3 Time post dosing (h) Figure 2 Mean percentage change in finger tremor at each time measured for the 3 h after each treatment. o placebo, o salbutamol 8 mg, 0 prenalterol 50 mg, * Ro 31-1118 160 mg, v atenolol 50 mg, v propranolol 80 mg, * pindolol 10 mg and * fiusoxolol. * P < 0.05 vs placebo, ** P < 0.01 vs placebo increased finger tremor to a maximum of 709 + agonist effects less than that of full agonists and 1252%. Ro 31-1118 and flusoxolol increased demonstrable antagonist effects. Because of the finger tremor to maximum values of 358 ± 137% number ofdrugs involved in this study, fixed oral and 297 ± 169% respectively. Finger tremor doses were used and no formal dose-response rose to a maximum of 876 ± 1335% after salbu- observations were made. However, in the second tamol and to a maximum of 283 ± 220% after study, as observations were made before and at prenalterol. half hourly intervals after dosing, some estimate The percentage increase in finger tremor after of the dose-response relationship may be inferred. salbutamol was significantly greater than that In particular the time effect curves plateau at after prenalterol, propranolol and atenolol. It about 2 h and there is no indication of a decrease was also higher after salbutamol than after Ro in agonist effect at 3 h when plasma concentrations 31-1118 and flusoxolol at 1, 1.5 and 2 h and after would be expected to be beginning to fall. This pindolol at 2 h. suggests that near maximal agonist effects are being observed. Also, as maximal partial agonism Exercise heart rate Exercise heart rate was sig- is usually seen at doses lower than those causing nificantly lower after propranolol (127 ± 14 antagonism (Bowman & Rand, 1980; Bilski et beats min-1), atenolol (130 ± 11 beats min-1), al., 1979) we are likely to be seeing an effect pindolol (123 ± 8 beats min-1), Ro 31-1118 (126 approaching maximal. The drugs with antagonist ± 8 beats min-') and flusoxolol (132 ± 10 beats activity caused similar reductions in exercise min-1) than after placebo (166 ± 12 beats min-') heart rate and as they are primarily adrenoceptor and was unchanged by salbutamol (169 ± 14 antagonists it seemed reasonable to compare beats min-1) and prenalterol (169 ± 13 beats them at these doses. During sleep, heart rate min-1). Exercise heart rate after pindolol was normally falls to reach its lowest level after 6 h significantly less than after atenolol and flusoxolol. (Kleitman, 1963). This fall is thought to be due Salbutamol and prenalterol caused on change in to predominance of parasympathetic and with- exercise heart rate compared with placebo. drawal of sympathetic tone during sleep (Baust & Bohnert, 1969). This reduced sympathetic Discussion activity provides ideal conditions for demon- strating 3-adrenoceptor partial agonism by an To fulfill the criteria for partial agonist activity, increase in heart rate. Sympathetic tone is also Ro 31-1118, flusoxolol and pindolol should have low in the resting supine position (Aellig, 1977) Partial agonist activity ofRo 31-1118, flusoxolol and pindolol 577 allowing a similar opportunity to assess partial shown a fall (Mc Devitt etal., 1975) or no change agonist activity. (Walker et al., 1972; Watson & Richens, 1974). Prenalterol and salbutamol increased both Salbutamol has been shown to improve indices sleeping and supine heart rate. Salbutamol has of myocardial contractility (Sharma & Goodwin, been shown to increase supine heart rate in 1978; Bourdillon et al., 1980) although it is not previous studies (Leitch et al., 1976; Philips et clear if this is due to a positive inotropic effects al., 1980; Kennedy & Simpson, 1969) and the or a reduction in afterload caused by vasodilation. specific 32-adrenoceptor antagonist, ICI 118,551 The rise in systolic blood pressure may have (Bilski et al., 1983) has been shown to abolish been partly due to stimulation of P32-adreno- this increase in heart rate (McCaffrey et al., ceptors on the myocardial cells (Stiles et al., 1986) indicating that it is mediated by the 12- 1983) causing a significant increase in heart rate adrenoceptor. However the mechanism of the and this could produce a rise in systolic blood rise in heart rate is unclear and may be partly pressure. However in a study comparing the reflex, secondary to peripheral vasodilation or effects of atropine and salbutamol it was noted due to direct stimulation of P2-adrenoceptors in that with comparable increases in heart rate the heart (Stiles et al., 1983) or stimulation of salbutamol increased cardiac output while atro- presynaptic 132-adrenoceptors facilitating nora- pine did not (Gibson & Coltart, 1970). Again, drenaline release at the sympathetic nerve end- stimulation of presynaptic 132-adrenoceptors ings (Stjarne & Brundin, 1976). has been shown to release catecholamines from The two 1-adrenoceptor antagonists, pro- human vasoconstrictor nerves (Stjarne & pranolol and atenolol reduced sleeping and Brundin, 1976) and this may have contributed to supine heart rate. Ro 31-1118, and pindolol the rise in systolic blood pressure. caused a smaller reduction in sleeping heart rate Propranolol and atenolol both reduced systolic and no change in supine heart rate, while flu- blood pressure. Flusoxolol increased systolic soxolol caused a smaller reduction in sleeping blood pressure compared with placebo and Ro heart rate and an increase in supine heart rate. 31-1118 caused an increase compared with base- These results would be in keeping with partial line but not compared to placebo. In agreement agonist activity at either the 13l- or 32-adreno- with these results a previous study showed that ceptor. Ro 31-1118 had no effect on supine systolic Disturbed sleep may increase heart rate but blood pressure in mild hypertension (Jamieson we were unable to detect an effect of the drugs et al., 1985): The apparent difference between on the quality of sleep. Previous studies using the two enantiomers may be due to the fact that subjective methods for assessing the effects of the baseline value was higher, although not signi- ,B-adrenoceptor antagonists on sleep have ficantly so, before flusoxolol than before both revealed conflicting results, with some groups placebo and Ro 31-1118. The most likely cause reporting adverse effects (Weiner & Rossner, of the rise in systolic blood pressure is agonist 1983; Betts & Alford, 1985) and others no effect activity at the 13l-adrenoceptor in the heart and (Bengtsson et al., 1980). Most studies using EEG this is consistent with the much greater rise in monitoring, have found that at the doses used in systolic blood pressure caused by the predomi- clinical practice 13-adrenoceptor antagonists do nantly 1l-adrenoceptor agonist, prenalterol. not affect quality of sleep (Dunleavy et al., 1971; Both salbutamol and prenalterol increased Bender et al., 1979). However, a recently forearm blood flow and reduced forearm vas- reported study using objective measurements of cular resistance. Prenalterol has previously been the quality of sleep has shown that pindolol, shown to increase forearm blood flow and propranolol and metoprolol adversely affect sleep decrease forearm vascular resistance (Fitzpatrick (Kostis & Rosen, 1987). Our study may have et al., 1983) and these effects have been inter- failed to detect an effect because our volunteers preted as being indicative of agonist activity at were young males, who sleep so well that they both the 13l- and 132-adrenoceptor. Propranolol are not easy to disturb (Oswald, 1980). The fact and atenolol reduced forearm blood flow while that changes were observed in sleeping heart Ro 31-1118 caused an increase and flusoxolol rate but not in supine heart rate for some of the and pindolol no change. The effects of the 1- drugs may be due to a lower sympathetic tone adrenoceptor partial agonists (Ro 31-1118, during sleep than when supine. flusoxolol and pindolol) on forearm blood flow Prenalterol caused a rise in systolic blood pres- lay between those of the full agonists, salbutamol sure as previously noted (Svendsen et al., 1980). and prenalterol and the 13-adrenoceptor The increase in systolic blood pressure produced antagonists atenolol and propranolol. This is in by salbutamol has been reported previously keeping with partial agonist activity at the P2- (Corea et al., 1984) although other authors have adrenoceptor. 578 P. M. McCaffrey, J. G. Riddell & R. G. Shanks There was a small but significant increase in measures Reid etal. (1986) showed that pindolol finger tremor after placebo. This increase may caused an increase in finger tremor in diabetic have been due to the fact that all these studies patients with autonomic neuropathy. were carried out in the morning following a light Ro 31-1118 and flusoxolol increased finger breakfast. It has previously been noted that tremor and tremor has also been reported as a omission of breakfast caused an increase in side effect of Ro 31-1118 (O'Connor et al., tremor by late morning (Tuttle et al., 1949) and, 1985). The antagonist activity of these drugs has in another study, fasting tended to increase finger been shown to be 01-selective (Blaber et al., tremor, although the increase did not reach 1983; O'Connor et al., 1985) but agonist activity statistical significance (Wharrad et al., 1985). at both adrenoceptors can be demonstrated in Stimulation of the 2-adrenoceptor has been man, in agreement with animal studies (Blaber shown to augment physiological finger tremor et al., 1983). The increase in finger tremor after (Larsson & Svedmyr, 1977) and 132-adrenocep- Ro 31-1118, flusoxolol and pindolol was much tor agonists would be expected to increase finger less than after the full agonist, salbutamol, fulfil- tremor. In this study tremor was increased by ling the criterion for partial agonist activity. salbutamol and to a lesser but significant degree The selectivity of the agonist activity may by prenalterol. The increase in finger tremor differ from the selectivity of the antagonist produced by prenalterol would be consistent activity. For example, Ro 31-1118 and flusoxolol with agonist activity at the P2-adrenoceptor, which are antagonists mainly at the ,l-adreno- which has been shown in previous animal (Matt- ceptor demonstrate agonist activity at both sson et al., 1982b) and human studies (Fitzpatrick receptors and pindolol which is an antagonist at et al., 1983). Some contribution from the ballis- both receptors but an agonist mainly at the 2- tocardiographic effect cannot be ruled out as adrenoceptor. Full dose-response curves for both prenalterol caused a marked increase in heart the agonist and antagonist activity ofthese drugs rate and is known to have positive inotropic would be required to confirm these findings. effects (Rasmussen et al., 1984). However, pre- In conclusion, Ro 31-1118, flusoxolol and vious studies have shown that the contribution pindolol fulfilled the criteria for the demonstra- of the ballistocardiographic effect accounts for tion of partial agonist activity. A measurable less than 10% of overall tremor (Marsden et al., agonist response was demonstrated by increases 1969) and the increase in tremor is probably due in sleeping heart rate, finger tremor and systolic to P-adrenoceptor stimulation. blood pressure which were less than the increase Atenolol and propranolol caused no change in produced by the full agonist. In contrast the two finger tremor over the 3 h period. After pro- ,3-adrenoceptor antagonists reduced these pranolol and atenolol the percentage change in parameters. A measurable antagonist response finger tremor was significantly less than after was illustrated by the reduction in exercise heart placebo at 3 h. This is consistent with previous rate which was comparable with that produced studies which have shown that both atenolol and by the ,-adrenoceptor antagonists, while the propranolol reduce physiological finger tremor full agonists caused no change. (Birmingham et al., 1981; Abila et al., 1985). Pindolol has been shown to have significant We are grateful to Roche Products Ltd for supplying agonist activity at the P2-adrenoceptor in animal Ro 31-1118 and flusoxolol and for financial support; to studies (Clark, 1984). The marked increase in Astra Pharmaceuticals for supplying prenalterol; to finger tremor caused by pindolol in this study Dr J. D. Merrett for statistical advice; and to the would indicate significant agonist activity at the Department of Geriatric Medicine, Queen's University of Belfast, for use of the equipment for recording and 32-adrenoceptor in man. Tremor has been analysing sleeping heart rate. reported as a side effect of pindolol (Hod et al., 1980; Rosenthal et al., 1979) and using objective

References

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