treatment with either metoprolol (100-200 mg/day) or pindolol (5-10 mg/day). The effects upon blood pressure and peripheral blood flow were determined.
425 s
Clinical Science (1981) 6 1 , 4 2 5 ~ 4 2 7 s
Metoprolol and pindolol in hypertension: different effects on peripheral haemodynamics
A. S V E N S S O N , T. G U D B R A N D S S O N , R . S I V E R T S S O N A N D L. H A N S S O N Hypertension Section, Departments of Medicine and Clinical Physiology, dstra Hospital, University of Goteborg, Goteborg, Sweden
Summary
1. Thirty-six patients with essential hypertension, were randomly allocated to double-blind treatment with either metoprolol (100-200 mg/day) or pindolol (5-10 mg/day). The effects upon blood pressure and peripheral blood flow were determined. Both drugs reduced blood pressure significantly. 2. Heart rate was significantly reduced by metoprolol but not by pindolol. 3. Vascular resistance at maximal dilatation was not changed by either compound. 4. At rest, pindolol reduced vascular resistance in the calf by 14% (P < 0.05) but metoprolol tended to increase the resistance slightly. The difference in effect was also significant (P < 0.005). 5. During leg muscle work there were no changes in vascular resistance in the forearm with either compound. 6. We conclude that pindolol appears to reduce blood pressure at least partly through vascular mechanisms, in contrast to metoprolol. The response to sympathetic stimulation induced by physical exercise does not differ between metoprolol- and pindolol-treated patients. Key words: P-adrenoceptor-blocking agents, haemodynamics, hypertension. Abbreviation: ISA, intrinsic sympathomimetic effect. Introduction
PAdrenoceptor-blocking agents have now been used in the treatment of hypertension for more than a decade. During this period a number of different drugs of this type have come into use, all Correspondence: Dr Anders Svensson, Hypertension Section, Ostra Hospital, Goteborg, Sweden.
of which share the PI-receptor-blocking property. On the other hand they differ in other respects, e.g. as regards their degree of intrinsic sympathomimetic effect (ISA) and selectivity for P1receptors. The way in which these drugs lower the blood pressure in hypertensive patients is still not fully understood, and it is not obvious that they reduce blood pressure by the same mechanisms. There seem to be differences in haemodynamic ,effects of different types of P-adrenoceptor-blocking drugs. Some researchers have found that substances with pronounced ISA will affect cardiac output and heart rate to a much lesser degree than substances without ISA, at least in acute experiments [ l , 21. However, in general, padrenoceptor-blocking drugs will reduce heart rate and cardiac output quite markedly. It has been claimed that selective PI-receptor blockade would be advantageous compared with non-selective P-blockade, e.g. by not blocking P,-receptor-mediated vasodilatation in the peripheral vascular bed. During cigarette smoking [31 and isometric exercise [41 peripheral vasoconstriction and blood pressure elevation have been reported with non-selective P-blockade. In this context, it is of interest to note that pindolol, a non-selective P-adrenoceptor-blocking agent with marked ISA, has been reported to reduce vascular resistance as well as blood pressure [51. In this study, we have compared pindolol and metoprolol, a P,-selective adrenoceptor-blocking drug devoid of ISA as regards effects on blood pressure and peripheral haemodynamics at rest, during physical exercise and ischaemia. Material
Altogether 36 patients with essential hypertension (WHO stage I) took part in the study. Some of their characteristics are listed in Table 1.
426s
A . Svensson et al.
TABLE1. Characteristics of hypertensive patients studied N.S., Not significant. Pindolol Metoprolol group group Age (years) Numbers Males Females Initial systolic B P (mmHg) Initial diastolic BP (mmHg) Heart rate (beatdmin)
Difference
45
45
N.S.
12 5 163 106
13
N.S. N.S. N.S. N.S. N.S.
13
6
162 104 71
Methods The patients were randomly assigned to doubleblind treatment with either pindolol (5-10 mg/ day) or metoprolol (100-200 mg/day) after a 6 week placebo period. At the end of the placebo period and after 6 weeks of active treatment venous occlusion plethysmography was performed in the forearm and the calves. For the calf plethysmography studies a modified Whitney mercury-in-rubber strainguage technique was used [61. One blood pressure cuff was placed just proximal to the knee and one around the ankle, the pressure being kept at about 55 mmHg during flow registrations. Blood pressure was measured indirectly in one arm simultaneously with the flow determinations. Vascular resistance was calculated from the mean blood pressure and mean blood flow. The same measurements were made during ‘maximal’ vasodilatation, which was induced by arterial ischaemia (the proximal cuff inflated to 250 mmHg) combined with calf-muscle work until exhaustion. For the forearm plethysmographic studies similar equipment was used. To produce a moderate sympathetic stimulus, the patients had to perform a certain amount of leg exercise on an ergometer bicycle. The load was adjusted so that a heart rate of about 125 beatshin was achieved during the placebo period. The same load was used after 6 weeks of active therapy. Plethysmographic measurements were made in one arm, while the blood pressure was measured indirectly in the other. Resistance could then be calculated from flow data and mean blood pressure. Results
Both drugs reduced resting blood pressure significantly and to the same extent, with a fall in mean arterial pressure of 15 mmHg in the pindolol group and 14 mmHg in the metoprolol group.
Heart rate was significantly reduced with metoprolol, from 67 to 56 beatshin (P < 0.01). Pindolol, on the other hand, produced a nonsignificant reduction from 67 to 63 beatshin. Vascular resistance at maximal vasodilatation was unchanged in the calves as well as in the forearm. In this respect there was no difference between the two drugs. At rest, resistance in the calves during pindolol therapy was reduced by 14% (P < 0-05). Metoprolol, on the other hand, tended to increase the vascular resistance slightly. The difference in effects between the two compounds was statistically significant (P < 0.005). During leg muscle work, vascular resistance in the forearm increased from 3 1 units to 5 1 units during the placebo period, calculated as the average at 1, 2, 3 and 4 min of work. With pindolol resistance increased to 50 units and in the metoprolol group it increased to 62 units, which was not significantly different from the placebo period. Blood pressure increased to the same extent in the two groups during physical exercise, but significantly less than during the placebo period. Exercise-induced tachycardia was equally reduced by the two compounds, by 20 b e a t s h i n in the metoprolol group and 19 b e a t s h i n in the pindolol group.
Discussion PAdrenoceptor-blocking agents are widely used in the treatment of hypertension. Available drugs differ in their degree of /?,-receptor selectivity and intrinsic sympathomimetic effect, but despite these differences, they usually reduce the blood pressure of hypertensive patients to the same extent [7, 81. We found that metoprolol and pindolol were equally effective in this regard, both at rest and during and after physical exercise. The finding that neither compound reduced vascular resistance at maximal vasodilatation was not unexpected, as it indicates that changes in vascular structure are not induced by 6 weeks of antihypertensive treatment of this kind. The fact that pindolol caused a reduction in resistance at rest but hardly reduced heart rate, suggests that the blood pressure reduction was caused mainly by vascular mechanisms. In this respect, our findings confirm earlier data. Thus, in intravenous acute studies, it has been noted that pindolol does not lower cardiac output or heart rate [ 1 I and during long-term treatment causes a reduction of peripheral vascular resistance [9]. The vasodilating effect is probably due to /?,-adrenoceptor stimulation linked to the marked
Metoprolol and pindolol
ISA of pindolol. In this respect pindolol differs from most other non-selective and selective Pblocking agents, as a general finding has been that cardiac output is reduced and vascular resistance increased, at least in the early phases of Pblockade 18, 101. Adrenaline may cause a rise in blood pressure when /?,-adrenoceptors are blocked 1111. This is supposedly due to unopposed a-adrenoceptor stimulation leading to vasoconstriction 1121. It has been demonstrated that handgrip [71 and cigarette smoking [3] will cause a higher blood pressure during treatment with non-selective Pblockade than during selective /?,-blockade with atenolol. Moreover, stimulation with industrial noise causes a more marked increase of blood pressure and vascular resistance in hypertensive patients after propranolol than after metoprolol administration [131. Therefore it has been suggested that /?,-selective blockers would be a more logical choice in the treatment of hypertension [14]. However, not all forms of ‘stress’ produce different haemodynamic effects after non-selective or /?,-selective adrenoceptor blockade. Thus cold pressor stimulation and mental arithmetic caused similar changes after acute blockade with propranolol and metoprolol respectively [ 151. Moreover, it is not certain that all non-selective Pblocking agents can be regarded as equal in this respect, as for example pindolol has a haemodynamic profile different from that of drugs without ISA [ll. We found that moderate physiological sympathetic stimulation, induced by physical exercise, did not result in differences between the pindolol group and the metoprolol group attributable to this mechanism. That the sympathetic system was activated is demonstrated by the fact that vascular resistance in the forearm did increase by about 70% during leg exercise, but there was no difference between placebo, metoprolol and pindolol in this respect. That an equal degree of /?-adrenoceptor blockade was achieved in the two groups can be assumed, since exercise-induced tachycardia was reduced to the same extent. In conclusion, the present study demonstrates that pindolol and metoprolol significantly and to the same extent lower blood pressure in patients with mild to moderate essential hypertension. However, the mechanisms by which these drugs reduce blood pressure appear to be different. The reduction of vascular resistance observed during pindolol therapy may constitute a clinical advantage with regard to side effects related to increased peripheral vascular resistance and
427s
reduced cardiac output [16, 171, such as cold extremities. Acknowledgment This study was made possible by a grant from Sandoz Sweden AB. References I I1 LYSBO-SVENDSEN, T., HARTHING,0.
& TRAP-JENSEN,J. (1979) Immediate haemodynamic effects of propranolol, practolol, pindolol, atenolol and ICI 89 406 in healthy volunteers. European Journal of Clinical Pharmacology, 15, 223-228. 121 SANNERSTEDT, R. (1975) Haemodynamic effects of adrenergic
beta-receptor blocking agents in arterial hypertension. In: Parhophysiology and Managemenr of Arterial Hypertension, pp. 194-200. Ed. Berglund, G., Hansson, L. & Werko, L. A. Lindgren and Sons, Molndal, Sweden. 131 TRAP-JENSEN,J., CARLSEN,J.E., LYSBO-SVENDSEN, T. & CHRISTENSEN,N.J. (1979) Cardiovascular and adrenergic effects of cigarette smoking during immediate non-selective beta adrenoceptor blockade in humans. European Journal of Clinical Investigation, 9,181-183. 141 NYBERG,G. (1977) Blood pressure and heart rate during sustained handgrip in hypertensive patients taking placebo, a non-selective beta-blocker (propranolol) and a selective beta,blocker (metoprolol). Current Therapeuric Research, 22, 828-838. 151 A ~ E R H ~J.-H., G , DUN& J. & PERNOW, B. (1976) Hemo-
dynamic effect of pindolol in essential hypertension with special reference to the resistance and capacitance vessels of the forearm. Acta Medica Scandinavica. 199.25 1-255. 161 WHITNEY,R.J. (1953) The measurements of volume changes in human limbs. Journal ofPhysiology (London), 121,1-27. I7 I WAAL-MANNING, H.J. (1979) Atenolol and three non-selective beta-blockers in hypertension. Clinical Pharmacological Therapeutics, 25,8-18. 181 LUND-JOHANSEN, P. (1978) Haemodynamic effects of antihypertensive agents. In: The Treatment of Hypertension, pp. 6 1-92. Ed. Freis, E.D. MTP Press, Lancaster. 191 ATTERH~G, J.-H., DUNER, H. & PERNOW,B. (1976) Experience with pindolol, a betareceptor blocker, in the treatment of hypertension. American Journal of Medicine, 60,872-876. I101 HANSSON,L., ZWEIFLER,A.J., JULIUS,S. & HUNYOR,S.N. (1974) Hemodynamic effects of acute and prolonged betaadrenergic blockade in essential hypertension. Acta Medica Scandinavica, 196,27-34. I I I 1 VAN HERWAARDEN, C.L.A., BINKHORST, R.A., FENNIS,J.F.M. & VAN’T LAAR, A. (1977) Effects of adrenaline during treatment with propranolol and metoprolol. British Medical Journal, i, 1029. I121 JOHNSSON, G. (1975) Influence of metoprolol and propranolol on hemodynamic effects induced by adrenaline and physical work. Acra Pharmacologica et Toxicologica, 36 (Suppl. V), 59-68. I131 ANDREN,L., HANSSON,L. & B J ~ R K M AM. N , (1981) Haemo-
dynamic effects of noise exposure before and after p,-selective and non-selective p-adrenoceptor blockade in patients with essential hypertension. Cllnical Science, 61 (Suppl. 7), 89s91s:. 1141 MCSORLEY.P.D. & WARREN, D.J. (1978) Effects of pro-
pranolol and metoprolol on the peripheral circulation. British Medical Journal, ii, 1598-1600. 1151 ANDREN,L. & HANSSON, L. (1981) Circulatory effects Of stress in essential hypertension. Acta Medica Scandinavica, Suppl. 646,69-72. 1161 GOKAL, R., DORMAN,T.L. & LEDINGHAM, J.G.G. (1979). Peripheral skin necrosis complicating beta-blockade. British Medical Journal, i, 721-722. 1171 GREENBLATT,D.J. & KOCH-WESER,J. (1974) Adverse reactions to beta-adrenergic receptor blocking drugs: a report from the Boston Collaborative Drug Surveillance Program.
Drugs,7,118- 129.
