Cardioselectivity: Short Communications

~-Adrenoceptor-linked Na/K ATPase The Effect of Cardioselective and Non-selective P-Blockade

A.D. Struthers, J.L. Reid, C.B. Lawrie and J. C. Rodger Department of Materia Medica, Stobhill Hospital, Glasgow, and Division of Medicine, Monklands General Hospital, Airdrie, Scotland

Plasma adrenaline levels are elevated after myo­cardial infarction and patients who are hypokal­aemic have an increased incidence of ventricular arrhythmias. We have investigated whether such elevation of adrenaline could act via a /3radreno­ceptor-linked Na/K ATPase to cause significant hypokalaemia and hence contribute 10 the devel­opment of arrhythmias.

Nine normal volunteers were studied on 3 oc­casions after 5 days' therapy with placebo, the cardioselective It-blocker atenolol IOOmg, or the non-selective (3-blocker timolol 20mg. On each study day, they received three 90-minute infusions of 5% dextrose containing 0, 0.01 and 0.06 jlg/kg/ min adrenaline. During the highest rate of infu­sion, the plasma adrenaline levels (5.5 ± 1.7 nmol/ L, normal range < I nmolfL) were similar to those previously observed after myocardial infarction (6.0 ± 3.3 nmoljL). Pretreatment did not significantly alter serum K+ (4.05, 4.03 and 4.09 mmol/L after placebo, atenolol and timolol, respectively). Dur-

Antihypertensive Effects and Kidney Function in Hypertensive Patients Treated with Atenolol and Oxprenolol

G. Bellini, G. Batti/ana, R. Carretta, B. Fabris, E. Puppis, A. Rigoni, L. Faccini and L. Campanacci Istituto di Patologia Medica dell'Universita di Trieste, Trieste, Italy

The principal antihypertensive effect of (3-block­ers is on the (31-cardiac receptors (Connolly et al. , 1976), although the precise mode of action is as

253

ing 0.06 jlg/kg/min adrenaline infusion, serum K+ fell to 3.21 mmol/L (p < 0.001) after placebo, to a lesser extent to 3.67 mmoIjL (p < 0.001) after atenolol, and increased to 4.25 mmol/L after ti­molo!. The haemodynamic effects of this infusion were as follows: systolic blood pressure + 11 ± 6mm Hg; diastolic blood pressure -14 ± 9mm Hg; and heart rate + 7 ± 9 beats/min. Corresponding changes after atenolol were +6 ± 3mm Hg, -4 ± 5mm Hg, and +1 ± 4 beats/min, respectively. After timolol, however, the haemodynamic effects were completely different. The systolic blood pressure still rose (+ 12 ± 5mm Hg) but this time the dia­stolic blood pressure also rose (+ 19 ± 4mm Hg) and heart rate fell (-8 ± 5 beats/min). Presum­ably, under the influence of non-selective it-block­ade, adrenaline principally causes a-adrenoceptor­mediated vasoconstriction, causing the diastolic pressure to rise with a compensatory bradycardia.

This study provides further evidence that cate­cholamines may be a factor in the production of both hypokalaemia and arrhythmias after myocar­dial infarction. The prevention or reduction of hypokalaemia may contribute to the beneficial ef­fects of (3-blockade following myocardial infarc­tion.

References Ceremuzynski, L. et at.: Cardiovascular Research 3: 190-197 (1959). Clausen, T. and Aatman, J.A.: British Journal of Pharmacology

68: 749-755 (1980). Cryer, P.E.: New England Journal of Medicine 303: 436444 (1980). Petch, M.e. et a!.: European Heart Journal 2: 123-126 (1981). Solomon. R. and Cole, A.: Royal Society of Medicine. Interna-

tional Congress Series 44: 12 (1980).

yet unclear. Non-selective /3-blockers may cause a reduction in renal blood flow (RBF) and glomer­ular filtration rate (GFR) [Bauer and Brooks, 1979; Ibsen and Sederberg-Olsen, 1973; Zech et a!. , 1977]. These effects have been attributed to extrarenal haemodynamic factors, in particular to a reduction in cardiac output, although blockade of renal th­receptors has also been suggested (Carriere, 1969). This study was designed to investigate this action of fj-blocking agents by comparing the effect of a non-selective drug (oxprenolol) with a selective /31-receptor blocker (atenolol) on renal function (GFR and RBF) in patients with WHO stage I and II essential hypertension.

42 patients (19 male, 23 female; age, 22-62 years, mean 47 years) were randomly allocated to treat­ment with either atenolol (50-100mg once daily) or

Cardioselectivity: Short Communications

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Fig. 1. Supine (a) and standing (b) blood pressure and heart rate before and during treatment with oxprenolol and atenolol.

oxprenolol (I20-320mg tid) for 7 weeks. All drugs were withdrawn 3 weeks before the start of the study and sodium and potassium intake was monitored over the treatment period. The following were re­corded at the end of each week: supine and stand­ing systolic and diastolic blood pressure; heart rate; bodyweight; and, at the end of the seventh week, blood and urine samples for routine analysis. GFR and RBF (inulin and p-hippuric acid clearances) were measured in 10 patients from each group be­fore and after treatment.

Results: All measurements of blood pressure and heart rate, both supine and standing, were signifi­cantly lowered by both drugs; diastolic BP ~ 90mm Hg being reached in 16 (80%) patients on atenolol and in II (50%) on oxprenolol (fig. 1). There was no significant change in blood and urine analyses before and after treatment with either drug. Three of the 20 atenolol-treated patients had some gas­trointestinal symptoms while 3 others complained of paraesthesia in the legs. Transient headaches oc­cured in 4 of the 22 patients given oxprenolol and 2 others complained of sexual problems. Differ­ences in GFR and RBF in 7 patients from each group who showed comparable response in terms

of blood pressure and heart rate to the 2 drugs were statistically analysed. Both drugs lowered RBF and GFR but the only statistical difference was with oxprenolol on GFR (p < 0.05).

Discussion: A reduction in RBF (GFR appar­ently being lowered sometime later) has been re­ported in hypertensive diseases (Campanacci et at, 1977) but RBF has also been found to be normal or even increased (Pedersen, 1979). One possible explanation for these conflicting data could be. variations in renal function related to the patient's age, stage of the disease, duration of the hyperten­sive state, and the presence of kidney structural changes.

There is some dispute over the effects of short or long term treatment with (j-blockers on RBF and GFR, in both normal and hypertensive patients. Propranolol has reduced RBF and GFR at doses too low to modify heart rate and cardiac output, while selective ,B-blockers have produced contro­versial results (Wilkinson et aI., 1980; Zech et aI., 1977). In the present study, both atenolol and ox­prenolol at doses which signifibantly lowered blood pressure to comparable levels reduced RBF, al­though not to a statistically significant level. GFR

was significantly reduced (p < 0.05) only by ox­prenolol. Atenolol could have tess effect than ox­prenolol on renal function both because of the lack of intrarenal ,ti2-vascular receptor blockade, and/or because of change in renin secretion which may be controlled in different ways by the 2 drugs (Gavras et aI. , 1979; RapeJli et al.. 1980).

These findings, if confirmed by a larger number of observations, may oot be central to the man­agement of hypertensive patients with normal renal function , but will make a careful evaluation ofthose hypertensive patients with impaired renal function mandatory.

Effects 01 Salbutamol, Indomethacin and Atenolol on Insulin Secretion

M. Stornelfo, G. Di Rao, M. lacheI/o, V. Bosco, S. Pantano, R. Pisani and L. Soap.llato Medical Department, Umberto I HospItal, Syracuse, Italy

Insulin secretion is increased by activation of p­receptors, and recent research has indicated that prostaglandins are also important in the regulation of honnooe secretion. We have investigated the nature of the ,ti-adrenergic receptors controlling in­sulin in man and the role played by prostaglandins in insulin release induced by the sympathetic nerv­ous system. The 6 palients (3 female, 3 male; av­erage age 50.4 ± 12.49 years) studied had normal glycolipid me13.bolism and were of nonnal weight.

Results: Blood glucose levels did not change sig­nificantly relative to basal values during the 4 phases of the experiment. Salbutamol alone in­duced a significant increase in immunoreactive in­sulin (lRI) at the second and third hour, and after indomethacin this was still present but at a re­duced level, reaching a mnimum by the second hour. Salbutamol with ,ti-blodcade induced by at­enolol, led to a reduced response in IRI, reaching a maximum at the second hour and returning to basal levels by the founh hour (fig. 1).

Salbulamol, a .Bl-agonist, induced a maximum increase of IRI of 12 ± 3.2 mU/mt compared with basal levels. AtenoIo!, a .BI-selective antagonist,

References Bauer, J .H. and Brooh. C.5.: American Journal of Medicine 66:

405 (1 979). . Campan"cti, L. el at: O iorn.1c CliniCli Medica 58: 89 ( 1917). Carricrt, S.: Can.d ia n Journal of PllysiololY . nd 'Pllarmacolo&y

47: ]99 ( ]969). Connolly, M.E. CI .1.: PJoaresI in Cardiovascular Disra5n 19: 203

(976). Gavru.l. C111.: Brililh Journal of Clinical PilannacolosY 7: 129

(1919). Ibsen, H. Ind ~..()br;n, P.:OiIDc:a1 Science 44: 129 (1919). ~encn, EoB.: AcU. MedieJ. ScandinavieJ. 6362: 15 ( 1979). Rapclli. A. et 11.: Experimetltalllld Oinkal Resnrc1l6: 665 (1980). Wilkinson, R. el.l. : British Journa] ofOinical Pharmacolosy 19:

51 (1980). ach. P.Y. CI "I.: POSl&f1duaIC Medical Journal 47: ll4s (1977).

partially antagonised' the effect of salbutamol on IRI with a maximum increase of 7.2 ± 3.2 mUt ml. Indomethacin, a non-steroidal anti-inflamma­tory agent and an inhibitor of prostaglandin syn­thesis, induced a significant shortening in the IRI response to salbutamol. The combination of in­domethacin and atenolol totally inhibited the re­sponse of IRI to salbutamol (fig. 2).

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