effect of celiprolol on large and small arteries of the forearm circulation in hypertensive patients

Cardiovascular Drugs and Therapy 4: 745-750, 1990 (c~ Kluwer Academic Publishers, Boston. Printed in U.S.A.

Effect of Celiprolol on Large and Small Arteries of the Forearm Circulation in Hypertensive Patients

Oscar Roman, Nelson Meza, Carmen Klenner Department of Internal Medicine, Universi(v of Chile, Paula Jaraquemada Hospital, Santiago, Chile

Summary. Celiprolol, a new highly cardioselective beta blocker, also has direct vasodilating properties. Since the noninvasive echo Doppler technique applied to the forearm circulation (brachial artery) allows the differentiation of arteriolar vasodilation (revealed by the increasing arterial blood flow velocity) from vasodilation of large arteries (shown by an increase in arterial diameter), it seems impor- tant to study the site of celiprolol's vasodilating effect. Thirty-five hypertensive patients, (21 male, 14 female; mean age, 59 - 11, range 42-79 years) were treated with increasing doses of celiprolol, 200 and 400 mg, over 15 days. The duplex echo Doppler technique (Aloka 7.5 M Hz probe) was used before and during each celiprolol dose period. Statistical analysis was performed by Student's paired t test. It was observed that celiprolol significantly increases the braehial artery diameter in a dose-dependent manner, and also increases the blood flow velocity (not being direct dose-related). Since the increase in diameter was clear with a higher dose, a dose- dependent increase in blood volume, a decrease in peripheral resistance, and an increase in compliance followed. Since the higher dose of eeliprolol did not further reduce blood pressure (BP) in comparison to the Ibwer dose, and a dose-dependent increase in arterial diameter and compliance occurred and a vasodilating effect of celiprolol on arterial wall ensued that was not related to BP.

In conclusion, in the doses used, celiprolol dilates both arterioles and large arteries, but the mechanism of action needs to be clarified.

Key Words. eeliprolol, vasodilation, beta-blockade, forearm large arteries

T h e hemodynamic effects of beta blockers and other anti-hypertensive drugs have been extensively studied by invasive methods involving the heart and great vessels [1-3]. The advent of noninvasive techniques such as echocardiogn'aphy and Doppler have enabled safe, accurate, and reproducible measurements of the hemodynamics of the heart, aorta, and pulmonary arteries [4-6]. Recently, Safar et al. described an origi- nal noninvasive method for the simultaneous study of peripheral large and small arteries [7,8].

Beta-blocker agents differ strikingly in their action on the arterial tree [8,9]. Propanolol used chronically does not normalize the elevated peripheral resistance in hypertensive subjects, but reduces the cardiac out-

put [1,3,10]. However, beta blockers with intrinsic sympathomimetic activity (ISA) tend to reduce arterial peripheral resistance and do not change the cardiac output (11,12). Celiprolol, a new cardioselective beta blocker [13], offers an advantage over similar drugs (pindolol, acebutolol) due to its direct vasodilating vascular properties, as has been shown by experimental and pharmacodynamic studies [1:3-15]. This direct vasodilating property in humans could be gn'eater than that caused by other beta blockers with selective beta., agonism [16]. In experimental and human studies, we prefer to use selective beta., agonism to further differentiate fi'om ISA drugs. Maarek et al. [17] have shown that pindolol (a beta blocker with selective beta._, agonism) could dilate large arteries as well as arterioles. Hence, it may be postulated that in hypertensive subjects celiprolol could dilate not only small arteries or arterioles, but also large arteries, such as the brachial, carotid, or femoral arteries [16].

In order to examine this hypothesis further, we decided to explore the peripheral hemodynamic action of celiprolol on the arterial tree using the echo Doppler noninvasive technique applied to the brachial artery in a gToup of chronic hypertensive patients.

Materials and Methods

Thirty-five outpatients (21 male and 14 female) with mild to moderate essential hypertension were studied before and after therapy with celiprolol. The age range was 42-79 years (mean, 59 +- 11 years). Admis- sion criteria included sustained systemic hypertension, on three fortnightly diastolic blood pressure (BP) readings (supine), of > 90 mmHg and < 130 mmHg. Patients had no sig~s, symptoms, or history of heart failure, coronary insufficiency, renal failure, heart block, unstable diabetes mellitus, or severe chronic

Address for correspondence and reprint requests: Oscar Roman, M.D., Department of Internal Medicine, University of Chile, Paula daraquemada Hospital, Santiago, Chile.

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746 Roma~, Meza attd Klenner

Table I. Effect o/ celiprolol on jbrearm circulatio~ in 35 h!lpertet~sive patients

Parameters

Placebo Celiprolol Celiprolol baseline 200 mg 4(10 mg

• SE X • SE X • SE

Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (beat/rain) Brachial artery diameter (cm) Brachial artery blood velocity (cm/seg) Bracbial aVtery blood flow Forearm vascular resist. (m/mmHg/s) Forearm vase. compl. (ml/mmHg • 10 ~)

180 • 3.4 106 • 1.7 80 • 1.4

0.430 • 0.008 32.7 • 1.1 288 • 12 29 • 1.3

510 • 0.029

160 _+ 3.1" 154 • 3.7 92 • 2.1" 88 • 1.9 77 _+ 1.4 78 • 1.5

0.460 • 0.008:' 0.480 • 0.009" 36.4 • 1.3" 37.4 • 1.3 361 • 17" 402 • 17"

20.5 • 1.0" 17.3 • 0.8 ~' 710 • 0.022" 830 • 0.043"

" p < 0.05 in comparison to previous values.

hepatic disease. Drugs that could interfere with celiprolol efficacy or that may cause untoward effects were excluded, such as calcium antagonists, beta blockers, ACE inhibitors, ant iarrhythmic agents, ni- t rates, vasodilators, or sympathomimetic drugs (c~- methyldopa, clonidine), etc.

All previous t r ea tments were discontinued for at least 3 weeks before the study, and all patients re- ceived a placebo during this washout phase. Then one tablet (200 rag) of celiprolol was administered once daily before breakfast for 2 weeks. I rrespect ive of the BP response at the end of this period, the once daily dose was increased to 400 mg over 2 weeks in order to s tudy a possible stepwise t rend of the BP response and the hemodynamic variables.

During the placebo phase and after 2 and 4 weeks of therapy, a noninvasive hemodynamic study on the forearm arterial circulation was performed using a two-dimensional pulsed-Doppler velocimeter (Aloka 725), which allows the measurement of the brachial a r te ry diameter and mean arterial blood flow velocity by electronic integTation of the instantaneous pulsed- Doppler velocity curve. Measurement of the diameter allows the estimation of the arterial lumen cross- sectional area using the formula A = ~D"/4. The brachial a r te ry blood flow was calculated as the product of the sectional area and the ar te ry ' s mean blood velocity

[7,81. All measurements of arterial diameter and velocity

were repeated three times in each patient, and average values were recorded as definite values. The vari- ability of these results was below 10% [18].

Forea rm circulation resistance was estimated by dividing the mean arterial pressure (diastolic pressure plus one third of the pulse pressure) by the brachial a r te ry blood flow and was expressed in mmHg/ml/s [17].

Forea rm arterial compliance was evaluated by ana- lyzing the brachial a r te ry blood velocity contour, since

blood velocity can be represented as the sum of two components: a constant velocity (equal to the diastolic velocity) and a phasic velocity, which is the part of the systolic velocity superimposed on the constant velocity. This phasic velocity represents the capacitance flow that distends the a r te ry during systole [8-17]. Hence, the systolic volume increment is equal to the integTal of the phasic velocity multiplied by the brachial a r te ry section. This systolic volume corresponds hemodynamically to the increase in pressure during systole, or the pulse pressure. The compliance can then be calculated as the ratio between the brachial systolic volume increment and the pulse pressure in ml /mmHg [ 16,17,19,20].

Statistical analysis was performed with Student 's t test for independent samples.

R e s u l t s

Effects on blood pressure and heart rate After the first 2 weeks of therapy with 200 mg of celiprolol, 25 of 35 patients reduced their BP to -< 90 mmHg. For the overall gYoup, BP dropped significantly from 181/106 m m H g to 160/92 m m H g on average (p < 0.001). Although the majori ty of patients attained normal or near-normal diastolic BP values with 200 nag of the drug, thereaf ter all of them l'e- ceived 400 mg according to protocol. With the 400-mg dose, the BP decreased even more, to 154/88 m m H g average, but the change was not significant (p < 0.06) (Table 1) in comparison to the lower initial dose.

The heart rate tended to decrease slightly with celiprolol, but mean values during therapy with 200 mg and 400 mg did not differ significantly fl'om each other nor from placebo baseline values.

Brachial artery diameter A significant increase in the diameter and cross- sectional area of the brachial a r te ry was observed

E[/'ect qf Celiprolol on Forearm Circulation 747

I PzOO|

Fig. 1. Effect qf celiprolol on brachicd artery diameter CA) ctnd blood flow velocity (B) in 3.5 hypertensive pctlienls.

f J~.r U l l b 14L~ r l ~ r l

Fig. 3. Effect q[celiprohfl (m fore<~rm i,~tscuhzr resishtnce CA) ~tnd compli(lnce (B) in 3.5 h//pertensi~,e pcttienls.

PI.,~CE80 CEL[PROLOL 200 I , IG PLACEBO CELIPROLOL 200 !'!C

BFV 35 cm/s 42 c,~,:/s BFV= 28 cm/s 39 cm/s

Fig. 2. EJ]ect qf celiprolol on brachicd ctrter!t blood flow eelocity (BFV). A. chcmge o.f BFV in ~t 69-.1e~ r-old.fem~de hqpertensiue pcttient, stctge II, WHO criterict. B: 6o-!leclr-old h!lperlensice merle, stctge I WHO criteri~t.

with the low close of celiprolol (p < 0.001) (Table 1 and Figure 1A). A further significant increase was also observed with the higher close (p < 0.001).

Blood flow velocity A concomitant increase fl'om 32 • 1.1 cm/s to 36 -+ 1.3 cm/s (p < 0.01) in the blood flow velocity was recorded with the low celiprolol dose. No fm'ther increase was observed with the higher dose (Figure 1B and 2).

Brachial artery blood ttow A stepwise dose-dependent increase in arterial blood flow was induced after celiprolol therapy. The differ-

ences between a high versus low close and between both closes versus baseline values were highly significant (p < 0.01 and p < 0.001, respectively).

Forearm vascular resistance Celiprolol causes a marked reduction in local vascular resistance that is close dependent and highly significant (p < 0.01) (Figure 3A and Table 1).

Forearm arterial compliance Forearm arterial compliance was significantly increased after celiprolol therapy in a dose-dependent manner (Table 1 and Figure 3B).

748 Ro,~a~t, Meza a~td Kle~o~er

Discussion

Our major finding was that chronic oral celiprolol therapy causes a significant vasodilation in forearm vessels in hypertensive patients. The increase in the arterial blood flow velocity suggests dilation of the global inner caliber of the arterioles that supply the forearm and hand circulation. As was pointed out by Safar et al. [7,8], vasodilation of arterioles induces an increase in the blood flow velocity of the brachial artery, provided that the arterial diameter does not change, or even decrease slightly.

If the reduction of BP had been caused by arteriolar vasodilation, the cross-sectional area changes (or diameter changes) of the brachial ar tery might be purely passive and thus be simply caused by an increase or decrease in the distending arterial pressure. In this case, the single mechanical change resulting would be a decrease in the brachial ar tery diameter. However, this was not the ease with celiprolol in our study, nor in other studies with the same [16] or other selective beta., agonists [17-21], since brachial ar tery diameter increased, or at least did not change, in all of these studies.

As with pindolol [17-21], ACE inhibitors, and calcium-entry blockers [22-24], the increase in diameter of a large ar tery may be caused via neurohumoral and pharmacologic intervention, which are able to change the arterial smooth muscle tone [8].

We have observed that the caliber of small and large arteries is simultaneously increased with celiprolol. Similar effects have been reported with beta blockers that have ISA properties [17] and with cap- topril [23] and nifedipine [25]. The fact that arterial diameter increased despite the reduction in BP inside the arterial lumen, which nmst passively contract the ar tery [8], demonstrated a direct vasodilating action of celiprolol on the ar tery 's smooth nmscle. The mechanism of this effect is still not clear, but it might be related to an intrinsic sympathomimetic action, like that of pindolol [17-21], or to a direct vasodilating effect. The second hypothesis is based on studies performed in vitro using human arteries, which have demonstrated that celiprolol produces a concentra- tion-dependent relaxation that is only partially an- tagonized or blocked by pre t rea tment with propranolol [13,14], an action that must be independent of the beta receptor.

Furthermore, Levenson et al. [26] reported that medroxalol, a drug that antagonizes beta:adrenerg-ic receptors in the heart but stimulates be ta : ad rene r - gic receptors in blood vessels, improves forearm arterial compliance. Since Trimarco [16] did not observe changes in arterial compliance in central hemodynamic

studies using celiprolol, as cardiac output did not change, it may be suggested that the arteriolar vasodilation induced by celiprolol was predominant in the muscular vascular bed, since a significant increase in brachial blood flow is associated with a lack of change in cardiac output.

The increase in forearm blood flow may be partially related to arteriolar vasodilation (an increase in blood flow velocity) and to brachial ar tery dilation (an increase in diameter). The beta-2 agonism may be re- sponsible for arteriolar dilatation and a decrease in peripheral resistance. However, since the presence of beta,, receptors was extensively recognized in large arteries, it must be hypothesized that celiprolol's vasodilating effect could be related to a direct action of the drug. Moreover, in our study we found that the higher dose of celiprolol did not reduce BP significantly, but it concomitantly increased arterial compliance. So the change in arterial compliance was independent of the BP change, suggesting a decrease in the braehial ar tery 's smooth muscle tone or an increase in the arterial wall's elasticity. In any event, a direct vasodilating action emerges, probably not related to ISA properties. The exact mechanism of this direct arterial vasodilation is unknown at present.

Trimarco [16] studied celiprolol's effect on peripheral hemodynamics and found no change in the brachial ar tery diameter with similar daily doses of the drug. Nevertheless, the blood flow velocity was increased, forearm blood flow rose significantly, perit)h- eral resistance fell, and arterial compliance did not increase significantly. In our study, the brachial artery diameter did increase with celiprolol, as did the arterial blood flow velocity. Although in Trimarco's study the brachial ar tery diameter did not change, this result must be interpreted cautiously, since when blood pressure falls the diameter should decrease. If the arterial diameter did not change, it means that a vasodilating action took place, as Safar recognized in another study with indapamide [27].

It would be necessary to perform other studies to add more information to these controversial findings in order to elucidate the mechanism of action of celiprolol on central and peripheral hemodynamic parameters.

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effect of celiprolol on large and small arteries of the forearm circulation in hypertensive patients

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