The central and peripheral hemodynamics of celiprolol

The cardiovascular effects of celiprolol in healthy subjects and in those with cardiovascular diseaee and hypertension are reviewed. Unlike classic &blockers, celiprolol does not depress cardiac contractility at rest while interfering to a lesser extent with cardiac function during exercise. Furthermore, celiprolol causes systemic vasodllatation, which, in hypertension, is mainly responsible for the blood pressure-reducing effects of the drug. Vasodilatation results from the reduction in vascular resistance of skeletal muscle tissues, but celtprolol also produces dilatation of vascular areas such as the kidney. This prevents a reduction in renal blood flow and consequently the salt and water retention associated with impaired perfusion. It is possible that such hemodynamic changes are dependent not on celiprolol’s selective @,-receptor-blocking properties but on certain additional properties. (AM HEART J lg88;118:1405.)

Giuseppe Mancia, MD Milan, Italy

In most patients with essential hypertension, the cardiac output (CO) is unusual and the elevation in blood pressure (BP) is explained by an increase in total peripheral resistance (TPR).’ Therefore the ideal hemodynamic effect of an antihypertensive agent should be to induce systemic vasodilatation while leaving both cardiac function and outflow un- impaired. Regrettably, this is not the case with many commonly used antihypertensive drugs. Indeed, certain antihypertensive agents, for exam- ple, p-blockers, often have opposite cardiovascular effects.2 This was shown in a study of the systemic hemodynamic parameters of 10 patients with essen- tial hypertension treated with atenolol for between 1 and 5 years (Fig. 1).3 In comparison with pretreat- ment values, atenolol reduced both the resting and exercise BP. However, the reduction in BP could be accounted for only by a decrease in CO, while the elevations in TPR, so typical of essential hyperten- sion, remained unaffected.”

In contrast, celiprolol combines cardioselective (PJ P-blockade with P,-partial agonist activity4 and possibly a mild a,-receptor-blocking influence and a nonadrenergic cardiostimulatory and vasodilating action5 These properties provide celiprolol with a

From the Cattedra di Semeiotica Medica e Istitudo di Clinica Medica, Generale e Terapia Medica, Universita di Milano, Centro di Fisiologia Clinica e Ipertensione.

Reprint requests: G. Mancia, MD, Cattedra di Semeiotica Medica e

Istitudo di Clinica Medica, Generale e Terapia Medica, Universita di Milano, Centro di Fisiologia Clinica e Ipertensione, Ospedale Maggiore, 20122 Milano, Italy.

multifaceted range of effects and a cardiovascular profile that differs from the traditional @-blockers.

This article examines whether such multifaceted properties are likely to affect celiprolol’s clinical use and views the published evidence on its hemody- namic effects among normal and hypertensive sub- jects.

CARDIAC FUNCTION AND TPR IN NORMOTENSIVE SUBJECTS WITH AND WITHOUT CORONARY DISEASE

An investigation of the effects of celiprolol on the systemic hemodynamics was initially undertaken in six healthy volunteers.” The CO was measured by thermodilution, BP was recorded intraarterially, and TPR was calculated from the mean BP and cardiac index values. At rest, there was a negligible effect on the normal BP by intravenous injections of either celiprolol or propranolol. Although proprano- 101 reduced CO and increased TPR, the converse was true of celiprolol, which increased CO and decreased TPR. Furthermore, the increased depressor influ- ence of propranolol on CO during the second exer- cise stage was less evident with celiprolol, which also caused less interference with the systemic vasodila- tation (Fig. 2).

Similar observations have been reported in patients with ischemic heart disease or reduced cardiac function as a result of myocardial infarction or the administration of cardiodepressant agents.7-11 The effects of two incremental intravenous doses of celiprolol on the hemodynamic changes from the baseline resting values of normotensive subjects with varying degrees of coronary artery stenosis

1405

1406 Mancia November lW38

American Heart Journal

CI (1 mine1 meP) 1x1

TPHI (dyn. E CIII-~ m-2)

5b0

c

5oQ lob0 VO2 (ml mine1 me2 )

IfFt (beats min) HR Weats min) x

V02 (ml min-l m-l)

Fig. 1. Hemodynamic effects of atenolol monotherapy in 10 patients with essential hypertension studied before and after 1 and 5 years of treatment (all data are mean f SE). CZ, cardiac index; MAP, mean arterial pressure; TPRZ, total peripheral resistance index; SZ, stroke volume; HR, heart rate). (Reproduced with permission from Lund-Johansen J. Hemodynamic consequences of long-term beta-blocker therapy: a 5-year follow-up study with atenolol. J Cardiovasc Pharmacol 1979;1:487-95.)

were compared against intravenous propranolol (Fig. 3).11 The increase in the TPR noted after propranolol was less evident or absent after celipro- 101. Similarly, propranolol reduced CO and cardiac contractility (measured by the rate of change of intraventricular pressure [dP/dt] and maximum shortening velocity in the absence of load [V,,,], respectively), but there was no change or an increase in these values when celiprolol was used. Although propranolol reduced the exercise-induced increase in CO and increased the left ventricular filling pressure of patients with coronary artery disease, celiprolol caused a smaller depression in the cardiac function of the stressed heart, with little alteration in cardiac performance compared with control sub- jects (Fig. 4).7,* It could be concluded that for normotensive subjects with normal or depressed cardiac function, celiprolol does not adversely affect resting CO or cardiac contractility, nor does it cause the immediate vasoconstriction so common with propranolol therapy. Such favorable features are sustained during exercise, which under celiprolol can be performed without the adverse constraints on CO and vasodilatation normally associated with drugs that act exclusively through /3-adrenoceptor blockade.

CARDIAC FUNCTION AND TPR IN HYPERTENSIVE

SUBJECTS

Although less conclusive, the evidence suggests that the administration of celiprolol to hypertensive patients reduces BP with little change in CO and a systemic vasodilatation. A double-blind, random- ized, crossover study in 20 patients with mild to moderate hypertension compared the effects of oral celiprolol, 200 or 400 mg daily over 6 weeks, with metoprolol, 100 or 200 mg (Fig. 5).12 The BP was measured by automatic sphygmomanometry, with CO determined from the echocardiography before and after each treatment period. Both celiprolol and metoprolol reduced the mean arterial pressure. Al- though metoprolol reduced both the heart rate and CO, neither were affected by celiprolol. Thus only celiprolol reduced the TPR and not metoprolol.

Since celiprolol’s antihypertensive effect is not accompanied by reductions in the CO, we can con- clude that this results from reduction in TPR. This is supported by a study involving patients with essential hypertension, whose BPS were measured intra-arterially over 24 hours: with CO dnterminecl

by radionuclide angiography.13 After the administra- tion of 200 to 600 mg celiprolol, systolic and diastolic BPS were reduced throughout the 24-hour period,

votw 11%

Number 5, Part 2 Hemodynamic effects of celiprolol 1407

co Vmin

2.5

2.0

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ij 0.0

I

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- 2.0

-2.5

Celiprolol

r 1 15 mg iv

Celiprolol

15 mg iv

Ropr5nolol

-250 + At rest 40% working capacity 80% working capacity

Fig. 2. The hemodynamic changes induced by intravenous celiprolol and propranolol in six healthy volunteers (all data are mean change, from at rest predrug values, and at 40% and 80% of exercise capacity). (Reproduced with permission from Bonelli J, Magometchwigg D, Hitzenberger C, et al. Naimodynamische Charakterisierung eines neuen P-Rezeptorenblockers: celiprolol (ST1369). In Ruhe und unter Ergsmeterbelastun verglichen mit propranolol (Inderal). Wien Klin Wochenschr 1978;90:350- 7.1

with hypotension recorded both at rest and during First, the CO was estimated indirectly from the exercise. The reduction was due to vasodilatation difference between the left ventricular systolic and because the resting ejection fraction was not altered diastolic volumes; second, the vasodilatation was by celiprolol. Indeed, during exercise the ejection inferred from the alterations in the TPR, that is, fraction was greater after administration of this from a derived rather than a direct index of arterio- drug than in the predrug condition. lar vasomotor tone.

SKELETALMUSCLEVASCULARBED

With such studies we might have two possible reservations about celiprolol’s hemodynamic effects.

Fortunately, several studies of essential hyperten- sive subjects have provided us with direct evidence that celiprolol’s vasodilating effects allow an increase in the skeletal muscle blood flow despite

1408 Man&

Maximum Percent Change from Baseline

5o r n celiprololO.07 mg/kg, i.v. k cellprololO.14 mg/kg, i.v. 401 1:

proprenololO.07 mg/kg, i.v.

MBP PAW dPldt Vmax (dev.)

TPR

Fig. 3. The hemodynamic response to 0.07 and 0.14 mg/kg of intravenous celiprolol and 0.07 mg/kg of intravenous propranolol in six patients undergoing diagnostic cardiac catheterization. The data are average maximal changes from predrug baseline values. Drugs were infused at a rate of 1 mg/min. In each group two patients had no coronary or left ventricular involvement, the remainder had various degrees of coronary obstruction, and a few had additional left ventricular hypertrophy or segmental left ventricular hypokinesis. HR, heart rate; MBP, mean blood pressure; PAW, pulmonary artery wedge pressure; CO, cardiac output; SV, stroke volume; dP/dt, rate of change of intraventricular pressure; V,,,,,, maximum shortening velocity in the absence of load. (Reproduced with permission from Gensini G, Dator C, Esente P, et al. Comparison of the acute hemodynamic effects of intravenous celiprolol and propranolol in patients with suspected coronary disease. J Cardiovasc Pharmacol 1986;8[suppl 4]:S83-S85.)

LV filling pressure h

Fig. 4. An idealized relationship between cardiac output and left ventricular (LV) filling pressure at rest and during exercise with celiproiol and propranolol compared with control studies. (Prepared from data provided by Ehringer et a1.15 and reproduced with permission from Taylor SH. Beta-blocking drugs and myocardial function. J Cardiovasc Pharmacol 1986;8[suppl 4]:S75-S82, and 311Ke B, Verm Yp, Frais MA, et al. Differential actions on atenolol and celiprolol on cardiac performance in ischemic heart disease. J Cardiovasc Pharmacol 1986;8[suppl 4]:S138-S44.)

F C e M

Fig. 5. The hemodynamic effects (mean + SE) of 6 weeks treatment with celiprolol (C) and metoprolol (M) compared with 2 weeks’ of placebo (P, and Pz) in 20 patients with essential hypertension (*p < 0.05 between drug and placebo). (Reproduced with permission frnm

Trimarco B, Lembo G, De Luca N, et al. Effects of celiprolol on systemic and forearm circulation in hyper- tensive patients: a double-blind crossover study versus metoprolol. J Cardiovasc Pharmacol [in press].)

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ml/mm/lOOg FBF

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‘to-

w-

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FVR -*-

Fig. 6. The effects of 5 to 7 days of treatment with celiprolol in six patients and 6 to 10 days of treatment with nadolol in nine patients, all with essential hyperten- sion. Data refers to baseline values shown as mean +- SE. MAP, mean arterial pressure; HR, heart rate: FBF, fore- arm blood flow; FVR, forearm vascular resistance; *, statistically significant difference (p < 0.05) between no drug and drug phases; NS, not significant. (Reproduced with permission from Mancia G, Grassi G, Parati G, et al. Effects of ceiiprolol in reflex control of the cardiovascular system in essential hypertension. J Cardiovasc Pharmacol 1986;8[suppl 4]:S67-S74.)

BP reductions.12s 14, I5 In a study involving six essen- tial hypertensive patients, BP was measured intra- arterially, heart rate was taken from the ECG, and forearm blood flow (i.e., a flow that extensively perfuses skeletal muscle tissues) was assessed by venous occlusion plethysmography, with the fore- arm vascular resistance estimated from the ratio between mean arterial pressure and blood flow values.14v l6 Compared with control values, 5 to 7 days’ administration of nadolol (80 to 240 mg once daily) resulted in marked bradycardia and reduced BP and forearm blood flow, but caused no signifi- cant change in forearm vascular resistance (Fig. 6). In contrast, a similar period (5 to 7 days) of celipro- lol(400 mg once daily) administration produced less bradycardia, the decreased BP was accompanied by an increase in forearm blood flow rates, and there was a marked reduction in forearm vascular resis- tance (Fig. 6). Similar observations also have been

'!i'i'b'i'i'j'-1' d CVP mmHp

Fig. 7. The effects of increased and decreased central venous pressures (CVP) induced by passive leg raising or 3 degrees of lower body negative pressure before and after administration of celiprolol. (These are mean + SE from the data on the six subjects from Fig. 6.) Measurements were made after 5 minutes of the leg raising and the lower body pressure negative maneuvers. MAP, mean arterial pressure; HR, heart rate; FBF, forearm blood flow; FVR, forearm vascular resistance; *, p < 0.05 and **, p < 0.01 statistically significant differences between no drug and drug phases. (Reproduced with permission from Mancia G, Grassi G, Parati G, et al. Effects of celiprolol in reflex control of the cardiovascular system in essential hyperten- sion. J Cardiovasc Pharmacol 1986;8[suppl 4]:S67-S74.)

reported in calf muscle blood flow and vascular resistance.15 Furthermore, the reduction in the fore- arm vascular resistance with celiprolol is not limited solely to baseline values, but can be found over a wide range of neurally mediated variations in fore- arm vasomotor tone. This has been shown through celiprolol’s effect on: (1.) the reduction in forearm vascular resistance reflexly induced by the increase in central venous pressure and the stimulation of cardiopulmonary receptors produced by passive leg raising, and (2) the rise in forearm vascular resis- tance reflexly induced by the decrease in central venous pressure and the deactivation of cardiopul- monary receptors produced by progressively greater degrees of lower body negative pressure.17

In both instances, the relative magnitude in the resistance changes above and below the baseline values were similar before and after the administra- tion of celiprolol, indicating that neural control of

1410 Man& November 1988

American Heart Journal

ml/min

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Fig. 8. The mean ( f SE) effects of placebo and 400 mg of celiprolol daily for 1 month on the renal hemodynamics of nine patients with essential hypertension in a randomized, double-blind, crossover study. MBP, mean blood pressure; RPF, renal plasma flow measured by para-aminohippu- rate clearance; RVR, renal vascular resistance; GFR, glo- merular filtration rate measured by creatinine clearance; P Aldo, plasma aldosterone level; PRA, plasma renin activity. (Reproduced with permission from Lucarini AR, and Salvetti A. Systemic and renal hemodynamic effects of celiprolol in essential hypertensive. Am J Cardiol 1988;61:45C-48C.)

skeletal muscle circulation remains unaffected by the drug. However, after celiprolol all resistance values were reduced, which implies a change in vasomotor tone toward persistent vasodilatation (Fig. 7).

OTHER REGIONAL VASCULAR BEDS

Celiprolol’s ability to increase forearm and calf muscle vasodilatation is important because, with f p\u Pyrontinnc thncn rIictr;ntr rnffnnt CL- h-b---: I .) _A-_1L . ..“CIIYYV IbLIb-cU tiLIL UC2 lavlor of

the circulation in all skeletal muscles,17 thus accounting for most TPR.

However, if vasodilatation is limited only to skel- etal muscle, then the resultant hypotension might

L-J __-- -- 1 4

Fig. 9. The change in plasma norepinephrine levels induced by passive leg raising or three progressive degrees of lower body negative pressure before and after celiprolol. NA, norepinephrine; B, baseline values; LR, passive leg raising; 1st LBNP, first-degree lower body negative pres- sure, 15.7.k 0.7 mm Hg before and 16.1 f 0.4 mm Hg after celiprolol; 2nd LBNP, second-degree lower body negative pressure, 26.1 f 0.5 mm Hg before and 25.7 of: 0.5 mm Hg after celiprolol; 3rd LBNP, third-degree lower body negative pressure, 38.1 k 0.7 mm Hg before and 38.8 f 0.8 mm Hg after celiprolol. (Reproduced with permission from Mancia G, Grassi G, Carati G, et al. Effects of celiprolol in reflex control of the cardiovascular system in essential hypertension. J Cardiovasc Pharmacol 1986;8[suppl 4]:S67-S94.)

lead to a reduction in the blood flow and conse- quently in the perfusion of the vital organs. To date there is insufficient data about celiprolol’s effects on the coronary, cerebral, and splanchnic circulations. On the other hand, its administration is not associ- ated with cutaneous vasodilatation or increased skin blood flow.15 More important, observations in patients with essential hypertension indicate that the decrease in BP that results from 1 month of celiprolol treatment does not adversely affect the renal blood flow; this is because of the precisely balanced dilatation of the renal resistance vessels and the reduction in renal perfusion pressure (Fig. 8).

Thus the relaxing influence of celiprolol on vascu- lar smooth muscle is not limited to skeletal muscles, but the viscera are also involved. Celiprolol pre- serves the kidney’s blood flow and affords protection against sodium and water retention during long- term administration. This has been supported by a lack of any significant rise in plasma renin activity

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Number 5, Part 2 Hemodynamic effects of celiprolol 1411

or plasma aldosterone levels while receiving a 30-day celiprolol regimen, which demonstrates that the drug does not lead to conditions favoring positive sodium balance (Fig. 9).

CONCLUSIONS

We still need to ascertain which of celiprolol’s additional properties are responsible for the differ- ence in cardiovascular effects in comparison with classic &blockers. This is the case for both the cardiostimulating and the vasodilating effects of the drug. However, there is some evidence that the induced vasodilatation is not mediated exclusively through P,-adrenergic stimulation because of its occurrence also in organs such as the kidney in which &adrenergic receptors are rare.” Renal vaso- dilatation is possibly triggered by autoregulation, while it is unlikely that postsynaptic a,-receptor blockade plays any significant part in celiprolol’s vasodilating activityzO because: (1) no vasodilatation is seen in the skin, an area in which a-receptor regulation has a prominent effect on blood flow, and (2) stimulation of the a-adrenergic receptors through increased neural drive produces similar vasoconstrictive effects both before and during celi- pro101 administration (Fig. 7).

Furthermore, the changes in plasma norepineph- rine levels in response to increased or reduced neural drive are also similar both before and during celipro- 101 therapy (Fig. 9). Therefore it is unlikely that celiprolol induces blockade of the presynaptic (Ye- adrenergic receptors or impairs their ability to mod- erate norepinephrine release in response to excita- tion of the sympathetic nerve terminals.21 Thus the mechanisms underlying the favorable hemodynamic effects of celiprolol still await clarification.

REFERENCES

1. Conway J. Nemodynamic aspects of essential hypertension in humans. Physiol Rev 1984;64:617-60.

L. Lund-Johansen P. The hemodynamics of’ essential hyperten sion. In: Robertson JIS, ed. Handbook of hypertension, vol 1. Clinical aspects of essential hypertension. Amsterdam: Else- vier Science Publishers BV, 1983151-73.

3. Lund-Johansen P. Hemodynamic consequences of long-term beta-blocker therapy: a 5-year follow-up study with atenolol. J Cardiovasc Pharmacol 1979;1:487-95.

4. Opie LH. The qualities of an ideal beta-blocker. Comparison of existing agents with a new cardioselective hydrophilic

vasodilatory beta-receptor agonist, celiprolol. Am J Cardiol 1988;61:8C-13C.

5. Pruss TP, Khandwala A, Wolf PS, et al. Celiprolol: a new beta-adrenoceptor antagonist with novel ancillary properties. J Cardiovasc Pharmacol 1987;8(suppl 4):S29-S32.

6. Bonelli J, Magometchwigg D, Hitzenberger C, et al. Haimo- dynamische Charakterisierung eines neuen /%Rezeptoren- blockers: celiprolol (ST1369). In Ruhe und unter Ergsmeter- belastun verglichen mit propranolol (Inderal). Wien Klin Wochenschr 1978;90:350-7.

7. Taylor SH. Beta-blocking drugs and myocardial function. J Cardiovasc Pharmacol 1986;8(suppl 4):S75-S82.

8. Silke B, Verm SP, Frais MA, et al. Differential actions of atenolol and celiprolol on cardiac performance in ischemic heart disease. J Cardiovasc Pharmacol 1986;8(suppl4):S138- s44.

9. Donaldson R, Williams LA, Lee EH. Acute hemodynamic effect of celiprolol. Am J Cardiol (in press).

10. Hitzenberner G. The cardiovascular effects of celinrolol in healthy vohrnteers and patients with coronary heart disease. Br J Clin Pratt 1985;39(suppl 40):46-51.

11. Gensini G. Dator C. Esente P. et al. Comnarison of the acute hemodynamic effects of intravenous celiprolol and proprano- 101 in patients with suspected coronary disease. J Cardiovasc Pharmacol 1986;8(suppl 4):S83-S85.

12. Trimarco B, Lembo G, De Luca N, et al. Effects of celiprolol on systemic and forearm circulation in hypertensive patients: a double-blind crossover study versus metoprolol. J Cardio- vast Pharmacol (in press).

13. Bridgen G, Haber M, Carnana MP, et al. Celiprolol in hypertension: ambulatory blood pressure profiles and left ventricular function. In: Proceedings of the Third European Meeting on Hypertension, Milan, 1987:59.

14. Man&a G, Grassi G, Parati G, et al. Effects of celiprolol in reflex control of the cardiovascular system in essential hyper- tension. J Cardiovasc Pharmacol 1986;8(suppl 4):S67-S74.

15. Ehringer H, Konecny U, Rasser E, et al. The effect of celiprolol on peripheral circulation in healthy volunteers. Br J Clin Pratt 1985;39(suppl 40):91-g.

16. Parati G, Pomidossi G, Grassi G, et al. Mechanisms of antihypertensive action of beta-adrenergic blocking drugs: evidence against potentiation of baroreflexes. Eur Heart J 1983;4(suppl D):19-25.

17. Mark AL, Mancia G. Cardiopulmonary receptors in humans. In: Shenherd JT. Abboud FM. eds. Handbook of nhvsioloav. section 2. The cardiovascular system IV. Bethesda: American Physiological Society, 1983;755-93.

18. Lucarini AR, Salvetti A. Systemic and renal hemodynamic effects of celiprolol in essential hypertensives. Am J Cardiol 1988;61:45C-48C.

19. Fitzgerald JT. Beta-adrenoceptor antagonists. In: Van Zwiet- en PA, ed. Handbook of hypertension. ~013. Pharmacology of antihypertensive drugs. Amsterdam: Elsevier Science Pub- lishers BV. 1984,249-306.

20. Darey MJ, Alabaster VA. The functional roles of post- junctional alpha, and alpha,-adrenoceptor subtypes in the modulation of vascular smooth muscle. In: Refsum H, Mjos OD, eds. Alpha-adrenoceptor blockers in cardiovascular dis- ease. Edinburgh: Churchill-Livingstone, 1985:19-29.

21. Van Zwieten PA. Interaction between alpha- and beta adrenoceptor mediated cardiovascular effects. J Cardiovasc Pharmacol 1986;8(suppl 4):S21-8.