Comparison of Relative Inotropic and Chronotropic Effects of Propranolol, Practolol, and Sotalol

@I

EXPERIMENTAL APPROACHES

Comparison of Relative lnotropic and Chronotropic Effects of Propranolol, Practolol, a'nd Sotalol

*,**

Robert E. Goldstein, M.D., CliffordA. Hall, M.D., and Stephen E. Epstein, M.D.OV

Several studies comparing p receptor blocking agents have raised the possibility that practolol or sotalol may act more selectivety on S receptors affecting heart rate than on p receptors influencing contractility. To further evaluate this potentially important hypothesis, the relative effects of practolol, sotalol and propran0101 on heart rate and contractile force were measured in thoracotomized dogs. Animals receiving substantial ,8 receptor stimulation manifested a dose-related reduction in both heart rate and contractile force after treatment with all three drugs. Furthermore, dasages of each drug matched to produce equal decreases in heart rate also caused equal decrements in contractile force. In contrast, dogs devoid of B receptor stimulation due to prior administration of reserpine and adrenalectomy responded to practold with a dose-related increase in contractile force (maximum 22 percent) and in heart rate. Effective ,+blocking doses of propranolol (up to 0.64 mg/kg) caused neither stimulatory nor depressant effects in reserpinized-adrenalectomizedpreparations. Thus, practolol differs from propranolol in that it exerts a positive indropic influence, detectable when p stimulation is absent. Nevertheless, such an effect is inapparent if p stimulation is substantial, which is often true when ,8 blockade is used clinically. Neither practolol nor sotalol, as used therapeutically, appear to act on heart rate more selectively than propranolol.

ach of the many physiologic alterations resulting from stimulation of p-adrenergic receptors can be attenuated by the competitive p-receptor blocking agent, pr~pranolol.'.~ In contrast, the p-receptor blocking agent practolol ( ICI 50 172) preferentially . ~ ~ possibility of influences cardiac p r e c e p t ~ r s The even greater specificity has been introduced by the observation that practolol does not appear to depress contractile function in human subject^.^-^ Such findings suggest that practolol might block chiefly those P receptors concerned with the regulation of heart rate, while exerting less influence on P 'From the Cardiology Branch, National Heart and Lung Institute, Bethesda, Md. "Richard McCill and William Parker, technical assistants. Reprint requests: Dr. Goldstein, NHLI-Cardiology Branch, B&. 10 7B15,Bethesdo 20014

CHEST, VOL. 64, NO. 5, NOVEMBER, 1973

receptors concerned with contractility. Sotalol (MJ1999), another P receptor blocking agent, may also have a similar specificity for chronotropic B receptors.'O.ll Chronotropic specificity would have considerable clinical importance, since it is often therapeutically desirable to reduce sympathetic stimulation of heart rate without diminishing sympathetic effects on contractility. However, the relative effects of /%receptor blocking agents on P receptors influencing heart rate and contractility have not been quantitatively assessed. Moreover; studies consistent with a selective action of practolol or sotalol on chronotropic P receptors have generally used indirect techniques to assess contractile function. To achieve a more precise definition of the relative influence of p-blocking agents on P receptors in-

GOLDSTEI N, HALL, EPSTEl N fluencing heart rate and on p receptors affecting contractility, we simultaneously measured both heart rate and contractile force responses to serial increments of either propranolol, practolol or sotalol in animals in which the background level of p-receptor stimulation was high, as a result of a continuous infusion of isoproterenol. Additional studies of propranolol and practolol were performed in catecholamine-depleted animals to assess the relative action of these drugs in the absence of appreciable B-receptor stimulation.

Twenty-two mongrel dogs of both sexes weighing 20 to 28 kg were anesthetized with 30 m g h g pentobarbital sodium and ventilated with an oxygen-air mixture. A midline thoracotomy was performed, and a Walton-Brodie s h a h gauge arch was sewn ( b y transmural stitches) to the epicardial surface of the body of the right ventricle. The long axis of the gauge was oriented parallel to the interventricular septum. The feet of the arch were progressively separated until maximum systolic tension was achieved ( a t this point the portion of muscle between the feet of the arch was stretched approximately 50 percent beyond its resting length). Previous experiencelz-18 has shown that the contractile force measurements derived from the optimally stretched portion of muscle are relatively insensitive to changes in ventricular preload and afterload. Possible alterations in contractile performance due to changes in coronary perfusion pressurele-21 and to baroreceptor-initiated changes in circulating catecholamines were excluded by holding systemic arterial pressure constant with a blood-filled reservoir bottle attached to the femoral arteries. To eliminate neurally mediated alterations in myocardial performance, both vagus nerves were sectioned in the neck and both stellate ganglia excised. In this way, the heart was isolated from the influence of changes initiated by actions of the pblocking agents on peripheral vessels. Strain-gauge arch output, brachial arterial pressure, heart rate and the electrocardiogram were recorded continuously throughout the study. In addition, the strain gauge signal was electronically differentiated to yield a signal proportional to the rate of change of contractile force ( d F / d t ) . Arterial blood pH, hemoglobin saturation, arterial carbon dioxide tension ( Pcos ) and oxygen tension ( Poz) remained within physiologic limits (except for elevated (Po*) in all animals.

Table 1-Phyridogic Treatment Group

.No.

Isoproterenol-infused dogs propranolol 8 practolol 9 5 sotalol

Reserpinized-adrenalectomizeddogs 4 propranolol practolol 6

+

At the beginning of the study a constant isoproterenol infusion, 0.04 pg/kg/min, was begun via the left brachial vein. Once steady state values were attained, logarithmically increasing doses of either powdered dl-propranolol ( Ayerst Laboratories, Inc ) (eight dogs), practolol ( Ayerst Laboratories) (nine dogs), or sotalol ( Mead Johnson & Co. ) (five dogs), dissolved in saline solution were administered via the right brachial vein. S d c i e n t time was allotted between each dose for all parameters to attain stable values (defined as the absence of any detectable change for at least two minutes). To study the action of p-receptor blocking agents in animals with low levels of 8-receptor stimulation, logarithmically increasing doses of practolol were administered to five dogs previously given propranolol, 2.56 m g h g . For comparison, the effects of increasing the dosage of propranolo1 were measured in six animals previously given practolol (average dose, 3.3 mg/kg). To further evaluate the i d u e n c e of practolol and propranolol in the absence of p receptor stimulation, 13 dogs were pretreated with intravenously administered reserpine, 0.25 mg/kg daily, on each of the two days prior to study. Eleven of these animals were also subjected to bilateral adrenalectomy one hour before drug infusions were initiated; the remaining two were adrenalectomized one week before study. Acutely adrenalectomized animals were given 100 mg cortisol intravenously just prior to surgery. Chronically adrenalectomized animals received daily maintenance doses of 25 mg cortisone acetate and 5 mg desoxycorticosterone acetate. During the two to three hour study period, all adrenalectomized animals were given a continuous intravenous infusion of 50 mg percent cortisol in normal saline solution at a rate of 30 ml/hr. The study protocol for reserpinized-adrenalectomized animals was the same as the protocol for normal animals, except that anesthesia was induced with only 15 mg/kg pentobarbital sodium, and isoproterenol infusion and stellectomy were omitted. Also, the e5cacy of the reserpine pretreatment was tested by parahydroxyphenylethylamine (Tyramine) infusions. No reserpinized-adrenalectomized animal manifested an increase in either contractile force or heart rate in excess of 3.5 percent after 50 pg/kg parahydroxyphenylethylamine intravenously (in two normal dogs parahydroxyphenylethylamine, 50 pg/kg intravenously, produced an average increase of 111 percent in contractile force and 14 percent in heart rate ) . ~

-

RESULTS

Baseline Data In both isoproterenol-infused and reserpinized-

Observafionafor Each Treatment Group Prior to Administration of p Blockers *

Heart Rate,** Beats/Min

Peak Contractile Force, ** G

156 f 3 (14.4 f 1.2%) 155 f 4 (14.3 f 2.5%) 149 f 7 (11.7 f 2.4%)

225 36 (71 f 7%) 8%) 187 It 12 (67 141 f 16 (61 f 12%)

*

+

Mean Blood Pressure, mm Hg 105 f 6 101 5 100 f 2

*

110 f 9 115 f 5

*Average standard error. **For dogs receiving isoproterenol, values shown are steady-state measurements made during infusion; percentage rise produced by isoproterenol is in parentheses. For reserpinized-adrenalectomizeddogs, values are baseline measurements.

CHEST, VOL. 64, NO. 5, NOVEMBER, 1973

INOTROPIC AND CHRONOTROPIC EFFECTS OF PROPRANOLOL, PRACTOLOL AND SOTALOL

adrenalectomized categories, pretreatment mean values of heart rate, peak contractile force and blood pressure in animals given propranolol were all very close to corresponding pretreatment mean values determined in animals given practolol (Table 1 ). The smaller group of dogs given sotalol had slightly lower mean values for both heart rate and contractile force, but only the difference in contractile force between practolol and sotalol achieved statistical significance ( P < .05 ) . Since mean baseline values were generally quite similar, our use of percentage change ( t o minimize the influence of individual variability) did not introduce artifactual differences in behavior among the three treatment groups.

621

DRUG DOSAGE (mg/kg)

influence of p Blockers in the Presence of p Stimulation

Cumulative dose-response curves to propranolol, practolol and sotalol in isoproterenol-infused animals were calculated for peak contractile force ( Fig 1A) and for heart rate ( Fig 1B ) . All three p blocking agents produced a dose-related depression in both contractile force and heart rate. Similar changes were observed in peak dF/dT. The maximum attainable reduction in either contractile force or heart rate was generally much less with practolol, however, than with propranolol or sotalol. Since the doseresponse curves to propranolol and to practolol are not parallel, it is not possible to express the relative potency of these two drugs by a single ratio. Thus, four times as much practolol produced the same 25 percent reduction in contractile force as 0.01 mg/kg propranolol, but even eight times as much practolol did not duplicate the 50 percent reduction in contractile force observed after administration of 0.32 mg/kg propranolol. Heart rate responses to treatment with practolol similarly showed an inability to attain the maximum reduction reached with propranolol or sotalol treatment, resulting in a divergence of dose-response curves similar to that observed when measuring contractile force. Since a decrease in heart rate per se can depress contractile force, the data as depicted in Figure 1A do not allow comparison of the effects of each drug on contractility independent of possible negative inotropic influences of diminished heart rate. Thus, a p-blocker may appear to have an important depressant influence on contractility simply because it is more effective in reducing heart rate. Therefore, to discriminate between the potency of the p blockers on decreasing contractile state, independent of alterations accompanying a slower heart rate, a method of data analysis was devised that permitted comparison of contractile force reduction produced CHEST, VOL. 64, NO. 5, NOVEMBER, 1973

FIGURE1A ( upper) and 1 B ( lower). Average percentage al-

teration in peak contractile force (Fig 1 A ) and in heart rate (Fig 1B) when isoproterenol-infused dogs were given either propranolol (circles), practolol (triangles), or sotalol (squares) in logarithmically increasing cumulative dosage, as indicated on horizontal axis. Vertical lines denote standard errors. Practolol curves did not parallel curves obtained with either propranolol or sotalol.

by drug dosage causing equal degrees of heart rate reduction. The decrease in contractile force after each successive drug dose was plotted against the accompanying decrease in heart rate, thus generating a separate curve for each experiment. The experimental curves resulting from propranolo1 and practolol administration to isoproterenol-infused dogs are shown in Figure 2A; propranolol and sotalol are similarly compared in Figure 2B. A drug with a greater negative inotropic influence for any given reduction in heart rate would produce curves

GOLDSTEIN, HALL, EPSTEIN

0-0

Propranolol

+-o Proctolol

the three blocking agents (Table 2 ) . Linear interpolation was performed if experimental values spanned the arbitrarily chosen percentage categories. Animals in which sufficient heart rate reduction was never attained, even after very large drug dosages, were eliminated from the corresponding percentage categories. The average reduction in contractile force produced by either practolol or sotalol did not diEer significantly from that produced by propranolol. To achieve a more comprehensive statistical analysis of these same data, each experimental curve relating change in contractile force to change in heart rate was fitted to the parabolic equation, y = Ax B J;;- Figure 3 demonstrates that the parabolas corresponding to the average values of A and B for practolol and sotalol do not differ significantly from the mean parabola calculated for propranolol. An analysis of variance indicated that the experimental curves fit the empirically chosen equation very closely. Comparing variations between drugs and between animals: F = 3871270 = 1.44, P>.05 (not significant). The lack of significance of the F test implies that the differences in the mean curves shown in Figure 3 are readily explained by variability of individual animals. There is no evidence indicating that these differences are attributable to the differing physiologic properties of the three p blockers. Thus, analytic techniques encompassing all of the data points from each of the experiments indicate that neither practolol nor sotalol cause any less myocardial depression than propranolol when doses producing equal reduction in heart rate are compared.

+

FICUHE2A ( ril~per)and 2B ( lower). Separate graphs compare propranolol with practolol ( Fig 2 A ) and propranolol with sotalol ( Fig 2 B ) . These graphs show percentage change in peak contractile force (vertical a x i s ) against sin~nltaneously

observed percentage change in heart rate (horizontal axis ) . Lines (solid for propranolol, du~hedfor practolol or sotalol) connect values sequentially obtained during course of each experiment. Note that upward and rightward directions indicate increasingly negative values. Shaded bar denotes 15 percent reduction in heart rate chosen for statistical comparison of curves ( see text ) .

more inclined toward the vertical axis, while a drug ... with less negative inotropic activity would result in curves nearer the horizontal axis. Although considerable variability was observed in the effects of all three drugs, - there was no consistent tendency for propranolol to differ from either practolol or sotalol in the degree of contractile depression associated with any given reduction in heart rate. To further quantify this comparison, the reduction in contractile force associated with a 15, 20, and 25 percent fall in heart rate was calculated for each of

influence of p Blockers in the Absence of p Stimulation

The action of p blocking agents in the absence of p receptor stimulation was studied initially by ad-

ministering propranolol to five animals previously receiving large doses of practolol and by giving practolol to six animals previously receiving large doses of propranolol. As shown in Figure 4, propranolol given after treatment with practolol had little effect on contractile force in doses of less than 0.64 mg/kg. Heart rate was similarly unaffected under these circumstances. Larger doses of propranolol caused progressively more severe depression of both contractile force and heart rate. In marked contrast, however, administration of practolol after treatment with propranolol produced a progressive, dose-related increase in contractile force and (to a lesser extent) in heart rate. For example, the largest dose of practolol given after administration of propranolo1 (5.12 mg/kg) was associated with a mean rise in CHEST, VOL. 64, NO. 5, NOVEMBER, 1973

INOTROPIC AND CHRONOTROPIC EFFECTS OF PROPRANOLOL, PRACTOLOL AND SOTALOL

623

Table S S u m n r a r y of Changes in Contractile Force Decrease in Hrart Rate, %

Drug

Dogs, No.

15

propranolol practolol sotalol

8 6 5

20

propranolol practolol sotalol

8 3

propranolol practolol sotalol

6 1

25

Decrease in Contractile Force,

O/o

T-Ratio Relative to Propranolol

Statistical Significance

5

4

*Mean f standard error.

contractile force of 38 percent, but a mean heart rate increase of only eight beats per minute (8.4 percent ). The corresponding dose of propranolol given after practolol treatment reduced contractile force a mean of 33 percent and reduction in heart rate a mean of 16 beats per minute ( 12 percent ) . Here again, changes in contractile force incorporate the influence of changing heart rate as well as the influence of primary alterations in contractile state. To assess the influence of heart rate on contractile force in the context of this phase of the study, atrial pacing was performed in four of the

animals receiving first propranolol then practolol. Pacing at rates 10, 20, 30 and 40 beats per minute above the spontaneous rate produced an essentially linear increase in contractile force (correlation coefficient ranged 0.97-0.99).However, the contractile force increase averaged only 3.7 percent for every ten beat per minute heart rate increase. Therefore, the rise in heart rate would be expected to contribute in only a minor way, less than 10 percent, to the total maximum observed rise in contractile force after administration of practolol. The greatest increase in contractile force observed when pacing DRUG DOSAGE (mg/kg)

-.-...

Propronolol

6 - O Proclolol

-60

Sotolol

% A HEART RATE

FICUHE 3. Plot of reduction in peak contractile force against si~nultaneouslyobserved reduction in heart rate, as in Figure 2A, 2 B . Parabola corresponding to average perfomlance after propranolol (solid line) does not differ significantly from averaged parabola for practolol (dashed line) or for sotalol (dotted line) at any of points indicated. Vertical hrackets denote standard errors at each point of comparison.

CHEST, VOL. 64, NO. 5, NOVEMBER, 1973

FIGURE 4. Dose-related increase in peak contractile force when practolol was given to dogs previously receiving propranolol, 2.56 mg/kg (triungbs), contrasts with dose-related reduction in peak contractile force when propranolol was given to dogs previously receiving practolol (average dose 3.3 mg/kg) (circles). However, significant reduction in contractility was not observed in this context until propranolol dosage exceeded 0.64 mg/kg. Values shown are means, with vertical lines indicating standard error.

GOLDSTEIN, HALL, EPSTEIN

.01

+40

l

DRUG DOSAGE ~ m g l k g l .04 .I6 .64 2.56

'

l

'

l

'

~

10.24

'

~

'

~

DRUG DOSAGE (mg/kg)

Propronolol

6- d Proctolol

UPropronolol &--A Practolol

FIGURE5A and 5B. Average changes in peak contractile force (Fig 5A) and in heart rate (Fig 5B) when either propranolol (circles) or practolol (triungbs) was administered to reserpinizedadienalectomized dogs in dosage indicated on horizontal axis. Vertical lines indicate standard errors. Propranolol produced decrease in both contractile force and heart rate in doses greater than 0.64 mg/kg. Practolol, however, signi6cantly increased both contractile force and heart rate, even in very small doses.

increased heart rate 40 beats per minute was just 18 percent. Thus, it seems likely that the rise in contractile force produced by administration of practolol after treatment with propranolol was due to direct enhancement of contractile state, in addition to the positive inotropic actions of increased heart rate. To further clarify the influence of propranolol and practolol in the absence of p receptor stimulation, cumulative dose-response curves were measured for each drug in animals depleted of catecholamines by prior treatment with reserpine and adrenalectomy 4

t

0

1 &--A

1

~

t

l

t

~

r

~

Practolol alone

W Practolol after Propranolol (0.32 mg/k

DRUG DOSAGE (rng/kg)

FIGURE 6. Average peak contractile force responses to practolol in reserpinized-adrenalectonlized dogs (triungbs) and in reserpinized-adrenalectomized dogs also given propranolol, 0.32 mg/kg ( circles ) . Prior propranolol shifted practolol dosageresponse curve to right, but did not alter maximum. Vertical lines denote standard errors.

( Fig 5A, 5B ) . Treatment with propranolol again caused little change in either contractile force or heart rate in doses less than 0.64 mglkg, while larger doses reduced both contractile force and heart rate. In the reserpinized-adrenalectomized animals, practo101 exerted a significant positive inotropic influence even in very low doses, eg, 0.005 mg/kg. The sustained increase in contractile force was successively greater for each increment of practolol up to 0.16 mglkg, when it reached an average of 22 percent; larger doses had no further effect on contractile force. A dosage-related rise was similarly observed r which I l also showed a mean maximum inin ~dF/dt, crease of + 22 percent. Parallel changes of a smaller magnitude were observed for heart rate. The mechanism of the inotropic action of practolo1 was investigated by pretreating three reserpinized-adrenalectomized dogs with propranolol, 0.32 mg/kg, and then determining cumulative doseresponse curves to practolol. This dose of propranolo1 produced no alteration in either contractile force or in heart rate in any of the three dogs. As shown in Figure 6, pretreatment with propranolol resulted in a rightward shift of the practolol dose-response curve, although the maximum attainable rise in contractile force was not altered. Similar results were obtained with respect to practolol-induced rises in heart rate. Thus, these data suggest that propranolol acted as a competitive inhibitor of the positive inotropic and chronotropic effects of practolol in the reserpinized-adrenalectomized dog.

+

~

DISCU~SION In the intact animal, p receptor blocking agents may initiate a variety of changes affecting cardiac performance. Our experimental model was designed to minimize peripherally mediated effects on cardiac function in order to focus more precisely on direct CHEST, VOL. 64, NO. 5, NOVEMBER, 1973

INOTROPIC AND CHRONOTROPIC EFFECTS OF PROPRANOLOL, PRACTOLOL AND SOTALOL effects of the three p blocking agents on the contractile state of the myocardium. Furthermore, the important effects of changing heart rate on contractile function were equalized for the three drugs by comparing those values of contractile force associated with an equal reduction in heart rate. This approach has the added advantage of offering physiologic change (rather than arbitrary drug dosage) as the standard for comparison. For a given reduction in heart rate (often the primary goal when administering p blocking agents) this method seeks to define the price that must be paid in terms of associated reduction in contractility for each of the three P blocking agents. As might be anticipated from previous studies of propranol~l,~ p r a ~ t o l o l , ~ ~and ~ ~ - s~o' t a l 0 1 , ~our ~~~ data indicate that all three p blockers significantly depress myocardial contractile function when administered to unpaced animals with high levels of Preceptor stimulation. More importantly, when isoproterenol-infused dogs are given practolol, sotalol or propranolol, dosage of each drug causing the same reduction in heart rate also results in an equal decrement in contractility. Thus, our data suggest that an equivalent degree of negative inotropic influence accompanies a given negative chronotropic effect of p blockade, regardless of whether the p blocking agent used is practolol, sotalol or proprano101. These data tend to reject the hypothesis that any of the three drugs studied exerts a selective blocking effect on ,B receptors exclusively affecting heart rate. Beta receptor blocking agents often are used clinically to reduce cardiac rate in patients in whom adrenergic stimulation of the heart is considered relatively excessive. Myocardial depression in this context usually represents an unwanted side effect. Thus, identification of a P blocking agent directed specifically at receptors influencing heart rate would obviously be highly desirable. Our study indicates that neither practolol nor sotalol exhibit such specificity. It also suggests that a reduction in heart rate achieved clinically with practolol or sotalol is associated with the same degree of myocardial depression as an equal reduction in heart rate following administration of propranolol. In contrast to its performance in the isoproterenolinfused animal, practolol causes a modest but significant, dose-related, sustained increase in contractile force and heart rate in animals with minimal or no baseline cardiac adrenergic activity (produced either by prior reserpinization and adrenalectomy or by administration of propranolol ) . In these studies, the observed rise in contractile force incorporates both the positive inotropic influence of increased heart rate and primary positive inotropic action of

CHEST, VOL. 64, NO. 5, NOVEMBER, 1973

625

the drug itself. Results during atrial pacing, however, suggest that the increase in contractile force observed after treatment with practolol is far in excess of that seen with an isolated elevation of heart rate of the same magnitude, thus implying an associated primary positive inotropic action of practolol. The inference that practolol has primary positive inotropic activity in the reserpinized animal is further supported by the recent work of Fitzgerald et who demonstrated an increase in peak rate of rise of left ventricular pressure in reserpinized dogs following treatment with practolol, when heart rate was held constant by atrial pacing. In contrast, these investigators failed to document either a positive or a negative inotropic influence of sotalol when this drug was studied in similar reserpinized preparations. The mechanism responsible for the positive inotropic and chronotropic actions of practolol was elucidated further by studying animals with both catecholamine depletion and propranolol-induced /3 receptor blockade. Prior treatment with propranolol in reserpinized-adrenalectomized dogs shifted the practolol dose-response curves to the right, with no reduction in maximum attainable response. This rightward shift in the practolol dose-response relation produced by propranolol indicates that propranolol acts as a competitive inhibitor of these cardiac actions of practolol, a finding consistent with the hypothesis that practolol has stimulatory as well as inhibitory effects on the p receptor. Such dual actions on the p receptor have been attributed previously to practolol on the basis of practolol-induced cardioacceleration in reserpinized cats3 and rats.29 Syrnpathomimetic properties also have been observed in several other /3 blocking drugs, for example, a l p r e n ~ l o l , ~oxprenol01,~~ ~*~l or dichloroisoprot e r e n ~ l . ~ ~Sotalol ." has been shown to augment contractility under certain circumstance^,^^^^ although this action is believed to be unrelated to stimulation of the B, receptors.37 The syrnpathomimetic properties of practolol may explain the inability of this agent to attain the same degree of contractile and heart rate depression in the isoproterenol-infused animal as that reached with propranolol or sotalol. The distinct negative inotropic effects of propranolol observed in isolated muscle preparations utilizing relatively high concentrations of propranoare likely due to primary myocardial depressant actions of propranolol, which are not seen with either practolol or sotalol even when these latter drugs are given in doses much higher than that of p r o p r a n o l ~ l . ~ - ~ ~ ~ ~ ~ It is noteworthy, however, that propranolol was

GOLDSTEIN, HALL, EPSTEIN

devoid of either stimulatory or depressant effects on contractility or heart rate when administered to animals lacking baseline P receptor stimulation in doses less than 0.64 mglkg. Similar findings were noted by Brunner et aP2 and by Fitzgerald et a1.28 Thus, the actions of propranolol in the dosage range usually employed clinically are probably due solely to inhibition of p receptor stimulation rather than to a superimposed primary myocardial depressant action. The findings of this study may help resolve conflicting reports concerning the inotropic effects of practolol, and possibly other similar "competitive When given to pdualists" such as alpren~lol.~' stimulated animals practolol causes a depression in contractile force, in agreement with previously published data.22-" When administered to animals devoid of p stimulation, however, an enhancement of contractility is noted. Investigators reporting changes consistent with an absence of inotropic change after treatment with practolo17 were studying subjects who were at rest and may therefore have had very little cardiac sympathetic tone. Withdrawal of this small amount of sympathetic stimulation may have been cancelled by the intrinsic sympathomimetic properties of practolol. Thus, the interpretation of changes occumng after the administration of a p receptor blocking agent must always be contingent on the pre-existing level of p receptor stimulation. ACKNOWLEDGMENTS: We are grateful to Mr. Morton RaR, M.A., statistician, and to Mr. William C. Blackwelder M.A., statistician, Biometries Branch, National Heart and Lung Institute, for their help in formulating the statistical analyses used in this study. 1 Black JW, Crowther AF, Shanks RF, et al: New adrenergic beta receptor antagonist. Lancet 1:1080, 1964

2 Epstein SE, Braunwald E: Beta-adrenergic receptor blocking drugs. Mechanism of action and clinical application. N Engl J Med 275: 1106, 1175, 1966 3 Dunlop D, Shanks RG: Selective blockade of adrenoceptive beta receptors in the heart. Br J Pharmacol Chemother 32:201, 1968 4 Shanks RG: The properties of beta-adrenergic blocking agents. Ir J Med Sci 2:351, 1969 5 Barrett AM: The pharmacology of practolol. Postgrad Med J 47:7, 1971 6 Brick I, Hutchinson KJ, McDevitt DG, et al: Comparison of the effects of ICI 50172 and propranoiol on the cardiovascular responses to adrenalin, isoprenalin, and exercise. Br J Pharmacol34: 127, 1968 7 Gibson D, Sowton E: Effects of ICI 50172 in man during erect exercise. Br Med J 1:213, 1968 8 Finegan RE, Marlon AM, Harrison DC: Hemodynamic effects of practolol ( abstract ) . Circulation ( Suppl 3 ) 42:40, 1970 9 Banas JS, Gaash WH, Oboler AA, et al: Chronotropic adrenergic blockade without intrinsic myocardial depres-

sion (abstract ) . Circulation ( Suppl3 ) 42: 133, 1970 10 Brooks H, Banas J Jr, Meister S, et al: Sotalol-induced beta blockade in cardiac patients. Circulation 42:99, 1970 11 Levy JV, Richards V: Inotropic and chronotropic metabolic effects of three beta-adrenergic receptor blocking drugs on isolated rabbit left atria. J Pharmacol Exp Ther 150:361, 1965 12 Beiser GD, Epstein SE, Goldstein RE, et al: Comparison of the peak inotropic effects of a catecholamine and a digitalis glycoside in the intact canine heart. Circulation 42:805, 1970 13 Cotten M DeV: Circulatory changes affecting measurement of heart force in situ with strain gauge arches. Am J Physiol 174:365, 1953 14 Cotten M DeV, Bay E: Direct measurement of changes in cardiac contractile force: relationship of such measurements to stroke work, isometric pressure gradient, and other parameters of cardiac function. Am J Physiol 187: 122, 1956 15 Cotten M DeV, Maling HM: Relationships among stroke work, contractile force and fiber length during changes in ventricular'function. Am J Physiol 189:580,1957 16 Reeves TJ, Hefner LL: Isometric contraction and contractility in the intact mammalian ventricle. Am Heart J 64:525, 1962 17 Brewster WR, Osgood PF, Isaacs JP, et al: Hemodynamic effects of a pressor amine (methoxamine) with predominant vasoconstrictor activity. Circ Res 8:980, 1960 18 Walton RP: Basic identity of certain drug responses of the canine and human myocardium. Arch Int Pharmacodyn Ther 140:615, 1963 19 Arnold G, Kosche F, Miessner E, et al: The importance of perfusion pressure in the coronary arteries for the contractility and oxygen consumption of the heart. Pfluegers Arch 299: 339,1968 20 Opie LH: Coronary flow rate and perfusion pressure as determinants of mechanical function and oxidative metabolism of isolated perfused rat heart. J Physiol (Lon) 180:529, 1965 21 Salisbury PF: Coronary artery pressure and strength of right ventricular contraction. Circ Res 3:633, 1955 22 Bussman WD, Rauh M, Krayenbuehl HP: Coronary and hemodynamic effects of myocardio-selective beta-receptor blockade by ICI 50172 in the closed-chest dog. Am Heart J 79:347, 1970 23 Ross G, Jorgenson CR: Effects of a cardio-selective betaadrenergic blocking agent on the heart and coronary circulation. Cardiovasc Res 4: 148, 1970 24 Mitchell JH, Vastagh GF, Cohen LS: Inotropic and chronotropic responses to newer beta-adrenergic blocking agents ( abstract ) Circulation ( Suppl3 ) 42: 123, 1970 25 Blinks JR: Evaluation of the cardiac effects of several beta adrenergic blocking agents. Ann NY Acad Sci 139: 673, 1967 26 Levy JV, Richards V: Inotropic and chronotropic effects of a series of p-adrenergic blocking drugs: some stmctureactivity relationships. Proc Soc Exp Biol Med 122:373, 1966 27 Hoffman BS, Grupp G: The effects of sotalol and propranolol on contractile force and atrioventricular conduction time of the dog heart in situ. Chest 55:229, 1969 28 Fitzgerald JD, Wale JL, Austin M: The haemodynamic effects of ( + )-propranolol, dexpropranolol, oxprenolol, practolol and sotalol in anaesthetised dogs. Eur J Pharmacol 17: 123, 1972 29 Barrett AM, Carter J: Comparative chronotropic activity

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Changing Approach to Diiagnosis and Treatment Goodpasture's syndrome can be cited as a good example of new orientation in the clinical utilization of advanced knowledge and technique. Purposeful research and logically interpreted clinical observations during the past two decades have brought about not only clearer understanding of the pathogenic mechanism of this condition but also its more successful treatment. In typical cases the onset is signalized by symptoms and signs referable to the respiratory tract, although in rare instances renal manifestations may precede pulmonary disease. The latter may begin with bouts of nonproductive cough, likely to be followed by recurrent hemoptysis or subsequent massive pulmonary hemorrhage. Also, the patient may complain of progressive, sometimes distressing dyspnea. Too, low-grade fever, easy fatigability, loss of appetite and loss of weight, pronounced weakness and pallor may be noted. X-ray evidence of lung involvement may be present when the patient is &st seen or when he is observed during exacerbation of the disease. One may note unilateral, bilateral, diffuse or localized changes, such as nodular, linear, ill-defined mottled, veil-like, woolly or dense homogeneous shadows which are either perihilar, peripheral or limited to one lobe. There may be enlargement of hilar lymph nodes. The pulmonary changes are sometimes ephemeral. They may clear within few days or weeks without specific treatment. Increased interstitial reticular markings may be observed between hemorrhagic episodes. Simultaneous or subsequent renal involvement may be associated with darkbrown or reddish discoloration of the urine or with frank hematuria, oliguria or anuria. Laboratory findings establish the diagnosis of glomerulonephritis. In 1940, Chikamitsu (Folia Endocrin Jap 16:85, 1940) made significant contributions to the understanding of the pathogenesis of Goodpasture's syndrome. He produced glomerulonephritis in rabbits by injection of anti-rabbitlung serum and also, of anti-rabbit-kidney serum. Eisen et a1 (J Immunol 65:543, 1950) ascertained experimentally the antigenic similarities between pulmonary alveolar basement membrane and renal glomerular basement membrane. To Coons et al (J Exper Med 91: 1, 1950 and 102:49, 1955) belongs the credit for the method of chromatic visualization of antigen-antibody complexes with the aid of fluorescent material. In 1955, Parkin et a1 (Am J Med 18:220, 1955) proposed the assumption that hypersensitivity might have a major role in the combined

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occurrence of recurrent pulmonary hemorrhages and nephritis. Subsequently several clinical and research studies supported the possibility of anti-lung antibody production due to a certain type of pulmonary disease which, in turn, induces glomerulonephritis. Others hypothesized an opposite train of events, namely that severe inflammatory damage to renal glomeruli leads to liberation of antibodies which exert destructive influence upon pulmonary alveoli. A number of cases are on record in which pulmonary hemorrhage ceased following bilateral nephrectomy, the patient remaining symptom-free after renal transplantation. Some investigators assert that a common antigen exists in the basement membrane of pulmonary alveoli and of the renal glomeruli. With these views in mind, it seems permissible to look upon Goodpasture's syndrome as a bipolar clinical entity in which either the kidneys or the lung may be the primary site of pathologic manifestations, with reciprocal involvement of other structures as the disease spreads. The immunologic aspects of this syndrome are being used in its diagnosis. Immunofluorescence microscopy is likely to reveal striking linear basement membrane fluorescence of heavy deposition of immunoglobulin G and beta 1-C globulin in renal biopsy specimens. Lerner et a1 (J Exper Med 126:989, 1967) and McPhaul et a1 (J Immunol 103: 1, 168, 1969) reported the simultaneous presence of circulating and fixed antibodies to glomerular basement membrane in cases of Goodpasture's syndrome. Lung biopsy and fluorescence microscopy may reveal linear deposition of immunoglobulin G and beta 1-C globulin along the basement membrane of alveolar septa. Current treatment of Goodpasture's syndrome is based on pertinent immunologic concepts. It consists of separate, combined or coordinated administration of corticosteroids (prednisone, prednisolone), immunosuppressive agents (azathioprine, mercaptopurine), peritoneal dialysis, hemodialysis, bilateral nephrectomy and renal transplantation. Even though competent reports are discordant relative to therapeutic results, the outcome of the disease is not considered inexorably fatal. The prognosis depends on the type and severity of the primary causal agent, the gravity of the condition when the patient is first seen, on his innate resistance, defense and repair capabilities, and on the promptness of optimal treatment. Andrew L. Banyai, M.D.