Blood Pressure Responses to Catecholamines during Beta-Adrenergic Blockade with Propranolol in Hypertensive Subjects

Blood Pressure Responses to Catecholamines during Beta-Adrenergic Blockade with Propranolol in Hypertensive Subiects· Nicholas D. Vlachakis, M.D.; Daisy DeGuia, M.D.; and Milton Mendlowitz, M.D., F.G.G.P. oo

In 14 patients with essential hypertension, the responses of the heart rate and blood pressure to iDfusion of norepinephrine and epinephrine separately while oft (control period) or on therapy with ,B-adrenergic receptor blockade was examined. By titrating dosage against the response of blood pressure and pulse rate, propranolol hydrochloride was administered orally at 160 mgl day In four divided doses. There was a significant decrease in systolic blood pressure aad in pulse rate during propranolol therapy, whereas diastoUc blood pressure decreased but not significantly so. Normal blood pressure

(140/90 mm Hg or less) was attained only in five patients. The infusion of epinephrine and then norepiDepluine pr0duced a signlficaat increase In both systoUc and diastoHc blood pressure during propranolol therapy, but the magnitude of the rise was significantly greater than that attained in the control period only during epinephrine infusion. We conclude that the transient hypertensive episodes wblch have been observed during oftice visits in some hypertensive patients treated with propranolol are due mainly to release of epinephrine.

Beta-adrenergic blocking agents have been sug-

sive response to "stress."8.10 This hemodynamic response to "stress" during ,8-adrenergic blockade has been explained on the basis of the unmasking by propranolol of the effect of catecholamines on the ,8adrenergic receptors. 11- 13 During mental stress, the excretion of epinephrine in the urine is increased, 14 and in some cases the excretion of norepinephrine may also be increased.t 5 It is not known whether the hypertensive response during propranolol therapy is due to epinephrine or norepinephrine. The present study was designed to examine the effects of administering norepinephrine and epinephrine separately on the blood pressure and heart rate in patients with essential hypertension treated with the ,8-adrenergic blocking agent, propranolol.

gested for the treabnent of essential hypertension for many years l -5 and have been considered by some investigators as the treatment of choice in patients with malignant hypertension,6 renovascular hypertension,6 and the hyperdynamic ,B-adrenergic state;7 however, in severe hypertension, the large doses (1,000 mg of propranolol daily or more) often necessary to attain a clinically satisfactory decrease in the blood pressure,5 the frequency of inadequate control of blood pressure despite such large doses, and the known untoward effect on the heart and respiration have resulted in some decrease of interest in the use of these drugs alone in the treatment of essential hypertension. Even in mild and moderately severe hypertension, propranolol as the sole antihypertensive agent has produced a significant reduction in blood pressure only in a small number of cases. 8.9 Furthennore, transient hypertensive episodes during office visits have been observed in patients treated with propranolol alone,9 and therapy with propranolol did not prevent or reduce the hyperten°From the Hypertension Division, Department of Medicine, Mount Sinai School of Medicine, City University of New York, New York. °°The Joe Lowe and Louis Price Professor of Medicine. Manuscript received January 29, 1976; revision accepted May 14. Reprint requests: Dr. Mendlowitz, Mt. Sinai School of Medicine, Fifth Avenue and 100th Street, New York City 10029

38 VlACHAKIS, DE GUIA, MENDLOWITZ

MATERIALS AND METHODS

Fourteen subjects with mild and moderate degrees of severity of essential hypertension were chosen from the hypertensive' clinic for the study. Routine investigation consisted of history, physical examination, and laboratory procedures, including a hemogram, urinalysis, six-channel and 12channel automated studies of blood chemistry, and assay for urinary catecholamine metabolites. A chest x-ray film and electrocardiogram were also obtained. A rapid-sequence intravenous pyelogram was obtained in all subjects. Patients with an abnonnal intravenous pyelogram, renal failure, coronary arterial disease, cardiac arrhythmias, or thyroid dysfunction were excluded from the study. The procedure was explained to each patient, a consent fonn was signed, and all previous medication was withdrawn.

CHEST, 71: 1, JANUARY, 1977

Following four weeks of receiving a placebo, (control period ), each patient was seen in the circulatOl"Y physiology laboratory, where infusions of norepinephrine and. epinephrine were administered in a protocol consisting of the following three phases. Phase A (Basal Period)

Each subject was asked to lie quietly on a bed, and a 5percent solution of dextrose in water was infused via a butterfly 21 infusion set. Following 45 minutes of complete relaxation, brachial blood pressure was measured with a standard pressure cuff and sphygmomanometer in the left arm, and the average of three consecutive measurements was used for the calculations. Immediately thereafter, the pulse rate was obtained; and, again, the average of three measurements, each for one minute, was used for the calculations. Phase B (Infusion of Epinephrine)

After vasodilatation was produced by indirect heating with electric blankets until a positive heat balance manifested by profound perspiration was attained, an infusion of epinephrine and trimethaphancamphorsulfonate (trimethaphan camsylate) in 250 ml of a 5-percent dextrose solution was administered for 15 minutes with an infusion pump. Epinephrine was given at a rate of O.IJoLg/kg of body weight per minute and trimethaphan camphorsuHonate at a rate of 0.15 mg/kg of body weight per minute. At the end of the infusion, the blood pressure and pulse rate were measured as described in phase A. Phase C (Infusion of Norepinephrine)

Keeping the condition in phase B constant and 20 minutes after the discontinuation of the infusion of epinephrine, an infusion of levarterenol bitartrate in 250 ml of a 5-percent dextrose solution, in addition to trimethaphan camphorsulfonate, was given for 15 minutes. Levarterenol bitartrate was administered at rates of 0.1 JoLg/kg to 0.15JoLg/kg of body weight per minute, while trimethaphan camphorsulfonate was given in the same amount as in phase B. From our experience, levarterenol bitartrate at a dosage of O.IJoLg/kg to O.15JoLgJkg of body weight per minute is needed to increase systolic blood pressure by at least 20 mm Hg in an average hypertensive subject, which is necessary for the comparison. Patients with mild hypertension were infused with the highest dose of levarterenol bitartrate, while subjects with more severe hypertension were given O.IJoLgJkg of body weight per minute. At the end of the infusion, the blood pressure and pulse rat8 were recorded, as in the previous phase. Under these conditions the blood pressure and pulse rate were found to be stable in three minutes from the beginning of infusion. In five cases, we compared the effect of administering norepinephrine alone with that of administering norepinephrine and mmethaphan camphorsulfonate and found no significant difference with respect to the levels of blood pressure and pulse rate (mean blood pressure and pulse rate were 135 mm Hg and 84 beats per minute, respectively, during norepinephrine infusion vs 132 mm Hg and 84 beats per minute during administration of norepinephrine and trimethaphan camphorsulfonate) ; however, the use of trimethaphan camphorsulfonate was helpful in stabilizing the circulation, and the fluctuations in results were more pronounced when norepinephrine was used alone (the standard deviation of the means for blood pressure and pulse rate ranged from ±4 to

CHEST, 71: 1, JANUARY, 1977

±9 and from ±2 to ± 10, respectively, during norepinephrine infusion vs ±2 to ±3 and ±O.l to ±l during administration of norepinephrine and trimethaphan camphorsulfonate). Following the studies of norepinephrine and epinephrine infusion, propranolol hydrochloride ( Inderal ) was given orally for two to three months. Dosage was begun at 80 mg/day and was titrated against the response of the blood pressure and pulse rate, up to a maximum dose of 160 mg/day in divided doses. At the end of the propranolol therapy, studies of norepinephrine and epinephrine infusion were repeated exactly as previously described. Norepinephrine and epinephrine were infused at the same rate as in the period when the subjects received the placebo. No attempt was made to test the degree of I)-adrenergic blockade by isoproterenol, and the plasma levels of propranolol were not measured; however, each patient took 40 mg of propranolol per os one hour prior to the study, and there was minimal or no significant discrepancy in the pulse rate between the recumbent and upright positions. REsULTS

Control Period In Table 1 are outlined the age and sex of patients, as well as the values for blood pressure and pulse rate" in the. control period. The infusion of epinephrine produced an increase in the mean systolic blood pressure from 164 mm Hg in the basal period to 172 mm Hg (not significant) and a decrease in the mean diastolic blood pressure from 99 mm Hg in the basal period to 86 mm Hg (P < 0.01). A hypertensive response (arbitrarily defined as an increase of 20 mm Hg or more in systolic blood pressure or a rise of 10 mm Hg or more in diastolic blood pressure) was observed in four cases. The mean pulse rate increased significantly during epinephrine infusion (P < 0.001 using the t-test for paired data). The infusion of norepinephrine was associated with a significant increase in both systolic and diastolic blood pressure (P < 0.(01) and with a significant decrease in mean pulse rate (P < 0.05). A hypertensive response, as defined herein, was observed in nine subjects.

Propranolol Period During propranolol therapy (Table 2), both systolic and diastolic blood pressures in the basal period decreased, but only the changes in systolic blood pressure reached a statistically significant level (P < 0.01). The decrease in mean pulse rate was also significant (P < 0.(01). The infusion of epinephrine produced a significant increase in systolic and diastolic blood pressure (P < 0.(01), and the magnitude .of the change was significantly greater than that attained in the control period (using 8tudenfs t-test, P < 0.005 for the changes in systolic blood pressure, and P < 0.001 for diastolic blood pressure) . The absolute level of diastolic BLOOD PRESSURE RESPONSES TO CATECHOLAMINES 39

Table I-Blood Pre.ure and PuLe Rate a' Re.. and Buri,.. Norepinephrine and Epinephrine In/u.on in .he Conlrol Period Blood Pressures, mm Hg

Pulse Rate, beats per minute

A

Patient Age (yr), Sex

Basal Period

Norepinephrine

Epinephrine A

A

1,55, F 2,72, F 3,35, F 4,44, F 5,57, F 6,60, F 7,55,F 8,72,F 9,46, M 10,66, F 11,29, M 12,53, F 13, 43, F 14,50, F Mean±SE 53±3

Diastolic .

A

Basal Period

Norepinephrine Epinephrine

Systolic

Diastolic

Systolic

Diastolic

Systolic

176 195 140 145 178 200 156 195 140 150 160 150 145 160

90 95 100 100 100 110 100 95 90 94 100 96 105 110

200 240 168 218

182 188 180 158 200 195 164 188 124 170 180 160 146 170

90 65 110 68 110 100 94 65 70 80 93 102 80 90

76 100 80 76 84 84 84 100 72 72 104 84 76 64

78 80

215 180 240 150 180 180 150 155 170

108 120 110 118 110 118 120 120 94 110 115 100 98 110

164±6

99±2

189 ±8*

111 ±2*

172±6

86±6**

83±3

76±2t

*p <0.001 compared to basal period.

204

**p <0.01 compared to basal period.

blood pressure was also significantly greater than that attained in the control period (P < 0.(05). A hypertensive response, as defined previously, was observed in all but one patient. The mean pulse rate decreased significantly during epinephrine infusion (P < 0.(01), and the magnitude of the decrease was significantly greater than that in the control period (P < 0.(01). The infusion of norepinephrine was associated with a significant rise in both systolic and diastolic pressure (P < 0.01) and with a significant decrease in pulse rate (P < 0.01); however,

68

64 76 84 72 80 92 72 76 84 76 56

80 106 92 104 88

116 94 106 96

84 120 116 92 86

99±3*

tP <0.05 compared to basal period.

during propranolol therapy, the magnitude of the changes, as well as the absolute levels of blood pressure attained during norepinephrine infusion, were less than those in the control period, although not signiBcantly so. A hypertensive response was observed in eight patients. Plasma renin activity was determined only in seven subjects (subjects 1, 2, 6 to 8, 11, and 14), with specimens obtained at midday after three hours of ambulation and on a regular diet at the end of the placebo period. A 24-hour collection of urine was

Table Z--Blood Preuure and Pube Rate at Rat and Durin« Nor:epinephrine and Epinephrine InflUion .ldle Reeeil1inc Propranolol Therapy

Blood Pressures, mm Hg

Pulse Rate, beats per minute

A

Basal Period

Norepinephrine

Epinephrine A

A

Patient

Systolic

Diastolic

Systolic

Diastolic

Systolic

Diastolic

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean±SE

160 170 140 138 190 170 160 170 130 140 138 140 150 130 152 ±5*

90 90

ISO 160 180 166 230 170 170 160 136 150 160 140 190 170 169±6**

94 90 110 114 130 104 120 90 98 100 106

210 192

110 100 120 78 146 110 120 100 110 100 114 122 120 100 111 ±4t§

90 90

110 100 110 90 96 102 88 84

100 90 95±2

84

128 100 105±4**

*p <0 01 compared to control period (no propranolol). **p <0 01 compared to basal period. tP <0 001 compared to basal period.

40 VLAeHAlIS, DE GUIA, MEMDLOWIll

200

132 250 180 200

192 150 170 160 206 178 180 186 ±8t~

A

Basal Period 66 60 60 64 76 60 60 60 60 72 64

54 70 72 64±2§

Norepinephrine Epinephrine 58 66 44

52 68 52 48 66

56 72 56 52 50 56 57 ±2**§

58 52 44 58 72 48 44 52 52 64 52 34 46 48 52 ±3t§

tP <0.005 compared to control period (no propranolol). IP <0.001 compared to control period (no propranolol).

CHEST, 71: 1, JANUARY, 1977

obtained concurrently from each patient for estimation of the excretion of sodium and potassium. Two patients (subjects 1 and 11) had normal plasma renin activity, and five had low plasma renin activity compared to our laboratory's normal renin values. Plasma renin activity was redetermined during propranolol therapy in three patients (subjects 7, 11, and 14) and was found to be significantly depressed in all of them. DISCUSSION

Beta-adrenergic blocking agents, especially propranolol, have been used in the treatment of angina pectoris,16.17 cardiac arrhythmias,18.19 hypertrophic obstructive cardiomyopathy,20 anxiety,21 hyperthyroidism,22 and hypertension. to9 The mechanisms by which propranolol exerts its antihypertensive effect are not yet exactly delineated, but it seems that the reduction in blood pressure produced by propranolol therapy might be related to its negative inotropic and chronotropic action on the heart,l,23 its antirenin activity,6 and its effect on the central nervous system.24 Although cardiac output is decreased to the same extent by short-term intravenous25 and long-term oral administration of propranolol,9,26 arterial blood pressure is reduced only with long-term administration, due probably to adaptation of the peripheral circulation. Initial studies of hypertensive subjects suggested that the reduction of blood pressure with propranolol therapy was correlated with the pretreatment level of cardiac output. 3 It has been also suggested that patients with tachycardia and labile hypertension have a hyperdynamic ,8-adrenergic state and a better hypotensive response to propranolol;7 however, recent hemodynamic studies failed to show a relation between the antihypertensive effect of propranolol and the pretreatment cardiacoutput state.9 When propranolol has been used as the sole antihypertensive agent, a significant reduction in blood pressure has been attained only in a small number of patients with mild and moderate severity of essential hypertension. 8.9 In our series a significant decrease in systolic blood pressure was observed, while diastolic blood pressure did not change significantly; and a clinically satisfactory reduction in blood pressure (140/90 mm Hg) was attained in only Dve out of 14 patients. Although the plasma renin activity was determined only in seven patients, the unsatisfactory decrease in blood pressure may be due to the fact that the majority of the patients had low plasma renin activity and some had normal plasma renin activity. A pressor response to propranolol has been observed by Drayer et al 27 in 11 percent of 188 patients treated with propranolol for CHEST, 71: 1, JANUARY, 1977

21 days. All of these patients belonged to the sub-

groups with low or normal plasma renin activity, and their plasma renin activity did not decrease significantly during propranolol therapy. Transient hypertensive episodes during propranolol therapy were observed in our series and have been reported by others. 9 During mental stress, pain, and apprehension-provoking situations, a twofold to threefold increase in urinary excretion of epinephrine 14 was found, although excretion of norepinephrine may also be increased in certain cases.15 Administration of epinephrine in large doses produces vasoconstriction with hypertension and bradycardia,28 whereas in smaller amounts, administration of epinephrine stimulates mainly ,8adrenergic receptors. 29 ,30 The rise in blood pressure produced by administration of epinephrine during ,8adrenergic blockade seen in the present study has also been reported by others 31 and has been explained on the basis of the unmasking by propranolol of the effects of epinephrine on the aadrenergic receptors. 11·13 Hemodynamic studies ~uring infusion of catecholamines31 demonstrated that propranolol converted the dilator effect of epinephrine into vasoconstriction, while the constrictor response to norepinephrine remained unchanged. In studying the effect of propranolol on the pressor responses to noxious stimuli in 11 hypertensive patients, Nicotero et al8 showed that administration of propranolol failed to affect either the basal blood pressure or the pressor response to cold and ischemic pain or to prevent the increase of urinary catecholamine excretion in response to such stimuli. Blum et al 32 have very recently reported the occurrence of progressive or precipitous elevation of blood pressure in eight out of 44 psychiatric patients treated with high doses of propranolol. The hypertension was accompanied by pallor, coldness, and clamminess of the skin and by marked tension and outbursts of psychomotor unrest. In all cases the hypertension responded immediately to the administration of the a-adrenergic blocking agents, phentolamine or phenoxybenzamine. In the present study, administration of norepinephrine, with an effect on a-adrenergic and ,8adrenergic receptors,33 produced a significant increase (P < 0.(05) in both systolic and diastolic blood pressures during propranolol therapy; however, these increases did not reach the levels attained in the control period. On the other hand, administration of epinephrine produced a significantly greater rise in blood pressure, as compared to that in the control period (P < 0.005 for systolic and P < 0.001 for diastolic blood pressure). Similar studies in our laboratory with a diuretic BLOOD PRESSURE RESPONSES TO CATECHOLAMINES 41

agent34 or a peripheral vasodilator drug35 clearly demonstrated a significant reduction in the blood pressure during catecholamine infusion. The addition of such a drug to p-adrenergic blockade has shown a greater hypotensive effect36 and will probably lessen the increase in blood pressure during stress. In studying the infusion of norepinephrine and epinephrine into 17 dogs receiving combined administration of phenoxybenzamine and pronethalol, Garrett et al37 found a significantly smaller increase in blood pressure during the combined therapy than in the control period. Similar results have also been reported by Gagnon28 and by others.38,39 In the present study the doses may not be comparable to the physiologic release of catecholamines in man. Furthermore, epinephrine and norepinephrine were administered separately, while in stressful situations of real life, release of both epinephrine and norepinephrine may be increased. Goldenberg et alSO observed that the vasoconstrictive effect of norepinephrine was abolished and blood pressure fell when epinephrine was simultaneously administered in equal doses in normotensive subjects not receiving any medication. It seems likely that stress producing epinephrine from the adrenal medulla becomes more vasconsbictive with propranolol therapy than without and can cause the blood pressure to rise at least transiently; however, paradoxic elevation of blood pressure may occur in any patient treated with p-adrenergic blocking agents when excessive amounts of catecholamines are released, especially in patients with pheochromocytoma or schizophrenic disorders. 32 REFERENCES

1 Prichard BNC, Gillam PMS: Use of propranolol in treatment of hypertension. Br Med J 2:725, 1964 2 Prichard BNC: Propranolol as an antihypertensive agent. Am Heart J 79:128,1970 3 Dorph S, Binder C: Evaluation of the hypotensive effect of tt-adrenergic bloclcade in hypertension. Acta Med Scand 185:443, 1969 4 Waal HJ: Hypotensive action of propranolol. Coo Pharmacol Ther 7 :588, 1966 5 Zacharias FJ, Cowen KJ: Controlled mal of propranolol in hypertension. Br Med J 1:471, 1970 6 Buehler FR, Laragh JH, Vaughan ED Jr, et al: The antihypertensive action of propranolol: Speci6c antirenin responses in high and normal renin forms of essential, renal, renovascular and malignant hypertension. In Laragh JH (ed): Hypertension Manual. New York, DunDonnelley Publishing Corp, 1974, p 873 7 Frohlich ED, Tarazi RC, Dustan HP: Beta-adrenergic blocking therapy in hypertension: Selection of patients. Int J Phannacol Ther Toxicol4: 151, 1970 8 Nicotero JA, Beamer V, Moutsos SE, et al: Effect of propranolol on the pressor receptor to noxious stimuli in hypertensive patients. Am J Cardiol22:657, 1968 9 Tarazi RC: Long-term hemodynamic effects of fJ-

42 MeHillS, DE GUIA, MENDLOWlll

10

11 12 13

14 15 16 17 18 19 20 21 22 23

24 25

26 27 28 29 30

~1

adrenergic blockade in hypertension. In Onesti G, Kim KE, Moyer JH (eds): Hypertension: Mechanisms and Management: Twenty-Sixth Hahnemann Symposium. New York, Grone and Stratton, Inc. 1973, p 343 Ulrych M: Changes of general hemodynamics during stressful mental arithmetic and nonstressing quiet conversation and modification of the latter by Ii-adrenergic blockade. Clin Sci 36:453, 1969 Youmans PL, Green HD, Denison AB Jr: Nature of the vasodilator and vasoconstrictor receptors in skeletal muscle of the dog. Circ Res 3:171, 1955 De La Lande IS, Whelan RF: The effect of antagonists on the response of the forearm vessels to adrenaline. J Physioll48:548, 1959 Assaykeen TA, Clayton PLA, Ganong WF: Effect of alpha- and beta-adrenergic blocking agents on the renin response to hypoglycemia and epinephrine in dogs. Endocrinology 87: 1318, 1970 von Euler US: Quantitation of stress by catecholamine analysis. Clin Phannacol Ther 5:398, 1964 Levi L: Stress and distress in response to physchosocial stimuli. Acta Med Scand (suppl) 528: 11, 1972 Hamer J, Grandjean T, Melendez 1.., et al: Effect of propranolol in angina pectoris: Preliminary report. Br Med J 2: 1136, 1964 Wolfson S, Heinle RA, Herman MV, et al: Propranolol and angina pectoris. Am J CardioI18:345, 1966 Harris A: Long-term treatment of paroxysmal cardiac arrhythmias with propranolol. Am J CardioI18:431, 1966 Stock JP, Dale N: Beta-adrenergic receptor bloclcade in cardiac arrhythmias. Br Med J 2:1230, 1963 Cherian G, Bronkington 1M, Shank PM, et al: Betaadrenergic blockade in hypertrophic obstructive cardiomyopathy. Br Med J 1:895, 1966 Bonn JA, Turner P, Hicks DC: Beta-adrenergic receptor blockade with practolol in treatment of anxiety. Lancet 1:814, 1972 Mackin JF, Canary JJ, Pittman CS: Current concepts: Thyroid storm and it management. N Engl J Med 291: 1936, 1974 Epstein SE, Robinson BF, Kahler RL, et a1: Effects of Iiadrenergic blockade on the cardiac response to maximal and submaximal exercise in man. J elin Invest 44: 1745, 1975 Kelliher GJ, Buckley JP: Central hypotensive activity of ell and d propranolol. J Pharm Sci 59:1276, 1970 Ulrych M, Frohlick ED, Dustan HP, et aI: Immediate hemodynamic effects of Ii-adrenergic blockade with propranolol in normotensive man. Circulation 37:411, 1968 Prichard BNC, Shineboume E, Fleming J, et al: Hemodynamic studies in hypertensive patients on oral propranolol. Br Heart J 32:236, 1970 Drayer JIM, Keirn HJ, Weber MA, et al: Propranolol induced pressor responses in essential hypertension. Clin Res 24:471A, 1976 (abstract) Gagnon DJ: Influence of oxprenolol on adrenaline-induced reflex bradycardia in dogs. Rev Can BioI 31:65, 1972 Alquist RP: A study of the adrenotropic receptors. Am J PhysioI153:586, 1948 Goldenberg M, Pines KL, Baldwin E, et a1: The hemodynamic response of man to norepinephrine and epinephrine in its relation to the problems of hypertension. Am J Med 5:792, 1948 Harris WS, Schoenfeld CD, Brooks RH, et aI: Effect of {j-

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32 33 34 35 36

adrenergic blockade on the hemodynamic responses to epinephrine in man. Am J CardioI17:484, 1966 Blum I, Atsmon A, Steiner M, et al: Paradoxical rise in blood pressure during propranolol treatment. Br Med J 4:623, 1975 Furchgott RF: The receptors for epinephrine and norepinephrine: Adrenergic receptors. Pharmacol Rev 11:429, 1959 Mendlowitz M, Naftchi NE, Gitlow SE, et al: The effect of spironolactone on digital vascular reactivity in essential hypertension. Am Heart J 76:795, 1968 DeGuia D, Mendlowitz M, Russo C, et al: The effect of trimazosin in essential hypertension. Curr Ther Res 15: 339, 1973 Hansson L, Olander R, Aberg H, et al: Treabnent of

hypertension with propranolol and hydralazine. Acta Med Scand 190:531, 1971 37 Garrett J, Malafaya-Baptista A, Osswald W: Effects of pronethalol on the cardiovascular actions of catech 01amines during blockade by phenoxybenzamine. Br J Pharmacol 27 :459, 1966 38 Shanks RG: The effect of propranolol on the cardiovascular responses to isoprenaline, adrenaline and noradrenaline in the anaesthetized dog. Br J Pharmacol 26: 322, 1966 39 Parratt JR, Wadsworth RM: The effect of catecholamine infusions on myocardial blood flow, metabolic heat production and on general hemodynamics, before and after alprenolol in anaesthetized cats. Br J Phannacol 38:554, 1970

Felis Domestica The cat has been man's companion since time immemorial. It is thought that cats appeared in Europe about 700 - 600 Be. According to a census of 1961 there were about 22 million cats in urban households in the United States, in addition to several millions owned by farmers. In the latter instance the cat proved to be an invaluable guardian of staple grains, wheat, corn, rice etc against rodents. In ancient China and Japan cats were kept for the protection of cocoons of silkwonns against rats 1,000 years BC. The average life-span of cats is 14-15 years. Their perception of sound is far beyond human hearing. By means of 27 muscles of the external ear the latter can be turned in several directions. Visual adaptation of their eyes is aided by contraction of the pupils to a vertical slit in bright light and their maximal dilatation in dim light. The strange shining of the cat's eyes when bright light strikes them is due to the tapetum, a reflecting layer in the chorioid. In the religious shrines of ancient Egypt the cat was exalted as a sacred creature; one of their goddesses, Bast, was depicted with the head of a cat. Throughout the ages, cats, paradigms of self-possession, perseverance, tidiness and relaxation, were pampered as pets by humans, including celebrities of religion, science and the seven arts. Cats lack the vociferous xenophobia of dogs. They are faithful servants of man and able to express their affection by rubbing their bodies against one's arms or legs, or by purring which is produced by a peculiar vibration of their vocal cords with the passing air flow. It is well to cite Manolson, F (C is for Cat, New York, Basic Books, 1965). Catgut is made from the intestine of sheep. These strands of sheep gut were originally used as strings on an Italian musical instrument called a kit. IGtgut doesn't really sound right, so they started calling it catgut. Lord Lister was the first who used it. Another great English pioneer, Blackley, CH (Exper Res, London, 1880) first recorded the occurrence of hypersensitivity to epidermal scales or dander of animal hair. Symptoms due to allergy to cat dander may develop through direct contact or through staying at a location where cats were or had been, also through exposure to

CHEST, 71: 1, JANUARY, 1977

material containing cat hair. Pertinent symptoms include pruritus, infrequent urticaria, conjunctival congestion, itching of the eyes, paroxysmal sneezing, rhinorrhea, tightness in the chest, cough and wheezing. Emmons, CW et al (Am J Hyg 61:40, 1955) found that 18 percent of cats studied harbored Histoplasma capsulatum. The latter may be detected in the saliva, urine and feces of infected animals. In 1932, Foshay, L, quoted by Daniels, WB et al (Ann Int Med 37:697, 1952) first identified ulceroglandular disease resulting from the scratch of cats. Thousands of cases of cat-scratch fever have been observed since the report of Debre, R et al (Bull Mem Soc Med Hop Paris, 66:76, 1950. The causal agent is a virus. In addition to localized manifestations and regional lymphadenitis, the salient features of this disease are malaise, headache, chills and fever. Its course is usually benign. Encephalomyelitis is a rare complication. Positive skin test to intracutaneous injection of antigen from a suppurating regional Iymphnode is diagnostic. The cat is highly susceptible to tularemia. Rare instances of tularemia transmitted through cat scratch have been reported. Three cases of febrile infection following cat bite were described by Francis, DP et al (JAMA 233:42, 1975). Such infection may result in severe localized cellulitis and associated with septicemia. The causal agent was Pasteurella multocida, a gram-negative coccobacillus often present in the oral cavity of healthy cats. Penicillin or a penicillin analogue is considered effective therapy. In reference to cancer, Levy, JA (JAMA 229:1654, 1974) asserts that leukemia virus can be found in the mucus of the oral cavity and of the trachea, and in the urine of unaffected cats and that this cat virus grows well in human cell cultures; even so, no clear-cut association of cat virus with human cancer has been proved. The first presumable case of human rabies in the continental United States in 15 years, originating from catbite was reported in the Medical News section of the JAMA (233:407, 1975). It is hoped that this article is not bringing about ailurophobia. Andrew L. Banyai, M.D.

BLOOD PRESSURE RESPONSES TO CATECHOLAMINES 43