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Comparison of haemodynamic effects of α-sympathomimetic drugs
EUROPEAN J OURNAL OF PHARMACOLOGY 13 ( 1971) 208 217. NORTH-HOLLAND PUBLISHING COMPANY
COMPARISON
OF HAEMODYNAMIC
EFFECTS
OF
c~-SYMPATHOMIMETIC DRUGS A.M. AUTRET, H. SCHMITT, S. FENARD and N. Pt~TILLOT Ddpartement de Pharmacologie, Facultd de Mddecine de Paris, Broussais, HOtel Dieu, 15, rue de l'Ecole de Mddeeine 75, Paris 6e, France
Received 16 June 1970
Accepted 17 September 1970
A.M. AUTRET, H. SCHMITT, S. FENARD and N. Pt~TILLOT, Comparison of haemodynamic effects of o~sympathomimetic drugs European J. Pharmacol. 13 (1971) 208 217.
Dose-response curves for nine Ct-sympathomimetic drugs were determined in pithed rats. The order of potency was: norepinephrine 1, phenylephrine 0.1, oxymetazoline 0.1, clonidine 0.029, LD 2855 0.028, naphazoline 0.087, tramazoline 0.030, tetryzoline 0.01, Bayer 1470 0.0003. Pretreatment with reserpine (10 mg/kg 24 hr before) did not change the dose-response curves; phentolamine (2 mg/kg) shifted the dose-response curve to the right but did not change the maximal response suggesting competitive antagonism; phenoxybenzamine (2 mg/kg) shifted the dose-response curve to the right and reduced the maximal response suggesting non-competitive antagonism. Cocaine (5 mg/kg) and imipramine (2 mg/kg) reduced the hypertension produced by clonidine but increased slightly hypertension following naphazoline. Clonidine (3-30 ~g/kg)induced biphasic changes in blood pressure - a rise followed by a long decrease, bradycardia, decrease in aortic blood flow, femoral and coronary blood flows. Naphazoline (5 to 45 ~g/kg) induced a rise in blood pressure, a fall in aortic blood flow, a bradycardia, a pulmonary hypertension, a decrease in femoral and coronary blood flows. Total, pulmonary, coronary and femoral resistances were elevated. Performances of the left ventricle were reduced. The mechanisms of these changes were discussed. o~-Sympathomimetic agents
Haemodynamic effects
1. INTRODUCTION According to the concept of Ahlquist (1949), adrenergic receptors are divided into two classes, c~ and fl; each sympathomimetic agent activates either one type o f receptors or exerts effects on both types. Much data has been published on the pharmacology o f catecholamines and /3-sympathomimetic drugs. However the literature on a-sympathomimetic agents is more scarse. Phenylephrine, a classic a - s y m p a t h o m i m e t i c agent has recently been reinvestigated (Schmitt et al., 1970). Mujic and van Rossum (1965) reported typical t~-sympathomimetic effects for compounds of the imidazoline series. However, tetryzoline (Hutcheon et al., 1958) and
Catapresan
Naphazoline
oxymetazoline (Hotovy et al., 1961) were only reported to reduce cardiac output. On the other hand, c~-sympathomimetic agents with marked central effects have been described; they induce biphasic changes in blood pressure: a short hypertension followed by a long-lasting decrease in blood pressure; they reduce heart rate and cardiac output and inhibit vasomotor centres. The substances which have been most commonly investigated are 2-(2,6-dichlorophenylamino)-2-imidazoline (clonidine, St 155, Catapresan O ) ( H o e f k e and Kobinger, 1966; Kobinger and Walland, 1967; Schmitt et al., 1967, 1968; Laubie and Schmitt, 1969; Maxwell, 1969); 2-(2,6-dimethylphenylamino)-4H-5,6-dihydro1,3-thiazin (xylazine, Bayer 1470) (Kroneberg et al.,
A.M.Autert et aL, Haemodynamic effects o f ot-sympathomimetic drugs
1967; Schmitt et al., 1970) and 2-(2,6-dimethylphenylamino)-2A 2-oxazoline-1,3 (LD 2855) (Giu~dicelli et al., 1958; Giudicelli and Schmitt, 1970). The present work was undertaken: a) to compare the pressor response to these a-sympathomimetic agents in pithed rats: b ) t o study the influence exerted by classic a-adrenergic blocking drugs and by compounds inhibiting axonal reuptake of catecholamines (cocaine, imipramine) on these responses; and c) to investigate the haemodynamic changes induced by naphazoline, tetryzoline and oxymetazoline and to compare these with the effects of phenylephrine and clonidine.
2. METHODS Pithed rats were prepared according to Shipley and Tilden (1949). Carotid blood pressure was recorded on a smoked drum by means of a Condon's mercury manometer. Six rats were used for each experiment. Drugs were injected into the femoral vein using a Latin square design until the maximal response was reached. Dose-response curves were drawn and the relative potencies of the drugs were calculated as the ratio of doses inducing half of the maximal response. Antagonism or potentiation was determined after intravenous injection of a-adrenergic blocking drugs (phentolamine, 2 mg/kg; phenoxybenzamine, 2 mg/ kg) or agents inhibiting the axonal reuptake of catecholamines (cocaine, 5 mg/kg; imipramine, 2 mg/ kg); the dose-response curve was determined 10 min after this injection. In another set of experiments, rats were pretreated with reserpine (10 mg/kg, i.p.; 2 4 h r beforehand) and dose-response curves were determined. To investigate haemodynamic changes, dogs of either sex weighing 10-25 kg were anaesthetized with pentobarbital (30mg/kg, i.v.). A cuffed endotracheal cannula was introduced and artificial respiration with a Bird Mark IV pump commenced. Carotid blood pressure was recorded by means of a Statham P 23 Db pressure transducer on a San'Ei recorder. A catheter was pushed into the pulmonary artery through the right jugular vein and pulmonary pressure was recorded by means of a second P 23 Db pressure transducer. The left chest wall was opened at
209
the level of the fourth intercostal space and the left lung was gently displaced to expose the heart. The pericardium was entered and approximately 20 mm of the ascending aorta was cleared of fat and separated from the pulmonary artery. Blood flow through the ascending aorta was monitored with a Statham flow probe (serie Q; 10-16 mm internal diameter) positioned around the external circumference of the vessel. The flow probe signals were fed into a Statham electromagnetic flowmeter 4001 and then relayed to the recording unit. Instantaneous and mean aortic blood flows were recorded on two separate channels. An aortic pulse measurement of zero was taken as diastolic flow. Heart rate was measured with a Racia cardiotachometer fed with the blood pressure signal. Femoral blood flow was measured continuously by means of a Statham flow probe (serie Q; internal diameter 2 - 3 ram) and recorded on the sixth channel of the polygraph. In one third of the experiments left ventricular pressure, left ventricular end diastolic pressure and the maximal rate of development in ventricular isometric tension were recorded instead of pulmonary pressure and femoral blood fow. For these recordings, a catheter connected to a Statham P 23 Db pressure transducer was pushed into the left ventricle through the right femoral artery. The left ventricular pressure was recorded on a channel of the recording unit and the left ventricular end diastolic pressure on another channel after a fivefold amplification. The LVP sign',d was differentiated with a resistance capacity network (time constant: 10-s) and the rate of rise of left ventricular pressure was recorded. Myocardial contractile force was measured with a Walton-Boniface gauge arch sutured to the left ventricle (Boniface et al., 1953; Cotten, 1953). Coronary blood flow was measured with a Statham flow probe (series S; 1.5-2.5 mm internal diameter) positioned around the left circonflex coronary artery. The signal was fed to an electromagnetic flowmeter 4001 and recorded on the polygraph. The following parameters were measured: systolic blood pressure in mm Hg; diastolic blood pressure in mm Hg; systolic pulmonary pressure in mm Hg; diastolic pulmonary pressure in mm Hg; heart rate in beats/min; left ventricular pressure in mm Hg; left ventricular end diastolic pressure in mm Hg; maximal
210
A.M.Autert et aL, Haemodvnamic effects o f o~-sympathomimetic drugs
rate of rise in isometric tension of left ventricle in mm Hg/sec; myocardial contractile force in g; phasic and mean aortic blood flow in 1/min; femoral blood flow in ml/min; coronary blood flow in ml/min. The following parameters were calculated: mean blood pressure = diastolic blood pressure + 0.43 (systolic blood pressure - diastolic blood pressure); mean pulmonary pressure = diastolic pulmonary pressure + 0.43 (systolic pulmonary pressure - diastolic pulmonary pressure); total peripheral resistance in dynes sec cm -s = m e a n blood pressure in cm Hg X 981 X 13.6 X 60/aortic blood flow in ml/min; stroke volume in ml = aortic blood flow in ml/heart rate in beats/min; left ventricular work in kg/min = mean blood pressure in mm Hg X 13.6 X 1.055 X aortic blood flow in 1/min; left ventricular stroke work in g = left ventricular work in g/heart rate in beats/min; right ventricular work in kg/min = mean pulmonary pressure in mm Hg X 13.6 X 1.055X aortic blood flow in l/rain; pulmonary resistance in dynes sec cm -s = pulmonary pressure in mm Hg X 981 X 13.6 X 60/aortic blood flow in ml/min; femoral resistance in mm H g / m l = m e a n blood pressure in mm Hg/mean femoral blood flow in ml/min; coronary resistance in mm Hg/ml = mean blood pressure in mm Hg/mean coronary blood flow in ml/min.
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Fig. 1. Dose-response curves for sympathomimetic drugs in pithed rats. The figure shows the dose-response curves for nine sympathomimetic drugs.
3. RESULTS 3.1. Dose-response curves of a-sympathomimetic agents in pithed rats The dose-response curves for each a-sympathomimetic agent was determined in six pithed rats (fig. 1). Dose-response curves were sigmoidal and parallel to each other. The maximal response was about 130 mm Hg. The relative potencies calculated from the doses producing half the maximal response (65 mm Hg) and taking the potency of noradrenaline as 1 were: oxymetazoline 0.1, phenylephrine 0.1, naphazoline 0.087, clonidine 0.029, LD 2855 0.028, tramazoline 0.030, tetryzoline 0.01, xylazine 0.0003. 3.2. Influence of ~-adrenergic blocking drugs on
dose-response curves of a-sympathomimetic agents Phentolamine (2 mg/kg) shifted the dose-response curve to the right but did not change the maximal
response. In contrast phencrxybenzamine (2 mg/kg) not only shifted the dose-response curve to the right but also reduced the maximal response (figs. 2 and 3). 3.3. Influence of cocaine and imipramine on the dose-response curves of a-sympathomimetic agents Cocaine (5 mg/kg) and imipramine (2mg/kg) shifted the dose-response curves of noradrenaline and phenylephrine to the left and increased somewhat the maximal response. In contrast, cocaine decreased the response to clonidine, LD 2855 but increased slightly responses to naphazoline (fig. 4). Guanethidine did not change the effects of the three drugs. 3.4. Actions on reserpinized rats Pretreatment with reserpine shifted the doseresponse curve to the left for noradrenaline and phenylephrine but did not change the dose-response
A.M.Autert et al., Haemodynamic effects of C~-sympathomimetic drugs
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Fig. 2. Antagonism induced by phentolamine (2 mg/kg) on the pressor responses to clonidine and naphazoline in pithed rats. The figure shows a parallel shift to the right of the dose-response curve.
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3.5. Haemodynamic effects o f clonidine and naphazoline Clonidine (3 to 30/~g/kg) induced a brief increase in blood pressure followed by a long-lasting fall. Heart rate slowed and bradycardia was most marked several minutes after injection. A dose-dependent reduction in aortic blood flow occurred (fig. 5); this reduction was more marked during the hypertensive phase; aortic blood flow began to decrease before any change in blood pressure and heart rate. Stroke volume was slightly decreased only during the hypertensive phase. Total peripheral resistance was markedly elevated during hypertension but was not altered during hypotension. With high doses, pulmonary pressure rose during the hypertensive phase; pulmonary vascular resistance was increased during both phases because of the reduction in aortic blood flow; left ventricular work and stroke work
were reduced during both phases. Clonidine reduced the indices of left ventricular performance: rate of rise in left ventricular pressure, velocity of blood in the ascending aorta; an increase in left ventricular end diastolic pressure appeared with a reduced stroke work and these reductions were more marked during hypertension. However, myocardial contractile force did not change or even slightly increased during hypertension and thereafter a progressive decline was seen. Femoral and coronary blood flows were significantly decreased. Table 1 and fig. 6 illustrate haemodynamic changes induced by naphazoline. Naphazoline (5 to 45/2g/kg) induced a dose-dependent increase in blood pressure lasting 5 to 60 min; pulse pressure was reduced. Low doses (5/2g/kg) did not alter heart rate but higher doses reduced heart rate and the bradycardia was very marked when the blood pressure was at its nadir. Aortic blood flow fell in a dose-dependent manner before any change in blood pressure and heart rate. Stroke volume was reduced. Left ventricular work increased significantly with the lower doses but decreased with the higher doses.
A.M.Autert et al., Haemodynamic effects o f Ot-sympathomimetic drugs
213
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Fig. 5. Haemodynarnic changes induced by clonidine. Clonidine (3 and 5 t~g/kg) induced biphasic changes in blood pressure-rise followed by a long-lasting decrease - a fall in aortic blood flow and heart rate; peripheral resistance rose during the hypertension. Stroke work was not changed. Pulmonary pressure was not changed by low doses but significantly increased with high doses; pulmonary pressure was significantly increased in both cases whereas femoral and coronary blood flows declined. The indices of ventricular performance were decreased in the same way as in the hypertensive
phase following clonidine. Atropine (0.3 mg/kg) and bilateral vagotomy reduced or even abolished bradycardia but did not alter the changes in the other parameters. In a few experiments, tetryzoline ( 1 0 - 1 0 0 #g/kg) and oxymetazoline (1-10/ag/kg) were shown to cause similar changes.
A:M.Autert et aL, Haemodynamic effects of ot-sympathomimetic drugs
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Fig. 6. H a e m o d y n a m i c changes induced by naphazoline. The figure shows: at left first line blood pressure, second line i n s t a n t a n e o u s flow in aorta ascendens, at right first line m e a n aortic blood flow, second line heart rate. Naphazoline (45 #g/kg) increased blood pressure, b u t induced a fall in aortic blood flow a n d heart rate. Peripheral resistance was markedly elevated.
Table 1 H a e m o d y n a m i c effects induced by naphazoline in dogs.
Systolic blood pressure ( m m Hg) Diastolic blood pressure ( m m Hg) Mean blood pressure ( m m Hg) Heart rate (beats/min) Aortic blood flow (1/min) Stroke volume (ml) Peripheral resistance (dynes sec cm -5) Left ventricular work (kg/min) Stroke work (g) Mean p u l m o n a r y pressure ( m m Hg) Pulmonary resistance (dynes sec cm -5) Right ventricular work (kg/min) Left ventricular end diastolic pressure ( m m Hg) d LVP/dt ( m m Hg/sec) Myocardial contractile force (p 100) Femoral blood flow (ml/min) Femoral resistance ( m m Hg/ml) Coronary blood flow (ml/min) Coronary resistance ( m m Hg/ml) * p(0.05,
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A.M.Autert et aL, Haemodynamic effects of Ot-sympathomimetic drugs
4. DISCUSSION In this paper the abilities of nine a-sympathomimetic agents to raise blood pressure in pithed rats were compared. Noradrenaline, phenytephrine and oxymetazoline were the most potent agents. Clonidine, LD2855, naphazoline and tramazoline were about equally effective. Tetryzoline was of intermediate potency and xylazine was the least active. Pretreatment with reserpine did not alter the pressor responses to these drugs in agreement with previous experiments performed with clonidine (Kobinger and Walland, 1967; Boissier et al., 1968), xylazine (Schmitt et al., 1970), naphazoline, tetryzoline, tramazoline and oxymetazoline (Mujic and van Rossum, 1965). Therefore these drugs are directly acting c~-sympathomimetic agents. Phentolamine shifted the dose-response curves to the right without changing the maximal effect suggesting competitive antagonism; phenoxybenzamine shifted not only the dose-response curve to the right but also redlaced the maximal effect suggesting non-competitive antagonism. These results confirm and extend previous observations (Kobinger and Walland, 1967; Boissier et al., 1968; Constantine and Mac Shane, 1968; Kroneberg et al., 1967; Schmitt et al., 1970; Bentley and Li, 1968; Giudicelli et al., 1958, 1970; Mujic and van Rossum, 1965, Hutcheon et al., 1955, 1958; Hotovy et al., 1961). Cocaine and imipramine shifted the dose-response curves of noradrenaline and phenylephrine to the left but reduced slightly the effects of clonidine; the action of naphazoline was slightly potentiated. The potentiating effect of both drugs is usually accounted for by inhibition of the axonal reuptake of catecholamines (Hertting and Axelrod, 1961 ; Hertting et al., 1961 ; Potter and Axelrod, 1965). Thus it would be concluded that this process of inactivation is only a minor one for these a-sympathomimetic drugs. It is noteworthy that the potency of these a-sympathomimetic drugs on peripheral a-adrenergic receptors was different from the potency on central receptors inhibiting the vasomotor centres and inducing sedation (Schmitt and F~nard, 1970; Delbarre and Schmitt, 1971). The haemodynamic changes induced by naphazoline were similar to those produced by phenyleph-
215
rine: a dose-dependent increase in blood pressure, bradycardia, fall in aortic blood flow, increase in total peripheral resistance, increased pulmonary pressure and resistance. Left ventricular performance was reduced as evidenced by the decrease in the velocity of aortic blood flow and in the maximal rate of rise of left ventricular pressure. Moreover an increase in left ventricular and diastolic pressure occurred with a reduced stroke work (Samoff and Berglund, 1954). However, the myocardial contractile force did not change revealing that naphazoline did not impair the contractile machinery directly or indirectly through the sympathetic system. Reduced aortic blood flow must therefore be due to three indirect causes: a) bradycardia; b) decreased venous return revealed in some experiments by changes in aortic blood flow without any alteration in other haemodynamic parameters, c)increased aortic pressure. The mechanism for reduction in venous return is unknown but is caused by activation of a-adrenergic receptors (Lewis and Weil, 1969). The reduction in left ventricular performance was indirectly produced and could be due to a) reduced venous return diminishing the size of the heart, b)bradycardia acting through the Bowditsch effect c)but the increased aortic pressure had opposite effects. Reduction in femoral blood flow was the result of direct a-sympathomimetic vasoconstriction, whereas the decrease in coronary blood flow could also be due to bradycardia reducing the oxygen comsumption of the heart. The elevation of left ventricular end diastolic pressure is difficult to account for; the hypertension tended to increase this pressure but the reduced venous return had the opposite effect. The haemodynamic changes induced by clonidine during the hypertensive phase were similar to those of naphazoline and were presumably produced by similar actions. However, the central reduction in sympathetic tone was an additional factor for the decrease in aortic blood flow and left ventricular performance; this factor was the predominant one during the hypotensive phase. Tetryzoline and oxymetazoline induced changes similar to naphazoline. Thus a-sympathomimetic agents produce a rise in blood pressure due to vasoconstriction, a fall in cardiac output and bradycardia. In addition, some of these
216
A.M.Autert et aL, Haemodynamie effects of ~-svmpathomirnetic drags
drugs, like clonidine, xylazine and LD 2855 also reduced centrally the sympathetic tone inducing a secondary fall in b l o o d pressure.
REFERENCES Ahlquist, R.P., 1949, A study of the adrenotropic receptors, Am. J. Physiol. 153,586. Bentley, G.A. and D.M. Li, 1968, Studies on the new hypotensive drug St 155, European J. Pharmacol. 4,124. Boissier, J.R., J.F. Giudicelli, J. Fichelle, H. Schmitt and Mine It. Schmitt, 1968, Cardiovascular effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155). I. Peripheral sympathetic system, European J. Pharmacol. 2, 333. Boniface, K.J., D.J. Brodie and R.P. Walton, 1953, Resistance strain gauge arches for direct measurement of heart contractile force in animals, Proc. Soc. Exptl. Biol. Med., 84,263. Cotten, M. de V., 1953, Circulatory changes affecting measurement of heart force in situ with strain gauges arches, Am. J. Physio. 174, 365. Giudicelli, R., M. Beauvallet, P. Chabrier and H. Najer, 1958, Sur Faction vasculaJre de quelques amino-2-oxazolidinesN-substitu@s, Compt. Rend. Acad. Sci. 247, 891. Constantine, J.W. and W.K. Mc Shane, 1968, Analysis of the cardiovascular effects of 2-(2,6-dichlorophenylamino)-2imidazoline hydrochloride (Catapres (~)), European J. Ph~macol. 4,109. Delbarre, B. and H. Schmitt, 1971, Sedative effects of oesympathomimetic drugs in chickens and mice and the antagonism by adrenergic and cholinergic blocking agents, European J. Pharmacol. 13, in press. Herrting, G. and J. Axelrod, 1961, Fate of tritiated noradrenaline at the sympathetic nerve endings, Nature 192, 172. Herrting, G., J. Axelrod and L.B. Whitby, 1961, Effects of drugs on the uptake and metabolism of 3H-norepinephrine, J. Pharmacol. Exptl. Therap. 134, 146. Hoefke, W. and W. Kobinger, 1966, Pharmakologische Wirkungen des 2-(2,6-Dichlorophenylamino)-2-imidazolin hydrochlorids einer neuen anti-hypertensiven Substanz, Arzneimittel-Forsch. 16, 1038. Hotovy, R., H.J. Enenkel, J. Gillissen, U. Jahn, H. Kieser, H.G. Kraft, H. Muller-Calgan, S. Sommer and H. Wandig, 1961, Zur Pharmakologie des 2-(4'-ter-Butyl-2',6'dimethyl-5 '-hy dr oxybenzyl) 2-imidazolinium, Arzneimittel-Forsch. 11, 1016. Hutcheon, D.E., S.Y. P'an, J.F. Gardocki and D.A. Jaeger, 1955, The sympathomimetic and other pharmacological properties of d- 1,2-( 1,2,3,4-tetrahydro- 1-naphthyl)imidazoline(tetrahydrozoline), J. Pharmacol. Exptl. Therap. 113,341. Hutcheon, D.E., A. Scriabine, J.S. Ling, S.Y. P'an and B.H. Bloom, 1964, Vascular and adrenergic blocking actions of
several substituted 2-amino-imidazolines, Arch. Intern. Pharmacodyn. 147, 146 Hutcheon, D.E., A. Scriabine and U.N. Niestler, 1958, The effects of tetrahydrozoline (tyzine) on cardiac and vasomotor functions, J. Pharmacol. Exptl. Therap. 122, 101. Hutcheon, D.E., S.A. Sweeney, J.SI. Ling and B.M. Bloom, 1958, Vasocontrictor and adrenergic blocking actions of a series of substituted 2-aminoimidazolines, J. Pharmacol. Exptl. Therap. 122, 34 A. Kobinger, W. and A. Walland, 1967, Untersuchungen fiber den Wirkungsmechanismus yon 2-(2,6-Dichlorophenylamino)-2-imidazolin hydrochlorid (Catapresan ®, St 155), Arch. Exptl. Pathol. Pharmacol. 257,291. Kobinger, W. and A. Walland, 1967, Circulatory studies with 2-(2,6-dichlorophenylamino)2-imidazoline hydrochloride, Arzneimittel-Forsch. 17,292. Kroneberg, G., A. Oberdorf, F. Hoffmeister and W. Wirth, 1967, Zur Pharmakologie von 2-(2,6-Dimethylphenylamino)-4H-5,6-dihydro-l,3-thiazin (Bayer 1470) eines Hemmstoffes adrenergischer und cholinergischer Neurone, Arch. Exptl. Pathol. Pharmacol. 256,257. Laubie, M., and H. Schmitt, 1969, Effets h~modynamiques du St 155 (2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride chez le chien hypertendu, Arch. Intern. Pharmacodyn. 179, 23. Lewis, C.M., and M.H. Weft, 1969, Haemodynamic spectrum of vasopressor and dilatator drugs, J. Am. Med. Assoc. 20 P, 1391. Maxwell, G.M., 1969, The effects of 2-(2,6-dichlorophenylamino)2-irnidazoline hydrochloride (Catapres (El) upon the systemic and coronary haemodynamics and metabolism of intact dogs, Arch. Intern. Pharmacodyn. 181, 7. Mujic, M. and J.M. van Rossum, 1965, Comparative pharmacodynamics of sympathomimetic imidazolines. Studies on intestinal smooth muscle of the rabbit and the cardiovascular system of the cat, Arch. Intern. Pharmacodyn. 155,432. Potter, L.T. and J. Axelrod, 1963, Studies on the storage of norepinephrine and the effects of drugs, J. Pharmacol. Exptl. Therap. 140, 199. Sarnoff, S.J. and E. Berglund, 1954, Ventricular function I. Starling's law of the heart studied by means of simultaneous right and left ventricular function curves in the dogs, Circulation 9, 706. Schmitt, H. and S. F~nard, 1970, Effects of sympathomimetic drugs on vasomotor centers, Arch. Intern. Pharmacodyn., in press. Schrnitt, H., G. Fournadjiev and Mme H. Schmitt, 1970, Central and peripheral effects of 2-(2,6-dimethylphenylamino)-4-H,5,6 dihydro-l,3-thiazin (Bayer 1470) on sympathetic system, European J. Pharmacol. 10, 230. Schmitt, H., J.F. Giudicelli, P. Viars and J.R. Boissier, 1970, Des effets cardiovasculaires de la n4osyn4phrine et de l'6thylnoradr~naline, J. Pharmacol. (Paris) 1,267. Schmitt, H., Mme H. Schmitt, J.R. Boissier and J.F. Giudicelli, 1967, Centrally mediated decrease in sympa-
A.M.Autert et aL, Haemodynamic effects of a-sympathomimetic drugs thetic tone induced by 2-(2,6-dichlorophenylamino)-2imidazoline (Catapresan(g), St 155), European J. Pharmacol. 2, 147. Schmitt, H., Mine H. Schmitt, J.R. Boissier, J.F. Giudicelli and J. Fichelle, 1968, Cardio vascular effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hvdrochloride
217
(St 155) II. Central sympathetic structures, European J. Pharmacol. 2, 340. Shipley, R.E. and J.H. Tilden, 1949, A pithed rat preparation suitable for assaying pressor substances, Proc. Soc. Exptl. Biol. Med. 64, 453.
COMPARISON
OF HAEMODYNAMIC
EFFECTS
OF
c~-SYMPATHOMIMETIC DRUGS A.M. AUTRET, H. SCHMITT, S. FENARD and N. Pt~TILLOT Ddpartement de Pharmacologie, Facultd de Mddecine de Paris, Broussais, HOtel Dieu, 15, rue de l'Ecole de Mddeeine 75, Paris 6e, France
Received 16 June 1970
Accepted 17 September 1970
A.M. AUTRET, H. SCHMITT, S. FENARD and N. Pt~TILLOT, Comparison of haemodynamic effects of o~sympathomimetic drugs European J. Pharmacol. 13 (1971) 208 217.
Dose-response curves for nine Ct-sympathomimetic drugs were determined in pithed rats. The order of potency was: norepinephrine 1, phenylephrine 0.1, oxymetazoline 0.1, clonidine 0.029, LD 2855 0.028, naphazoline 0.087, tramazoline 0.030, tetryzoline 0.01, Bayer 1470 0.0003. Pretreatment with reserpine (10 mg/kg 24 hr before) did not change the dose-response curves; phentolamine (2 mg/kg) shifted the dose-response curve to the right but did not change the maximal response suggesting competitive antagonism; phenoxybenzamine (2 mg/kg) shifted the dose-response curve to the right and reduced the maximal response suggesting non-competitive antagonism. Cocaine (5 mg/kg) and imipramine (2 mg/kg) reduced the hypertension produced by clonidine but increased slightly hypertension following naphazoline. Clonidine (3-30 ~g/kg)induced biphasic changes in blood pressure - a rise followed by a long decrease, bradycardia, decrease in aortic blood flow, femoral and coronary blood flows. Naphazoline (5 to 45 ~g/kg) induced a rise in blood pressure, a fall in aortic blood flow, a bradycardia, a pulmonary hypertension, a decrease in femoral and coronary blood flows. Total, pulmonary, coronary and femoral resistances were elevated. Performances of the left ventricle were reduced. The mechanisms of these changes were discussed. o~-Sympathomimetic agents
Haemodynamic effects
1. INTRODUCTION According to the concept of Ahlquist (1949), adrenergic receptors are divided into two classes, c~ and fl; each sympathomimetic agent activates either one type o f receptors or exerts effects on both types. Much data has been published on the pharmacology o f catecholamines and /3-sympathomimetic drugs. However the literature on a-sympathomimetic agents is more scarse. Phenylephrine, a classic a - s y m p a t h o m i m e t i c agent has recently been reinvestigated (Schmitt et al., 1970). Mujic and van Rossum (1965) reported typical t~-sympathomimetic effects for compounds of the imidazoline series. However, tetryzoline (Hutcheon et al., 1958) and
Catapresan
Naphazoline
oxymetazoline (Hotovy et al., 1961) were only reported to reduce cardiac output. On the other hand, c~-sympathomimetic agents with marked central effects have been described; they induce biphasic changes in blood pressure: a short hypertension followed by a long-lasting decrease in blood pressure; they reduce heart rate and cardiac output and inhibit vasomotor centres. The substances which have been most commonly investigated are 2-(2,6-dichlorophenylamino)-2-imidazoline (clonidine, St 155, Catapresan O ) ( H o e f k e and Kobinger, 1966; Kobinger and Walland, 1967; Schmitt et al., 1967, 1968; Laubie and Schmitt, 1969; Maxwell, 1969); 2-(2,6-dimethylphenylamino)-4H-5,6-dihydro1,3-thiazin (xylazine, Bayer 1470) (Kroneberg et al.,
A.M.Autert et aL, Haemodynamic effects o f ot-sympathomimetic drugs
1967; Schmitt et al., 1970) and 2-(2,6-dimethylphenylamino)-2A 2-oxazoline-1,3 (LD 2855) (Giu~dicelli et al., 1958; Giudicelli and Schmitt, 1970). The present work was undertaken: a) to compare the pressor response to these a-sympathomimetic agents in pithed rats: b ) t o study the influence exerted by classic a-adrenergic blocking drugs and by compounds inhibiting axonal reuptake of catecholamines (cocaine, imipramine) on these responses; and c) to investigate the haemodynamic changes induced by naphazoline, tetryzoline and oxymetazoline and to compare these with the effects of phenylephrine and clonidine.
2. METHODS Pithed rats were prepared according to Shipley and Tilden (1949). Carotid blood pressure was recorded on a smoked drum by means of a Condon's mercury manometer. Six rats were used for each experiment. Drugs were injected into the femoral vein using a Latin square design until the maximal response was reached. Dose-response curves were drawn and the relative potencies of the drugs were calculated as the ratio of doses inducing half of the maximal response. Antagonism or potentiation was determined after intravenous injection of a-adrenergic blocking drugs (phentolamine, 2 mg/kg; phenoxybenzamine, 2 mg/ kg) or agents inhibiting the axonal reuptake of catecholamines (cocaine, 5 mg/kg; imipramine, 2 mg/ kg); the dose-response curve was determined 10 min after this injection. In another set of experiments, rats were pretreated with reserpine (10 mg/kg, i.p.; 2 4 h r beforehand) and dose-response curves were determined. To investigate haemodynamic changes, dogs of either sex weighing 10-25 kg were anaesthetized with pentobarbital (30mg/kg, i.v.). A cuffed endotracheal cannula was introduced and artificial respiration with a Bird Mark IV pump commenced. Carotid blood pressure was recorded by means of a Statham P 23 Db pressure transducer on a San'Ei recorder. A catheter was pushed into the pulmonary artery through the right jugular vein and pulmonary pressure was recorded by means of a second P 23 Db pressure transducer. The left chest wall was opened at
209
the level of the fourth intercostal space and the left lung was gently displaced to expose the heart. The pericardium was entered and approximately 20 mm of the ascending aorta was cleared of fat and separated from the pulmonary artery. Blood flow through the ascending aorta was monitored with a Statham flow probe (serie Q; 10-16 mm internal diameter) positioned around the external circumference of the vessel. The flow probe signals were fed into a Statham electromagnetic flowmeter 4001 and then relayed to the recording unit. Instantaneous and mean aortic blood flows were recorded on two separate channels. An aortic pulse measurement of zero was taken as diastolic flow. Heart rate was measured with a Racia cardiotachometer fed with the blood pressure signal. Femoral blood flow was measured continuously by means of a Statham flow probe (serie Q; internal diameter 2 - 3 ram) and recorded on the sixth channel of the polygraph. In one third of the experiments left ventricular pressure, left ventricular end diastolic pressure and the maximal rate of development in ventricular isometric tension were recorded instead of pulmonary pressure and femoral blood fow. For these recordings, a catheter connected to a Statham P 23 Db pressure transducer was pushed into the left ventricle through the right femoral artery. The left ventricular pressure was recorded on a channel of the recording unit and the left ventricular end diastolic pressure on another channel after a fivefold amplification. The LVP sign',d was differentiated with a resistance capacity network (time constant: 10-s) and the rate of rise of left ventricular pressure was recorded. Myocardial contractile force was measured with a Walton-Boniface gauge arch sutured to the left ventricle (Boniface et al., 1953; Cotten, 1953). Coronary blood flow was measured with a Statham flow probe (series S; 1.5-2.5 mm internal diameter) positioned around the left circonflex coronary artery. The signal was fed to an electromagnetic flowmeter 4001 and recorded on the polygraph. The following parameters were measured: systolic blood pressure in mm Hg; diastolic blood pressure in mm Hg; systolic pulmonary pressure in mm Hg; diastolic pulmonary pressure in mm Hg; heart rate in beats/min; left ventricular pressure in mm Hg; left ventricular end diastolic pressure in mm Hg; maximal
210
A.M.Autert et aL, Haemodvnamic effects o f o~-sympathomimetic drugs
rate of rise in isometric tension of left ventricle in mm Hg/sec; myocardial contractile force in g; phasic and mean aortic blood flow in 1/min; femoral blood flow in ml/min; coronary blood flow in ml/min. The following parameters were calculated: mean blood pressure = diastolic blood pressure + 0.43 (systolic blood pressure - diastolic blood pressure); mean pulmonary pressure = diastolic pulmonary pressure + 0.43 (systolic pulmonary pressure - diastolic pulmonary pressure); total peripheral resistance in dynes sec cm -s = m e a n blood pressure in cm Hg X 981 X 13.6 X 60/aortic blood flow in ml/min; stroke volume in ml = aortic blood flow in ml/heart rate in beats/min; left ventricular work in kg/min = mean blood pressure in mm Hg X 13.6 X 1.055 X aortic blood flow in 1/min; left ventricular stroke work in g = left ventricular work in g/heart rate in beats/min; right ventricular work in kg/min = mean pulmonary pressure in mm Hg X 13.6 X 1.055X aortic blood flow in l/rain; pulmonary resistance in dynes sec cm -s = pulmonary pressure in mm Hg X 981 X 13.6 X 60/aortic blood flow in ml/min; femoral resistance in mm H g / m l = m e a n blood pressure in mm Hg/mean femoral blood flow in ml/min; coronary resistance in mm Hg/ml = mean blood pressure in mm Hg/mean coronary blood flow in ml/min.
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Fig. 1. Dose-response curves for sympathomimetic drugs in pithed rats. The figure shows the dose-response curves for nine sympathomimetic drugs.
3. RESULTS 3.1. Dose-response curves of a-sympathomimetic agents in pithed rats The dose-response curves for each a-sympathomimetic agent was determined in six pithed rats (fig. 1). Dose-response curves were sigmoidal and parallel to each other. The maximal response was about 130 mm Hg. The relative potencies calculated from the doses producing half the maximal response (65 mm Hg) and taking the potency of noradrenaline as 1 were: oxymetazoline 0.1, phenylephrine 0.1, naphazoline 0.087, clonidine 0.029, LD 2855 0.028, tramazoline 0.030, tetryzoline 0.01, xylazine 0.0003. 3.2. Influence of ~-adrenergic blocking drugs on
dose-response curves of a-sympathomimetic agents Phentolamine (2 mg/kg) shifted the dose-response curve to the right but did not change the maximal
response. In contrast phencrxybenzamine (2 mg/kg) not only shifted the dose-response curve to the right but also reduced the maximal response (figs. 2 and 3). 3.3. Influence of cocaine and imipramine on the dose-response curves of a-sympathomimetic agents Cocaine (5 mg/kg) and imipramine (2mg/kg) shifted the dose-response curves of noradrenaline and phenylephrine to the left and increased somewhat the maximal response. In contrast, cocaine decreased the response to clonidine, LD 2855 but increased slightly responses to naphazoline (fig. 4). Guanethidine did not change the effects of the three drugs. 3.4. Actions on reserpinized rats Pretreatment with reserpine shifted the doseresponse curve to the left for noradrenaline and phenylephrine but did not change the dose-response
A.M.Autert et al., Haemodynamic effects of C~-sympathomimetic drugs
211 Controls
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212
A.M.Autert et al., Haemodynamic effects of OL-sympathomimetic drugs C o c a I ne
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3.5. Haemodynamic effects o f clonidine and naphazoline Clonidine (3 to 30/~g/kg) induced a brief increase in blood pressure followed by a long-lasting fall. Heart rate slowed and bradycardia was most marked several minutes after injection. A dose-dependent reduction in aortic blood flow occurred (fig. 5); this reduction was more marked during the hypertensive phase; aortic blood flow began to decrease before any change in blood pressure and heart rate. Stroke volume was slightly decreased only during the hypertensive phase. Total peripheral resistance was markedly elevated during hypertension but was not altered during hypotension. With high doses, pulmonary pressure rose during the hypertensive phase; pulmonary vascular resistance was increased during both phases because of the reduction in aortic blood flow; left ventricular work and stroke work
were reduced during both phases. Clonidine reduced the indices of left ventricular performance: rate of rise in left ventricular pressure, velocity of blood in the ascending aorta; an increase in left ventricular end diastolic pressure appeared with a reduced stroke work and these reductions were more marked during hypertension. However, myocardial contractile force did not change or even slightly increased during hypertension and thereafter a progressive decline was seen. Femoral and coronary blood flows were significantly decreased. Table 1 and fig. 6 illustrate haemodynamic changes induced by naphazoline. Naphazoline (5 to 45/2g/kg) induced a dose-dependent increase in blood pressure lasting 5 to 60 min; pulse pressure was reduced. Low doses (5/2g/kg) did not alter heart rate but higher doses reduced heart rate and the bradycardia was very marked when the blood pressure was at its nadir. Aortic blood flow fell in a dose-dependent manner before any change in blood pressure and heart rate. Stroke volume was reduced. Left ventricular work increased significantly with the lower doses but decreased with the higher doses.
A.M.Autert et al., Haemodynamic effects o f Ot-sympathomimetic drugs
213
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Fig. 5. Haemodynarnic changes induced by clonidine. Clonidine (3 and 5 t~g/kg) induced biphasic changes in blood pressure-rise followed by a long-lasting decrease - a fall in aortic blood flow and heart rate; peripheral resistance rose during the hypertension. Stroke work was not changed. Pulmonary pressure was not changed by low doses but significantly increased with high doses; pulmonary pressure was significantly increased in both cases whereas femoral and coronary blood flows declined. The indices of ventricular performance were decreased in the same way as in the hypertensive
phase following clonidine. Atropine (0.3 mg/kg) and bilateral vagotomy reduced or even abolished bradycardia but did not alter the changes in the other parameters. In a few experiments, tetryzoline ( 1 0 - 1 0 0 #g/kg) and oxymetazoline (1-10/ag/kg) were shown to cause similar changes.
A:M.Autert et aL, Haemodynamic effects of ot-sympathomimetic drugs
214
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Table 1 H a e m o d y n a m i c effects induced by naphazoline in dogs.
Systolic blood pressure ( m m Hg) Diastolic blood pressure ( m m Hg) Mean blood pressure ( m m Hg) Heart rate (beats/min) Aortic blood flow (1/min) Stroke volume (ml) Peripheral resistance (dynes sec cm -5) Left ventricular work (kg/min) Stroke work (g) Mean p u l m o n a r y pressure ( m m Hg) Pulmonary resistance (dynes sec cm -5) Right ventricular work (kg/min) Left ventricular end diastolic pressure ( m m Hg) d LVP/dt ( m m Hg/sec) Myocardial contractile force (p 100) Femoral blood flow (ml/min) Femoral resistance ( m m Hg/ml) Coronary blood flow (ml/min) Coronary resistance ( m m Hg/ml) * p(0.05,
** p ( 0 . 0 1 .
Naphazoline (5 ug/kg)
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A.M.Autert et aL, Haemodynamic effects of Ot-sympathomimetic drugs
4. DISCUSSION In this paper the abilities of nine a-sympathomimetic agents to raise blood pressure in pithed rats were compared. Noradrenaline, phenytephrine and oxymetazoline were the most potent agents. Clonidine, LD2855, naphazoline and tramazoline were about equally effective. Tetryzoline was of intermediate potency and xylazine was the least active. Pretreatment with reserpine did not alter the pressor responses to these drugs in agreement with previous experiments performed with clonidine (Kobinger and Walland, 1967; Boissier et al., 1968), xylazine (Schmitt et al., 1970), naphazoline, tetryzoline, tramazoline and oxymetazoline (Mujic and van Rossum, 1965). Therefore these drugs are directly acting c~-sympathomimetic agents. Phentolamine shifted the dose-response curves to the right without changing the maximal effect suggesting competitive antagonism; phenoxybenzamine shifted not only the dose-response curve to the right but also redlaced the maximal effect suggesting non-competitive antagonism. These results confirm and extend previous observations (Kobinger and Walland, 1967; Boissier et al., 1968; Constantine and Mac Shane, 1968; Kroneberg et al., 1967; Schmitt et al., 1970; Bentley and Li, 1968; Giudicelli et al., 1958, 1970; Mujic and van Rossum, 1965, Hutcheon et al., 1955, 1958; Hotovy et al., 1961). Cocaine and imipramine shifted the dose-response curves of noradrenaline and phenylephrine to the left but reduced slightly the effects of clonidine; the action of naphazoline was slightly potentiated. The potentiating effect of both drugs is usually accounted for by inhibition of the axonal reuptake of catecholamines (Hertting and Axelrod, 1961 ; Hertting et al., 1961 ; Potter and Axelrod, 1965). Thus it would be concluded that this process of inactivation is only a minor one for these a-sympathomimetic drugs. It is noteworthy that the potency of these a-sympathomimetic drugs on peripheral a-adrenergic receptors was different from the potency on central receptors inhibiting the vasomotor centres and inducing sedation (Schmitt and F~nard, 1970; Delbarre and Schmitt, 1971). The haemodynamic changes induced by naphazoline were similar to those produced by phenyleph-
215
rine: a dose-dependent increase in blood pressure, bradycardia, fall in aortic blood flow, increase in total peripheral resistance, increased pulmonary pressure and resistance. Left ventricular performance was reduced as evidenced by the decrease in the velocity of aortic blood flow and in the maximal rate of rise of left ventricular pressure. Moreover an increase in left ventricular and diastolic pressure occurred with a reduced stroke work (Samoff and Berglund, 1954). However, the myocardial contractile force did not change revealing that naphazoline did not impair the contractile machinery directly or indirectly through the sympathetic system. Reduced aortic blood flow must therefore be due to three indirect causes: a) bradycardia; b) decreased venous return revealed in some experiments by changes in aortic blood flow without any alteration in other haemodynamic parameters, c)increased aortic pressure. The mechanism for reduction in venous return is unknown but is caused by activation of a-adrenergic receptors (Lewis and Weil, 1969). The reduction in left ventricular performance was indirectly produced and could be due to a) reduced venous return diminishing the size of the heart, b)bradycardia acting through the Bowditsch effect c)but the increased aortic pressure had opposite effects. Reduction in femoral blood flow was the result of direct a-sympathomimetic vasoconstriction, whereas the decrease in coronary blood flow could also be due to bradycardia reducing the oxygen comsumption of the heart. The elevation of left ventricular end diastolic pressure is difficult to account for; the hypertension tended to increase this pressure but the reduced venous return had the opposite effect. The haemodynamic changes induced by clonidine during the hypertensive phase were similar to those of naphazoline and were presumably produced by similar actions. However, the central reduction in sympathetic tone was an additional factor for the decrease in aortic blood flow and left ventricular performance; this factor was the predominant one during the hypotensive phase. Tetryzoline and oxymetazoline induced changes similar to naphazoline. Thus a-sympathomimetic agents produce a rise in blood pressure due to vasoconstriction, a fall in cardiac output and bradycardia. In addition, some of these
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A.M.Autert et aL, Haemodynamie effects of ~-svmpathomirnetic drags
drugs, like clonidine, xylazine and LD 2855 also reduced centrally the sympathetic tone inducing a secondary fall in b l o o d pressure.
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