- Email: [email protected]
KETANSERIN: A SELECTIVE SEROTONIN ANTAGONIST
859 dose of corticosteroids the ultimate
prognosis is good. comprehensive but contributed little to the underlying pathogenesis. IgG, IgA, and complement factors C3 and C4 were all increased but circulating immune complexes were not found with increased frequency. There was no evidence of increased transformation of lymphocytes exposed to arterial wall homogenate as reported by others." Despite this painstaking study of immunological mechanisms the cause of this curious disease still eludes us. Jonathan Hutchinson suggested it might be the pressure from Mr Rumbold’s hat which provoked the inflammation. Perhaps we have not come so far
Laboratory
investigations
were
since 1890.
KETANSERIN: A SELECTIVE SEROTONIN ANTAGONIST SEROTONIN (5-HT) is an important neurotransmitter in the central nervous system, has a neuroendocrine role in the gut, mediates painful stimuli peripherally, and is one of several substances in platelets which when released promote platelet aggregation. It also has an effect on vascular smooth muscle, largely constrictive. Various substances, particularly methysergide, will stimulate or block the effects of serotonin at some of these sites. With the development of ketanserin, serotonin receptors can now be studied in more detail. Two types of serotonin receptor have been distinguished in homogenised rat cerebral frontal cortex by means of tritiated 5-HT and tritiated spiroperidol; the receptors are denoted 5- HT and 5- HT 2’ Ketanserin displays a high binding affinity at 5-HT receptors and is inactive at 5-HT sites. Such differential binding in favour of 5-HT2 receptors is not a property of some other 5-HT antagonists (metergoline, lysergide, methysergide, cyproheptadine, and pizotifen).22 Initial results from animal and clinical studies suggest that 5-HT receptors exist in vascular smooth muscle and possibly platelets. Ketanserin is also bound somewhat to histamine (HI) and a1pharadrenergic receptors, the affinity at both these receptors being about one-fifth of that observed with 5-HT receptors.’I In the central mediation of blood-pressure, the physiological role of serotonin is uncertain. Manipulation of cerebral serotonin levels in laboratory animals has variable effects on vascular tone; for example, the effects in rats are 3 generally opposite to those seen in cats and dogs.3 Peripherally, serotonin causes vascular smooth-muscle contraction in rats and dogs directly and via an amplification effect on alpha I-adrenergic stimulation. These effects are antagonised by ketanserin at lower doses than would be required to block adrenergic stimulation-i.e., the low dose of ketanserin abolishes the amplifying effect of serotonin on alphal-adrenergic stimulation without affecting the contractile response to noradrenaline.4 Likewise, in rings of rabbit femoral arteries serotonin amplifies the pressor effect
of histamine, angiotensin II, and prostaglandin F2a, and this amplification effect was antagonised by ketanserin. When used acutely, ketanserin has a hypotensive action in man. In 12 patients with essential hypertension intravenous fall in arterial blood-pressure (measured directly), pulmonary artery pressure, pulmonary wedge pressure, and right atrial pressure. The calculated total peripheral resistance fell despite increases in plasma noradrenaline and active renin (probably a baroceptor response).6 Likewise, in a group of 23 elderly hypertensives systolic and diastolic blood-pressure fell significantly within five minutes after intravenous ketanserin (10 mg) and remained low for 30 minutes.’ In 8 patients with severe congestive cardiac failure already treated with digitalis, diuretics, and in some cases vasodilators, a single intravenous dose of ketanserin significantly improved cardiac output.8 Ketanserin has also been tried in thrombophlebitis. Effective pain relief was recorded in a double-blind, placebo-controlled study of 22 patients. Whether the drug blocks serotonininduced venoconstriction, directly inhibits serotonininduced pain, or works through some other mechanism is 9 ketanserin caused
unknown.
M, MacLennan ICM, Hazleman BL. Lymphocyte sensitivity to skeletal muscle in patients with polymyositis and other disorders. Clin Exp Immunol 1973; 14: 25. 1. Peroutka SJ, Snyder SH. Multiple serotonin receptors: differential binding of [3H] 5-hydroxytryptamine, [3H]lysergic acid diethylamide and[3H] spiroperidol. Molec Pharmacol 1979; 16Z: 687-99. 2 Lysen JE, Awonters F, Kennis L, Laduron PM, Vanderberk J, Janssen PAJ. Receptor binding profile of R41 468, a novel antagonist at 5-HT2 receptors. Life Sci 1981; 28: 1015-22. 3. Kuhn
4
DM, Wolf WA, Lovenburg W. Review of the role of the central serotonergic neuronal system in blood pressure regulation. Hypertension 1980; 2: 243-55. Van Nueten JM, Janssen PAJ, Van Beek J, Xhonneux R, Verbeuren TJ, Vanhoutte PM Vascular effects of ketanserin (R41 468), a novel antagonist of 5-HT2 serotonergic receptors. J Pharmacol Exp Ther 1981; 218: 217-30.
,
Another area of possible relevance is coronary artery spasm, the pathogenesis of which remains controversial stimulation, 10 despite evidence in favour of alpha-adrenergic thromboxane A2 release,1I and a local deficit of prostacyclin.l2 Any of these mechanisms could theoretically result in the increased number -of platelet aggregates in coronary-sinus blood observed after episodes of coronary artery spasm.’3 Henry and Yokoyama 14 studied the threshold for ergometrine-induced contractile responses in isolated rabbit aortas in two populations, one on a normal diet and the other on a high cholesterol diet. The high cholesterol group showed supersensitivity to the contractile effects of ergometrine and this was little affected by previous alphaadrenergic blockade; cyproheptadine did, however, reduce the effect, suggesting that contraction in this experiment was mediated by a serotonergic mechanism. These experimental and preliminary clinical results will encourage further work on the possible therapeutic role of ketanserin in cardiovascular medicine. In particular it is important to establish whether the mechanism of action in man is by 5- HT receptor inhibition rather than via blockade of other pressor substances. 5. Van Nueten
JM, Janssen PAJ, De Ridder W, Vanhoutte PM. Interactions between 5-hydroxytryptamine and other vasoconstrictor substances in the isolated femoral artery of the rabbit; effect of ketanserin (R41 468). Europ J Pharmacol 1982; 77: 281-97.
Man in ’t Veld AJ, Woittiez AJ, Boomsma F, Schalekamp MADH. Treatment of hypertension with ketanserin, a new selective 5-HT2 receptor antagonist. Br Med J 1982; 284: 537-39. 7. De Cree J, Verhaegen H, Symoens J. Acute blood pressure lowering effect of ketanserin. Lancet 1981; i: 1161-62. 8. Demoulin J-C, Bertholet M, Soumagne D, David J-L, Kalbertus HE. 5-HT2receptor blockade in the treatment of heart failure; a preliminary study. Lancet 1981; i: 1186-88. 9. De Roose J, Symoens J. Ketanserin in acute superficial thrombophlebitis. Lancet 1982; 6.
Wenting GJ,
i: 440-41. 10. Yasue H, Tonyama 11.Esiri
a
M, Kato H, Tanaka S, Akiyama F. Prinzmetal’s variant form of manifestation of alpha-adrenergic receptor mediated coronary artery spasm: a documentation by coronary arteriography. Am Heart J 1976; 91: 148-55. 11. Ellis EF, Oelz O, Roberts IJ, Payne NA, Sweetman BJ, Nico AS, Oates JA. Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2. Science 1977; 193: 1135-37. 12. Lefler A, Ogletree M, Smith J, Silver M, Nicolaou K, Barnett W, Gasic G. Prostacyclin: a potentially valuable agent for preserving myocardial tissue in acute myocardial ischaemia. Science 1978; 200: 52-54. 13. Robertson RM, Robertson D, Friesinger GC, Timmons S, Haniger J. Platelet aggregates in peripheral and coronary sinus blood in patients with coronary artery spasm. Lancet 1980; ii: 829-31. 14. Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine. J Clin Invest 1980; 66: 306-13. angina
as a
prognosis is good. comprehensive but contributed little to the underlying pathogenesis. IgG, IgA, and complement factors C3 and C4 were all increased but circulating immune complexes were not found with increased frequency. There was no evidence of increased transformation of lymphocytes exposed to arterial wall homogenate as reported by others." Despite this painstaking study of immunological mechanisms the cause of this curious disease still eludes us. Jonathan Hutchinson suggested it might be the pressure from Mr Rumbold’s hat which provoked the inflammation. Perhaps we have not come so far
Laboratory
investigations
were
since 1890.
KETANSERIN: A SELECTIVE SEROTONIN ANTAGONIST SEROTONIN (5-HT) is an important neurotransmitter in the central nervous system, has a neuroendocrine role in the gut, mediates painful stimuli peripherally, and is one of several substances in platelets which when released promote platelet aggregation. It also has an effect on vascular smooth muscle, largely constrictive. Various substances, particularly methysergide, will stimulate or block the effects of serotonin at some of these sites. With the development of ketanserin, serotonin receptors can now be studied in more detail. Two types of serotonin receptor have been distinguished in homogenised rat cerebral frontal cortex by means of tritiated 5-HT and tritiated spiroperidol; the receptors are denoted 5- HT and 5- HT 2’ Ketanserin displays a high binding affinity at 5-HT receptors and is inactive at 5-HT sites. Such differential binding in favour of 5-HT2 receptors is not a property of some other 5-HT antagonists (metergoline, lysergide, methysergide, cyproheptadine, and pizotifen).22 Initial results from animal and clinical studies suggest that 5-HT receptors exist in vascular smooth muscle and possibly platelets. Ketanserin is also bound somewhat to histamine (HI) and a1pharadrenergic receptors, the affinity at both these receptors being about one-fifth of that observed with 5-HT receptors.’I In the central mediation of blood-pressure, the physiological role of serotonin is uncertain. Manipulation of cerebral serotonin levels in laboratory animals has variable effects on vascular tone; for example, the effects in rats are 3 generally opposite to those seen in cats and dogs.3 Peripherally, serotonin causes vascular smooth-muscle contraction in rats and dogs directly and via an amplification effect on alpha I-adrenergic stimulation. These effects are antagonised by ketanserin at lower doses than would be required to block adrenergic stimulation-i.e., the low dose of ketanserin abolishes the amplifying effect of serotonin on alphal-adrenergic stimulation without affecting the contractile response to noradrenaline.4 Likewise, in rings of rabbit femoral arteries serotonin amplifies the pressor effect
of histamine, angiotensin II, and prostaglandin F2a, and this amplification effect was antagonised by ketanserin. When used acutely, ketanserin has a hypotensive action in man. In 12 patients with essential hypertension intravenous fall in arterial blood-pressure (measured directly), pulmonary artery pressure, pulmonary wedge pressure, and right atrial pressure. The calculated total peripheral resistance fell despite increases in plasma noradrenaline and active renin (probably a baroceptor response).6 Likewise, in a group of 23 elderly hypertensives systolic and diastolic blood-pressure fell significantly within five minutes after intravenous ketanserin (10 mg) and remained low for 30 minutes.’ In 8 patients with severe congestive cardiac failure already treated with digitalis, diuretics, and in some cases vasodilators, a single intravenous dose of ketanserin significantly improved cardiac output.8 Ketanserin has also been tried in thrombophlebitis. Effective pain relief was recorded in a double-blind, placebo-controlled study of 22 patients. Whether the drug blocks serotonininduced venoconstriction, directly inhibits serotonininduced pain, or works through some other mechanism is 9 ketanserin caused
unknown.
M, MacLennan ICM, Hazleman BL. Lymphocyte sensitivity to skeletal muscle in patients with polymyositis and other disorders. Clin Exp Immunol 1973; 14: 25. 1. Peroutka SJ, Snyder SH. Multiple serotonin receptors: differential binding of [3H] 5-hydroxytryptamine, [3H]lysergic acid diethylamide and[3H] spiroperidol. Molec Pharmacol 1979; 16Z: 687-99. 2 Lysen JE, Awonters F, Kennis L, Laduron PM, Vanderberk J, Janssen PAJ. Receptor binding profile of R41 468, a novel antagonist at 5-HT2 receptors. Life Sci 1981; 28: 1015-22. 3. Kuhn
4
DM, Wolf WA, Lovenburg W. Review of the role of the central serotonergic neuronal system in blood pressure regulation. Hypertension 1980; 2: 243-55. Van Nueten JM, Janssen PAJ, Van Beek J, Xhonneux R, Verbeuren TJ, Vanhoutte PM Vascular effects of ketanserin (R41 468), a novel antagonist of 5-HT2 serotonergic receptors. J Pharmacol Exp Ther 1981; 218: 217-30.
,
Another area of possible relevance is coronary artery spasm, the pathogenesis of which remains controversial stimulation, 10 despite evidence in favour of alpha-adrenergic thromboxane A2 release,1I and a local deficit of prostacyclin.l2 Any of these mechanisms could theoretically result in the increased number -of platelet aggregates in coronary-sinus blood observed after episodes of coronary artery spasm.’3 Henry and Yokoyama 14 studied the threshold for ergometrine-induced contractile responses in isolated rabbit aortas in two populations, one on a normal diet and the other on a high cholesterol diet. The high cholesterol group showed supersensitivity to the contractile effects of ergometrine and this was little affected by previous alphaadrenergic blockade; cyproheptadine did, however, reduce the effect, suggesting that contraction in this experiment was mediated by a serotonergic mechanism. These experimental and preliminary clinical results will encourage further work on the possible therapeutic role of ketanserin in cardiovascular medicine. In particular it is important to establish whether the mechanism of action in man is by 5- HT receptor inhibition rather than via blockade of other pressor substances. 5. Van Nueten
JM, Janssen PAJ, De Ridder W, Vanhoutte PM. Interactions between 5-hydroxytryptamine and other vasoconstrictor substances in the isolated femoral artery of the rabbit; effect of ketanserin (R41 468). Europ J Pharmacol 1982; 77: 281-97.
Man in ’t Veld AJ, Woittiez AJ, Boomsma F, Schalekamp MADH. Treatment of hypertension with ketanserin, a new selective 5-HT2 receptor antagonist. Br Med J 1982; 284: 537-39. 7. De Cree J, Verhaegen H, Symoens J. Acute blood pressure lowering effect of ketanserin. Lancet 1981; i: 1161-62. 8. Demoulin J-C, Bertholet M, Soumagne D, David J-L, Kalbertus HE. 5-HT2receptor blockade in the treatment of heart failure; a preliminary study. Lancet 1981; i: 1186-88. 9. De Roose J, Symoens J. Ketanserin in acute superficial thrombophlebitis. Lancet 1982; 6.
Wenting GJ,
i: 440-41. 10. Yasue H, Tonyama 11.Esiri
a
M, Kato H, Tanaka S, Akiyama F. Prinzmetal’s variant form of manifestation of alpha-adrenergic receptor mediated coronary artery spasm: a documentation by coronary arteriography. Am Heart J 1976; 91: 148-55. 11. Ellis EF, Oelz O, Roberts IJ, Payne NA, Sweetman BJ, Nico AS, Oates JA. Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2. Science 1977; 193: 1135-37. 12. Lefler A, Ogletree M, Smith J, Silver M, Nicolaou K, Barnett W, Gasic G. Prostacyclin: a potentially valuable agent for preserving myocardial tissue in acute myocardial ischaemia. Science 1978; 200: 52-54. 13. Robertson RM, Robertson D, Friesinger GC, Timmons S, Haniger J. Platelet aggregates in peripheral and coronary sinus blood in patients with coronary artery spasm. Lancet 1980; ii: 829-31. 14. Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine. J Clin Invest 1980; 66: 306-13. angina
as a