287
Kinins and their antagonists peptides that were classified as a group because they were found to have potent pharmacological properties in common. All cause Kinins
are
hypotension and lead to contraction of many isolated smooth muscle preparations. They relax rat duodenum, increase vascular permeability in man and
animals, and produce pain in animals and in human skin when applied to a blister base. They induce bronchoconstriction in guineapigs, which is antagonised specifically by salicylate and by other non-steroidal anti-inflammatory compounds.1 The prototype of this group of compounds is bradykinin, a nonapeptide with the formula H-Arg-Pro-Pro-Gly-
Phe-Ser-Pro-Phe-Arg-OH. Bradykinin and kallidin (Lys-bradykinin) are the main peptides generated by limited proteolysis from an inactive precursor, kininogen. The active peptide is inactivated by several peptidases, kininases, in tissues and body fluids. Kininase II, one of the most effective of these enzymes, also converts angiotensin I to angiotensin II. Knowledge of these systems led to the synthesis of captopril, an orally active drug that inhibits the generation of angiotensin II and stabilises bradykinin; both effects tend to lower blood pressure.2,3 Kinins are released by the proteolytic action of a group of endogenous serine proteases called kallikreins (or kininogenases), which are present in many tissues. A "kallikrein" in plasma has a similar catalytic site but a different general chemical structure and less substrate specificity. Most of these proteases release kallidin-ie, Lys bradykinin-from kininogen, whereas the serine proteases trypsin and plasma kallikrein release bradykinin. Bradykinin and kallidin show only slight quantitative variation in their pharmacological properties and also react similarly to antagonists. Some kallikreins exist in tissues in an active form, but plasma kallikrein and most tissue kallikreirs (eg, trypsin) are present as inactive precurso s. However, these precursors are readily activated by other enzymes, and can then release kinins. There are also endogenous inhibitors which can bind kallikrein.4-6 Aprotinin, a polyvalent protease inhibitor present in mast cells, has been used with limited success in pancreatitis. This compound also reduces perioperative blood loss after open heart and other major surgery, although its mechanism of action in this respect is obscure.7,8 The chemical structures of bradykinin and kallidin were established in 1960 and 1961, respectively. Hundreds of analogues were synthesised but no effective antagonists were found for 25 years. Bradykinin receptors were first classified by Regoli5 into BK1 and BK2 types. des-Arg9-BK is a specific agonist ofBK1 receptors whereas [leu’]-des-Arg9-BK is a specific antagonist; BK1 receptors arise in damaged tissues or those treated with endotoxin. However, since these analogues had little or no effect on kinin-sensitive tissues in vitro or
in vivo,s,9receptors in these tissues were classified as BK2. In 1985 Stewart and Vavrek9,lO found that replacing the aminoacid in position 7 of bradykinin with a D-aminoacid conferred antagonist properties on the molecule. Unlike the BK1 antagonists, these compounds antagonise, both in vitro and in vivo, the many usual bradykinin effects. The first successful competitive antagonist of BK2 effects was (D-Phe7] BK. Many BKz antagonists were soon synthesised, the most potent being D-Arg [Hyp3 The 5,8 Phe7]-BK. These compounds, studied extensively from 1985 to 1990, are specific antagonists of bradykinin, kallidin, Lys-bradykinin, and Met-Lys-bradykinin in many isolated preparations in vitro. They antagonise the effects of the kinins in vivo on arterial blood pressure, vasodilatation in the coronary and other vascular beds, guineapig bronchoconstriction, and induction of pain in animals and in human blister base; they also diminish the increased cutaneous vascular permeability in rabbits. 3,11-14 Nevertheless, these agents have a serious drawback for therapeutic use-their effects in animals wear off after 1-15 min.3,9 There is evidence that the objective of synthesising
potent long-acting bradykinin antagonists of the BKz type has been achieved in 1991. Synthesis involves the inclusion of several unnatural aminoacids in the molecule. The most potent of these compounds is called Hoe 140 (D-Arg [Hyp3, This, D-Tic7, Oic8]BK);15-17 this is an effective and specific antagonist of bradykinin in several in-vitro bioassay preparations of visceral and vascular smooth muscle. In vivo it inhibits bradykinin-induced hypotension (rat),
bronchoconstriction (guineapig), carrageenaninduced inflammatory oedema (rat paw), and nociceptive stimulation (perfused rabbit ear). In vivo, inhibition often lasts for several hours. Bradykinin activates many secondary messengers, and Hoe 140 prevents the following bradykinin-induced effects: release of prostaglandin Ez, release of prostacyclin and endothelium-derived relaxing factor (nitric oxide), and increase in cytosolic calcium in cultured endothelial cells. We are now very close to obtaining bradykinin antagonists that would be suitable for clinical evaluation. Their potency, specificity, and duration of action appear to be satisfactory and the synthesis of an orally active compound seems realistic. A Lancet editoriah8 about kinins and blood pressure in 1978 stated "Clinically they [kinins] have been implicated in the pathogenesis of shock, inflammation, pancreatitis, arthritis, carcinoid flush, postgastrectomy dumping syndrome, anginal pain, and migraine". To this list can be added hereditary angio-oedemasand psoriasis.19 Much indirect and circumstantial evidence has been presented for allergic rhinitis and asthma.11,20,21 Perhaps the most tempting prediction is for a role of kinins in the pain associated with inflammatory conditions,11-17 which could be reduced by the new antagonists.
288
1. Schachter M. Kinins. A group of active 1964; 49: 281-92.
peptides. Annu Rev Pharmacol
2. Kinins IV. Greenbaum LM, Margolius HS, eds. Advances in experimental medicine and biology, vols 198 A and B. New York:
Plenum, 1986. 3. Fritz H, Schmidt I, Dietze
G, eds. The kallikrein system in health and
disease. Braunschweig: Lunbach-Verlag, 1989. 4. Schachter M. Kallikreins (kininogenases)—a group of serine proteases with bioregulatory actions. Pharmacol Rev 1980; 31: 1-17. 5. Regoli D, Barabe J. Pharmacology of bradykinin and related kinins. Pharmacol Rev 1980; 32: 1-46. 6. MacDonald RJ, Margolius HS, Erdös EG. Molecular biology of tissue kallikrein. Biochem J 1988; 243: 313-21. 7. van Oeveren W, Jansen NJG, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass. Ann Thorac Surg 44: 640-45. 8. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987; ii: 1289-91. 9. Vavrek RJ, Stewart JM. Competitive antagonists of bradykinin. Peptides 1985; 6: 161-64. 10. Stewart JM, Vavrek RJ. Chemistry of peptide B2 bradykinin antagonists. In: Burch RM, ed. Bradykinin antagonists: basic and clinical research. New York: Marcel Dekker, 1991: 51-96. 11. Griesbacher T, Lembeck. Effects of bradykinin antagonists on
bradykinin-induced plasma extravasation, venoconstriction, prostaglandin E2 release, and nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit. Br J Pharmacol 1987; 92: 333-340. 12. Steranka LR,
Manning DC, DeHaas CJ, et al. Bradykinin as a pain mediator: receptors are localized to sensory neurons and antagonists have analgesic actions. Proc Natl Acad Sci USA 1988; 85: 3245-49. 13. Haley JE, Dickenson AH, Schachter M. Electrophysiological evidence for a role of bradykinin in chemical nociception in the rat. Neurosci Lett 1989; 97: 198-202. 14. Whalley ET, Clegg S, Stewart JM, Vavrek RJ. The effect of kinin agonists and antagonists on the pain response of the human blister base. Naunyn-Schmiedeberg Arch Pharmacol 1987; 336: 652-55. 15. Lembeck F, Griesbacher T, Eckhardt M. et al. New, long-acting, potent bradykinin antagonists. Br J Pharmacol 1991; 102: 297-304. 16. Hock FJ, Wirth K, Albus U, et al. Hoe 140 a new potent and long-acting bradykinin antagonist: in vitro studies. Br J Pharmacol 1991; 102: 769-73. 17. Wirth K, Hock FJ, Albus U, et al. Hoe 140 a new potent and long-acting bradykinin antagonist: in vivo studies. Br J Pharmacol 1991; 102: 774-77. 18. Editorial. Kinins and blood pressure. Lancet 1978; ii: 663-65. 19. Poblete MT, Reynolds NJ, Figueroa CD, et al. Tissue kallikrein and kininogen in human sweat glands and psoriatic skin. Br J Dermatol 1991; 124: 236-41. 20. Proud D, Naclerio RM, Givaltney JM, Hendley J. Kinins are generated in nasal secretions during natural rhinovirus colds. J Infect Dis 1990; 161: 120-23. 21. Barnes PJ. Asthma as an axon reflex. Lancet 1986; i: 242-45.
Aortic
distensibility and screening for coronary atheroma
Although coronary atheromatosis is essentially a disorder of the vessel wall, clinical manifestations depend on obstruction of the lumen. Consequently, disease may be far advanced before symptoms or electrocardiographic changes become apparent. Detection of atheromatosis at an earlier stage is an important clinical goal but is seldom achieved. Fluoroscopy is a long-established but insensitive technique for displaying coronary wall calcification. Ultrafast computed tomographic screening to detect calcific microdeposits is much more sensitive, but its clinical worth has yet to be established. The coronary wall can be examined directly by transluminal echocardiography and by angioscopy,2 but these procedures are too invasive for routine use.
A less direct but more practicable approach is to study the aorta as an accessible "surrogate" vessel, and then to make correlations between aortic and coronary disease. Measurement of aortic distensibility, corrected for blood pressure, is most widely used; distensibility can be assessed both by
echocardiography3 and by magnetic resonance imaging.4 Echocardiography, which is the less demanding in terms of equipment though not necessarily operator skill, was used by the Australian on p 270. Dart and confirmed earlier reports of a progressive colleagues increase in aortic stiffness with age. They found that patients with clinically overt coronary disease had stiffer aortas, and they were able to correlate aortic stiffness in heart transplant recipients with the presence of atheroma in the hearts removed at transplantation. Curiously, a group of patients with hypercholesterolaemia but no other features of coronary disease had more distensible aortas than did normocholesterolaemic controls. So, is it bad news to have a stiff aorta and good news to have a distensible one, and can anything be done about it? The answers will have to await the results of long-term follow-up studies, which are already in progress. Lucky possessors of an elastic aorta should not become too complacent because isolated atheromatous plaques can still cause coronary thrombosis and infarction. Detection of a rigid aorta might lead to advice about risk factor reduction, but should not, on existing evidence, be grounds for invasive procedures. It will be interesting to see how well aortic distensibility measurements correlate with the scoring systems based on the history and simple clinical investigations that have already been validated for prediction of coronary disease risk.5 It seems unlikely that assessment of aortic distensibility could ever be a cost-effective method of population screening; more realistically, this approach will be used as an investigative technique, with potential applications to specific clinical conditions. We already know that age and gender influence aortic distensibility. In view of the differences in patterns of hypertension and atherosclerosis in different racial groups it may be important to investigate the relation to ethnic origin as well. Diagnosis from the pulses featured in ancient Chinese medicine-will it return in hi-tech disguise?
group whose paper appears
1. Editorial. Ultrafast CT for coronary calcification. 2. Mizuno
K, Miyamoto A, Satomura K, et al. Angioscopic coronary macromorphology in patients with acute coronary disorders. Lancet 1991; 337: 809-12.
3. Isnard RN, Pannier BM, Laurent S, London GM, Diebold B, Safar ME. Pulsatile diameter and elastic modulus of the aortic arch in essential hypertension: a non invasive study. JACC 1989; 13: 399-405.
RH, Underwood SR, Bogren HG, et al. Regional aortic compliance studied by magnetic resonance imaging: the effects of age, training and coronary artery disease. Br Heart J 1989; 62: 90-96. Shaper AG, Pocock SJ, Phillips AN, Walker M. Identifying men at high risk of heart attacks: a strategy for use in general practice. Br Med J
4. Mohiaddin
5.
1986; 293: 474-79.
Kinins and their antagonists peptides that were classified as a group because they were found to have potent pharmacological properties in common. All cause Kinins
are
hypotension and lead to contraction of many isolated smooth muscle preparations. They relax rat duodenum, increase vascular permeability in man and
animals, and produce pain in animals and in human skin when applied to a blister base. They induce bronchoconstriction in guineapigs, which is antagonised specifically by salicylate and by other non-steroidal anti-inflammatory compounds.1 The prototype of this group of compounds is bradykinin, a nonapeptide with the formula H-Arg-Pro-Pro-Gly-
Phe-Ser-Pro-Phe-Arg-OH. Bradykinin and kallidin (Lys-bradykinin) are the main peptides generated by limited proteolysis from an inactive precursor, kininogen. The active peptide is inactivated by several peptidases, kininases, in tissues and body fluids. Kininase II, one of the most effective of these enzymes, also converts angiotensin I to angiotensin II. Knowledge of these systems led to the synthesis of captopril, an orally active drug that inhibits the generation of angiotensin II and stabilises bradykinin; both effects tend to lower blood pressure.2,3 Kinins are released by the proteolytic action of a group of endogenous serine proteases called kallikreins (or kininogenases), which are present in many tissues. A "kallikrein" in plasma has a similar catalytic site but a different general chemical structure and less substrate specificity. Most of these proteases release kallidin-ie, Lys bradykinin-from kininogen, whereas the serine proteases trypsin and plasma kallikrein release bradykinin. Bradykinin and kallidin show only slight quantitative variation in their pharmacological properties and also react similarly to antagonists. Some kallikreins exist in tissues in an active form, but plasma kallikrein and most tissue kallikreirs (eg, trypsin) are present as inactive precurso s. However, these precursors are readily activated by other enzymes, and can then release kinins. There are also endogenous inhibitors which can bind kallikrein.4-6 Aprotinin, a polyvalent protease inhibitor present in mast cells, has been used with limited success in pancreatitis. This compound also reduces perioperative blood loss after open heart and other major surgery, although its mechanism of action in this respect is obscure.7,8 The chemical structures of bradykinin and kallidin were established in 1960 and 1961, respectively. Hundreds of analogues were synthesised but no effective antagonists were found for 25 years. Bradykinin receptors were first classified by Regoli5 into BK1 and BK2 types. des-Arg9-BK is a specific agonist ofBK1 receptors whereas [leu’]-des-Arg9-BK is a specific antagonist; BK1 receptors arise in damaged tissues or those treated with endotoxin. However, since these analogues had little or no effect on kinin-sensitive tissues in vitro or
in vivo,s,9receptors in these tissues were classified as BK2. In 1985 Stewart and Vavrek9,lO found that replacing the aminoacid in position 7 of bradykinin with a D-aminoacid conferred antagonist properties on the molecule. Unlike the BK1 antagonists, these compounds antagonise, both in vitro and in vivo, the many usual bradykinin effects. The first successful competitive antagonist of BK2 effects was (D-Phe7] BK. Many BKz antagonists were soon synthesised, the most potent being D-Arg [Hyp3 The 5,8 Phe7]-BK. These compounds, studied extensively from 1985 to 1990, are specific antagonists of bradykinin, kallidin, Lys-bradykinin, and Met-Lys-bradykinin in many isolated preparations in vitro. They antagonise the effects of the kinins in vivo on arterial blood pressure, vasodilatation in the coronary and other vascular beds, guineapig bronchoconstriction, and induction of pain in animals and in human blister base; they also diminish the increased cutaneous vascular permeability in rabbits. 3,11-14 Nevertheless, these agents have a serious drawback for therapeutic use-their effects in animals wear off after 1-15 min.3,9 There is evidence that the objective of synthesising
potent long-acting bradykinin antagonists of the BKz type has been achieved in 1991. Synthesis involves the inclusion of several unnatural aminoacids in the molecule. The most potent of these compounds is called Hoe 140 (D-Arg [Hyp3, This, D-Tic7, Oic8]BK);15-17 this is an effective and specific antagonist of bradykinin in several in-vitro bioassay preparations of visceral and vascular smooth muscle. In vivo it inhibits bradykinin-induced hypotension (rat),
bronchoconstriction (guineapig), carrageenaninduced inflammatory oedema (rat paw), and nociceptive stimulation (perfused rabbit ear). In vivo, inhibition often lasts for several hours. Bradykinin activates many secondary messengers, and Hoe 140 prevents the following bradykinin-induced effects: release of prostaglandin Ez, release of prostacyclin and endothelium-derived relaxing factor (nitric oxide), and increase in cytosolic calcium in cultured endothelial cells. We are now very close to obtaining bradykinin antagonists that would be suitable for clinical evaluation. Their potency, specificity, and duration of action appear to be satisfactory and the synthesis of an orally active compound seems realistic. A Lancet editoriah8 about kinins and blood pressure in 1978 stated "Clinically they [kinins] have been implicated in the pathogenesis of shock, inflammation, pancreatitis, arthritis, carcinoid flush, postgastrectomy dumping syndrome, anginal pain, and migraine". To this list can be added hereditary angio-oedemasand psoriasis.19 Much indirect and circumstantial evidence has been presented for allergic rhinitis and asthma.11,20,21 Perhaps the most tempting prediction is for a role of kinins in the pain associated with inflammatory conditions,11-17 which could be reduced by the new antagonists.
288
1. Schachter M. Kinins. A group of active 1964; 49: 281-92.
peptides. Annu Rev Pharmacol
2. Kinins IV. Greenbaum LM, Margolius HS, eds. Advances in experimental medicine and biology, vols 198 A and B. New York:
Plenum, 1986. 3. Fritz H, Schmidt I, Dietze
G, eds. The kallikrein system in health and
disease. Braunschweig: Lunbach-Verlag, 1989. 4. Schachter M. Kallikreins (kininogenases)—a group of serine proteases with bioregulatory actions. Pharmacol Rev 1980; 31: 1-17. 5. Regoli D, Barabe J. Pharmacology of bradykinin and related kinins. Pharmacol Rev 1980; 32: 1-46. 6. MacDonald RJ, Margolius HS, Erdös EG. Molecular biology of tissue kallikrein. Biochem J 1988; 243: 313-21. 7. van Oeveren W, Jansen NJG, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass. Ann Thorac Surg 44: 640-45. 8. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987; ii: 1289-91. 9. Vavrek RJ, Stewart JM. Competitive antagonists of bradykinin. Peptides 1985; 6: 161-64. 10. Stewart JM, Vavrek RJ. Chemistry of peptide B2 bradykinin antagonists. In: Burch RM, ed. Bradykinin antagonists: basic and clinical research. New York: Marcel Dekker, 1991: 51-96. 11. Griesbacher T, Lembeck. Effects of bradykinin antagonists on
bradykinin-induced plasma extravasation, venoconstriction, prostaglandin E2 release, and nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit. Br J Pharmacol 1987; 92: 333-340. 12. Steranka LR,
Manning DC, DeHaas CJ, et al. Bradykinin as a pain mediator: receptors are localized to sensory neurons and antagonists have analgesic actions. Proc Natl Acad Sci USA 1988; 85: 3245-49. 13. Haley JE, Dickenson AH, Schachter M. Electrophysiological evidence for a role of bradykinin in chemical nociception in the rat. Neurosci Lett 1989; 97: 198-202. 14. Whalley ET, Clegg S, Stewart JM, Vavrek RJ. The effect of kinin agonists and antagonists on the pain response of the human blister base. Naunyn-Schmiedeberg Arch Pharmacol 1987; 336: 652-55. 15. Lembeck F, Griesbacher T, Eckhardt M. et al. New, long-acting, potent bradykinin antagonists. Br J Pharmacol 1991; 102: 297-304. 16. Hock FJ, Wirth K, Albus U, et al. Hoe 140 a new potent and long-acting bradykinin antagonist: in vitro studies. Br J Pharmacol 1991; 102: 769-73. 17. Wirth K, Hock FJ, Albus U, et al. Hoe 140 a new potent and long-acting bradykinin antagonist: in vivo studies. Br J Pharmacol 1991; 102: 774-77. 18. Editorial. Kinins and blood pressure. Lancet 1978; ii: 663-65. 19. Poblete MT, Reynolds NJ, Figueroa CD, et al. Tissue kallikrein and kininogen in human sweat glands and psoriatic skin. Br J Dermatol 1991; 124: 236-41. 20. Proud D, Naclerio RM, Givaltney JM, Hendley J. Kinins are generated in nasal secretions during natural rhinovirus colds. J Infect Dis 1990; 161: 120-23. 21. Barnes PJ. Asthma as an axon reflex. Lancet 1986; i: 242-45.
Aortic
distensibility and screening for coronary atheroma
Although coronary atheromatosis is essentially a disorder of the vessel wall, clinical manifestations depend on obstruction of the lumen. Consequently, disease may be far advanced before symptoms or electrocardiographic changes become apparent. Detection of atheromatosis at an earlier stage is an important clinical goal but is seldom achieved. Fluoroscopy is a long-established but insensitive technique for displaying coronary wall calcification. Ultrafast computed tomographic screening to detect calcific microdeposits is much more sensitive, but its clinical worth has yet to be established. The coronary wall can be examined directly by transluminal echocardiography and by angioscopy,2 but these procedures are too invasive for routine use.
A less direct but more practicable approach is to study the aorta as an accessible "surrogate" vessel, and then to make correlations between aortic and coronary disease. Measurement of aortic distensibility, corrected for blood pressure, is most widely used; distensibility can be assessed both by
echocardiography3 and by magnetic resonance imaging.4 Echocardiography, which is the less demanding in terms of equipment though not necessarily operator skill, was used by the Australian on p 270. Dart and confirmed earlier reports of a progressive colleagues increase in aortic stiffness with age. They found that patients with clinically overt coronary disease had stiffer aortas, and they were able to correlate aortic stiffness in heart transplant recipients with the presence of atheroma in the hearts removed at transplantation. Curiously, a group of patients with hypercholesterolaemia but no other features of coronary disease had more distensible aortas than did normocholesterolaemic controls. So, is it bad news to have a stiff aorta and good news to have a distensible one, and can anything be done about it? The answers will have to await the results of long-term follow-up studies, which are already in progress. Lucky possessors of an elastic aorta should not become too complacent because isolated atheromatous plaques can still cause coronary thrombosis and infarction. Detection of a rigid aorta might lead to advice about risk factor reduction, but should not, on existing evidence, be grounds for invasive procedures. It will be interesting to see how well aortic distensibility measurements correlate with the scoring systems based on the history and simple clinical investigations that have already been validated for prediction of coronary disease risk.5 It seems unlikely that assessment of aortic distensibility could ever be a cost-effective method of population screening; more realistically, this approach will be used as an investigative technique, with potential applications to specific clinical conditions. We already know that age and gender influence aortic distensibility. In view of the differences in patterns of hypertension and atherosclerosis in different racial groups it may be important to investigate the relation to ethnic origin as well. Diagnosis from the pulses featured in ancient Chinese medicine-will it return in hi-tech disguise?
group whose paper appears
1. Editorial. Ultrafast CT for coronary calcification. 2. Mizuno
K, Miyamoto A, Satomura K, et al. Angioscopic coronary macromorphology in patients with acute coronary disorders. Lancet 1991; 337: 809-12.
3. Isnard RN, Pannier BM, Laurent S, London GM, Diebold B, Safar ME. Pulsatile diameter and elastic modulus of the aortic arch in essential hypertension: a non invasive study. JACC 1989; 13: 399-405.
RH, Underwood SR, Bogren HG, et al. Regional aortic compliance studied by magnetic resonance imaging: the effects of age, training and coronary artery disease. Br Heart J 1989; 62: 90-96. Shaper AG, Pocock SJ, Phillips AN, Walker M. Identifying men at high risk of heart attacks: a strategy for use in general practice. Br Med J
4. Mohiaddin
5.
1986; 293: 474-79.
