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Calcium antagonist binding sites
j Mol Cell Cardiol 18 (Supplement 1) (1986) 03CALCIUM ANTAGONISTSAND ISCHEMICVENTRICULARARRHYTNMIAS LH Opie, FT Thandroyen, Heart Research Unit, University of Cape Town, South Africa. All three primary calcium antagonists (verapami], diltiazem, nifedipine) can inhibit ischemic ventricular arrhythmias in isolated hearts, as can niludipine or nisoldipine (all in relatively high concentrations). Added fast channel blockade may play a role in the case of dl-verapamil and tiapamil, but cannot explain the effects of l-verapamil and dihydropyridines, d-Verapamil is without effect. Nisoldipine, a "pure" calcium blocker, does not affect outward potassium currents, and inhibits ventricular f i b r i l l a t i o n in the rat in situ (Fagbemi and Parratt, Brit J Pharm 74: 12, 1981). Post-ischemic f a l l in ventricular f i b r i l l a t i o n threshold can be prevented by a low external calcium or by ryanodine which inhibits calcium flux in and out of the sarcoplasmic reticulum. Ryanodineand caffeine may be prototypes of a new class of antiarrhythmic agent. Metabolic evidence supports the role of increased internal calcium in ischemia because ( i ) diastolic tension rises as glycolytic flux is inhibited, and ( i i ) ischemic cyclic AMP rises at the time of ventricular f i b r i l l a t i o n in the pig and presumably increases the chances that calcium channels will be "open". In reperfusion arrhythmias, calcium antagonists also inhibit ventricular arrhythmias (Lubbe e t a ] , Am Heart J 105: 331, 1983); the mechanism may involve calcium-dependent afterpotentials. Summary: High-doses of calcium antagonists can inhibit ventricular arrhythmias utb-6T--a-direct role for calcium in ischemic arrhythmogenesis is not yet proven.
04CALCIUM ANTAGONISTBINDING SITES. H.Glossmann, D.R.Ferry, A.GolI, J.Striessnig and G.Zernig. Departmentof Biochemical Pharmacology,University of Innsbruck, Austria .................................................................................... Calcium antagonists, f i r s t discovered by the eminent german physiologist F1eckenstein, were essential in radiolabelled form to characterize three interdependent drug receptor domains (1,2,3) of the calcium channe! (1,4dihydropyridine-selective domain (I), phenylalkylamine-selective domain (2) and the benzothiazepine (d-cis-diltiazem)-selective domain (3). The three domains of the channel are connected to each other by reciprocal a11osteric coupling mechanisms and to high or low a f f i n i t y calcium binding sites of the channel. The calcium channe! is a unique ionic pore as calcium within the channel is required for function. The target size of each domain has been determined by radiation-inactivation, the channel receptors have been purified and photoaffining labelled. The allosteric interaction between the receptor sites has a biophysical equivalent: the size of receptor domain (I) is decreased by 60 KDa when d-cis diltiazem occupies site (3). T h i s effect is stereospecific as 1-cis diltiazem has no effect. The largest glycoprotein component of the channel (145 KDa) is about half of the size of the alpha subunit of the sodium channel, whereas the smallest has 50 KDa. With the aid of so called channel agonists (e.g. Bay K 8644 enantiomers) the functional relevance of the receptor sites (e.g. in brain) has been demonstratedwith respect to the inositolphosphate response.
9 5 CALCIUM ANTAGONIST DRUGS IN THE TREATMENT OF ANGINA PECTORIS, CORONARY ARTERY SPASM AND HYPERTENSION. S. B. Freedman. Hallstrom Institute of Cardiology, Royal Prince Alfred Hospital, Sydney. The clinical use of calcium antagonist drugs in coronary artery disease preceeded knowledge of the mechanism of their action. Basic research into their pharmacological actions, and development of a wide range of compounds which block calcium entry into cells, enabled clinicians to greatly expand the indications for their use. Thus the calcium antagonists were rediscovered and found to be potent antianginal drugs when used in adequate dosage for effort related angina. Knowledge of their potent relaxing action on vascular smooth muscle led to their use in coronary artery spasm. The exact trigger mechanism/s for spasm and the reason for enhanced vascular reactivity remain unclear, perhaps explaining the failure of specific antagonist therapy. Calcium antagonists on the other hand inhibit both induced and spontaneous attacks of vasospastic angina, and may favourably influence the prognosis, and are now drugs of first choice for this condition. The vasodilator action of these drugs has most recently been utilized to treat hypertension, with efficacy confirmed in many controlled trials. Unlike other vasodilators, the calcium antagonists reduce blood pressure without salt and water retention, and with mild or no stimulation of renin, aldosterone, or sympathetic nervous overactivity, and without postural effects. This spectrum of action makes them ideal therapeutic agents, and current guidelines are changing to include calcium antagonists as first or second line therapy.
04CALCIUM ANTAGONISTBINDING SITES. H.Glossmann, D.R.Ferry, A.GolI, J.Striessnig and G.Zernig. Departmentof Biochemical Pharmacology,University of Innsbruck, Austria .................................................................................... Calcium antagonists, f i r s t discovered by the eminent german physiologist F1eckenstein, were essential in radiolabelled form to characterize three interdependent drug receptor domains (1,2,3) of the calcium channe! (1,4dihydropyridine-selective domain (I), phenylalkylamine-selective domain (2) and the benzothiazepine (d-cis-diltiazem)-selective domain (3). The three domains of the channel are connected to each other by reciprocal a11osteric coupling mechanisms and to high or low a f f i n i t y calcium binding sites of the channel. The calcium channe! is a unique ionic pore as calcium within the channel is required for function. The target size of each domain has been determined by radiation-inactivation, the channel receptors have been purified and photoaffining labelled. The allosteric interaction between the receptor sites has a biophysical equivalent: the size of receptor domain (I) is decreased by 60 KDa when d-cis diltiazem occupies site (3). T h i s effect is stereospecific as 1-cis diltiazem has no effect. The largest glycoprotein component of the channel (145 KDa) is about half of the size of the alpha subunit of the sodium channel, whereas the smallest has 50 KDa. With the aid of so called channel agonists (e.g. Bay K 8644 enantiomers) the functional relevance of the receptor sites (e.g. in brain) has been demonstratedwith respect to the inositolphosphate response.
9 5 CALCIUM ANTAGONIST DRUGS IN THE TREATMENT OF ANGINA PECTORIS, CORONARY ARTERY SPASM AND HYPERTENSION. S. B. Freedman. Hallstrom Institute of Cardiology, Royal Prince Alfred Hospital, Sydney. The clinical use of calcium antagonist drugs in coronary artery disease preceeded knowledge of the mechanism of their action. Basic research into their pharmacological actions, and development of a wide range of compounds which block calcium entry into cells, enabled clinicians to greatly expand the indications for their use. Thus the calcium antagonists were rediscovered and found to be potent antianginal drugs when used in adequate dosage for effort related angina. Knowledge of their potent relaxing action on vascular smooth muscle led to their use in coronary artery spasm. The exact trigger mechanism/s for spasm and the reason for enhanced vascular reactivity remain unclear, perhaps explaining the failure of specific antagonist therapy. Calcium antagonists on the other hand inhibit both induced and spontaneous attacks of vasospastic angina, and may favourably influence the prognosis, and are now drugs of first choice for this condition. The vasodilator action of these drugs has most recently been utilized to treat hypertension, with efficacy confirmed in many controlled trials. Unlike other vasodilators, the calcium antagonists reduce blood pressure without salt and water retention, and with mild or no stimulation of renin, aldosterone, or sympathetic nervous overactivity, and without postural effects. This spectrum of action makes them ideal therapeutic agents, and current guidelines are changing to include calcium antagonists as first or second line therapy.