- Email: [email protected]
The effects of verapamil on myocardial metabolism
232 CALCIUM BLOCKING ACTIVITY OF DILAZEP IN RELATION TO ITS ADENOSINE UPTAKE INHIBITION IN DOG CORONARY ARTERY. S.J. Mustafa and Y. Nakagawa, Dept. of Pharmacol., Sch. of Med., E. Car. Univ. Greenville, NC, USA and M. Gudenzi, Degussa Pharma Gruppe, FRG Dilazep (D), a vasodilator drug has been reported (Mustafa, S. J. Biochem. Pharmacol. 28:X17, 1979) to fnhibft the uptake of adenosine (Ad). This lnhibitfon tn the uptake of Ad has been proposed as the possible mechanism for the action of D. This investigation is a" attempt to study the calcium (Ca) blocking activity of D in relation to its Ad inhibiting effect. Dog coronary artery strips (circumflex, lmm wide and 2-3 mm O.D.) were mounted in a muscle bath under 100 mg initial tension at 37°C in Krebs-Henseleit solution (95% 02+5X C02, pH 7.4). At the end of equilibration, the bath was changed to Ca-free (with 100 mM KCl) Krebs-Henseleit solution. At the completion of the contraction, Ca was added in a cummulative manner to obtain a dose-response curve. The strips were incubated for 30 min with the drug and the dose-response curve for Ca was obtained again. Diltiazem (DL) and Dipyridamole (Di) were used for comparison. Potency ratios (using verapamil as 1.0) were calculated from the pA2 values and were 0.28, 0.01 and 0.0001 for DL, D and Di, respectively. The EDSO for DL and D was 0.235.02 and 5.46+.5 pM, respectively. S-phenyltheophylline (10m5M) was unable to block the Ca-antagonistic activity of D. Since both D and Di are equipotent inhibitors of Ad uptake and Di had no Ca blocking activity, it is concluded that D has a direct Ca blocking effect on coronary smooth muscle.
233 THE EFFECTS OF VEBAPAMIL ON MYOCARDIAL METABOLISM T. Mastersand G. Duncan, Heineman Med. Res. Ctr., Charlotte Mem. Hosp. & Med. Ctr., Charlotte,
N.C. 28232
Myocar+al pyruvate, lactate, glucose and free fatty acids (FFA) uptake and O1 consumption were studied in openchest, heparinized mongrel dogs in which Verapamil(20ug/min) was infused directly into the LAD coronary artery. Venous samples were collected from the vein draining the LAD area and from the coronary sinus which allowed metabolic comparison of infused and non-infused myocardium. Verapamil was infused for 15 min.and samples taken before, 7'12 and 15 min.duringtheinfusion and aftera 15 min.recovery period. In the LAD supplied tissue infused with verapamil, there was a 93% increase in glucose uptake after 7% mins. and 213% after 15 mins. Concomitantly, FFA uptake was reduced by 52%after 7% mins. and 4096after 15 mins. and continued to drop to 73% during a I5 min. recovery period. The venous drainage from the LAD area increased significantly after 7% mins. (27%) and 15 mins. (22%) with no significant change in coronary sinus outflow. Lactate uptake was significantly reduced in the LAD area in response to verapamil but not in the rest of the heart. Oz consumption was unchanged in response to verapamil in both infused and non-infused myocardium. Hemodynamically, no changes were observed in LV pressure, arterial pressure or heart rate. Significant reductions in dp/dt and strain gauge contractile force of the LAD perfuied area were seen after 15 mins. and 7’/2 and 15 mins. respectively. The results indicate that verapamil at the concentration used in these experiments reduces FFA uptake by the heart and concomitantly increases glucose uptake with no change in O2 uptake. This would suggest a possible contraindication in diabetics. 234 Calcium Agonism, a new pharmacological BAY K 8644 M. Schramm, R. Towart, G. Franckowiak, Wuppertal 1, F.R.G.
principle: Bayer
the Pharma
haemodynamic -Research
Centre,
effects
of
D5600
Minor changes to the nifedipine molecule lead to a novel dihydropyridine derivative, BAY K 8644 (Methyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl~pyridine-5-carboxylate), which promotes instead of inhibiting the influx of calcium ions into the cell. In the pentobarbitone anaesthetised dog BAY K 8644 has positive inotropic and vasoconstricting properties. Beginning at O.O03mg/kg i.v. there is a dose-dependent increase in blood pressure in the aorta and in the left ventricle, in left ventricular dp/dt(max) and in peripheral resistance. I" the first seconds after i.v. administration the coronary blood flaw is markedly reduced, followed by an The maximal effects are increase, probably due to metabolic counter-regulation. reached at a dose of 0.3mg/kg. Neither a- nor !3-adrenoceptor blockade is able to inhibit these actions. On the other hand nifedipine antagonises or eve" reverses these effects in the same dose range. These findings suggest that BAY K 8644 and nifedipine bind to the same receptor causing opposite effects. Due to the coronary constricting activity of BAY K 8644 this compound does not seem to be useful as a therapeutic agent, but may be a useful pharmacological tool.
233 THE EFFECTS OF VEBAPAMIL ON MYOCARDIAL METABOLISM T. Mastersand G. Duncan, Heineman Med. Res. Ctr., Charlotte Mem. Hosp. & Med. Ctr., Charlotte,
N.C. 28232
Myocar+al pyruvate, lactate, glucose and free fatty acids (FFA) uptake and O1 consumption were studied in openchest, heparinized mongrel dogs in which Verapamil(20ug/min) was infused directly into the LAD coronary artery. Venous samples were collected from the vein draining the LAD area and from the coronary sinus which allowed metabolic comparison of infused and non-infused myocardium. Verapamil was infused for 15 min.and samples taken before, 7'12 and 15 min.duringtheinfusion and aftera 15 min.recovery period. In the LAD supplied tissue infused with verapamil, there was a 93% increase in glucose uptake after 7% mins. and 213% after 15 mins. Concomitantly, FFA uptake was reduced by 52%after 7% mins. and 4096after 15 mins. and continued to drop to 73% during a I5 min. recovery period. The venous drainage from the LAD area increased significantly after 7% mins. (27%) and 15 mins. (22%) with no significant change in coronary sinus outflow. Lactate uptake was significantly reduced in the LAD area in response to verapamil but not in the rest of the heart. Oz consumption was unchanged in response to verapamil in both infused and non-infused myocardium. Hemodynamically, no changes were observed in LV pressure, arterial pressure or heart rate. Significant reductions in dp/dt and strain gauge contractile force of the LAD perfuied area were seen after 15 mins. and 7’/2 and 15 mins. respectively. The results indicate that verapamil at the concentration used in these experiments reduces FFA uptake by the heart and concomitantly increases glucose uptake with no change in O2 uptake. This would suggest a possible contraindication in diabetics. 234 Calcium Agonism, a new pharmacological BAY K 8644 M. Schramm, R. Towart, G. Franckowiak, Wuppertal 1, F.R.G.
principle: Bayer
the Pharma
haemodynamic -Research
Centre,
effects
of
D5600
Minor changes to the nifedipine molecule lead to a novel dihydropyridine derivative, BAY K 8644 (Methyl 1,4-Dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl~pyridine-5-carboxylate), which promotes instead of inhibiting the influx of calcium ions into the cell. In the pentobarbitone anaesthetised dog BAY K 8644 has positive inotropic and vasoconstricting properties. Beginning at O.O03mg/kg i.v. there is a dose-dependent increase in blood pressure in the aorta and in the left ventricle, in left ventricular dp/dt(max) and in peripheral resistance. I" the first seconds after i.v. administration the coronary blood flaw is markedly reduced, followed by an The maximal effects are increase, probably due to metabolic counter-regulation. reached at a dose of 0.3mg/kg. Neither a- nor !3-adrenoceptor blockade is able to inhibit these actions. On the other hand nifedipine antagonises or eve" reverses these effects in the same dose range. These findings suggest that BAY K 8644 and nifedipine bind to the same receptor causing opposite effects. Due to the coronary constricting activity of BAY K 8644 this compound does not seem to be useful as a therapeutic agent, but may be a useful pharmacological tool.