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Vasorelaxant effect of the potassium channel activator, RWJ 29009, is tissue selective
Life Sciences, Vol. 52, pp. PL 233-238 Printed in the USA
Pergamon Press
PHARMACOLOGY LETTERS Accelerated
Communication
VASORELAXANT EFFECT OF THE POTASSIUM CHANNEL ACTIVATOR, RWJ 29009, IS TISSUE SELECTIVE Henry I. Jacoby, Karen A. Tomko 1 , Catherine Steffler, and David K.H. Lee
Drug Discovery, The R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 194770776, U.S.A. (Submitted February 19, 1993; accepted March i, 1993; received in final form March 15, 1993)
Abstract. Potassium channel activators have potential cardioprotective properties, in part due to their ability to increase coronary blood flow. We compared the vasorelaxant properties of potassium channel activators, a calcium channel blocker (nicardipine) and a direct smooth muscle relaxant (sodium nitroprusside) in the canine coronary artery, the femoral artery and the saphenous vein precontracted with 0.03 ~tM endothelin-1. In the circumflex coronary artery, RWJ 29009, a novel and potent potassium channel activator, maximally relaxed the precontracted rings with an EC50 of 1.9 nM. Cromakalim (EC50=220 nM) and nitroprusside (EC50=109 nM) were also active. Nicardipine (EC50=16.6 nM) produced only a 70% relaxation at 1 I~M concentration. In both femoral artery and saphenous vein, all agents relaxed the precontracted rings only at much higher concentrations, and the relaxations were only 75% of maximal relaxation. The results show that while all vasodilators preferentially relax the coronary artery, potassium channel activators appear to be the most selective and potent of these agents. Inmoducfion Potassium channel activators are a recently defined class of drugs with potential use for treating hypertension, peripheral vascular diseases, and coronary vasospasm (1,2). In the vascular smooth muscle cell, these agents open potassium channels leading to an efflux of potassium ions out of the cell and hyperpolarization of the membrane potential. This hyperpolarization opposes the opening of the voltage-sensitive calcium channels, reduces the frequency of depolarization of cells and thus reduces the vascular smooth muscle tone. Recent studies have shown that potassium channel activators reduce myocardial infarct size and attenuate myocardial stunning in the canine (3-5). Cromakalim and pinacidil have been shown to improve postischemic dysfunction in the globally ischemic rat heart (6). The cardioprotective effects of these agents were deemed to be a direct action on the myocardium; however, one cannot rule out the contribution, at least in part, by their ability to improve coronary blood flow (3,4,7). Consistent with this observation, Iwaki provided evidence suggesting that coronary spasm is the result of a decrease in potassium permeability of the smooth muscle cell (8). It must be pointed out, however, that recent studies also showed that cromakalim and celikalim may not be effective in protecting the myocardium from ischemic injury (9). The reason for the different observations is not clear. The present study explored the relaxant effects of various vasodilators in the coronary artery as compared to peripheral vasculature. If selectivity for the coronary artery was observed, then treatment of coronary vasospasm and ischemic heart diseases with these agents may be relatively free
1Author~ whomrepfintrequestshouldbe~&essed.
0024-3205/93 $ 6 . 0 0 + .00 Copyright © 1993 Pergamon Press Ltd All rights reserved.
PL-234
Vasorelaxant
Effect
Is T i s s u e
Selective
Vol.
52, No.
21,
1993
of undesirable cardiovascular side effects. Vasodilators tested were RWJ 290092 (10,11) and cromakalim (1,2) (potassium channel activators), nicardipine (a calcium channel blocker) and sodium nitroprusside (a guanylate cyclase stimulator). The femoral artery and the saphenous vein were used for comparison. The results demonstrated that the endothelin-l-contracted coronary artery is preferentially relaxed by all agents, and in particular, by the potassium channel activators. Methods Mature male or female beagles weighing 8-16 kg were obtained from Marshall Farms or Hazelton Laboratories. The dogs were anesthetized with pentobarbital (35 mg/kg iv) and the heart, femoral artery and saphenous vein were quickly removed and placed in chilled Kreb's bicarbonate (118.4 mM NaC1; 1.18 mM MgSO4.7H20; 4.75 mM KC1; 2.5 mM CaCI2.2H20; 1.18 mM KH2PO4; 25 mM NaHCO3; and 11 mM dextrose) solution. The circumflex coronary artery was carefully dissected away from the heart, cleaned, and cut into rings approximately 3-5 mm long. The femoral artery and saphenous veins were treated similarly. Each ring was mounted in a heated (37oc) tissue bath containing 15 mL of oxygenated Kreb's bicarbonate buffer. Each ring was attached to a tissue holder below and to a Grass FT03 isometric transducer above. The tissues were allowed to equilibrate for at least 1 hr with frequent changes of Kreb's solution and adjustment of tension. Final resting tension was set at 1 g for femoral artery and saphenous vein and 0.5 g for the coronary artery. Tissues were precontracted with 0.03 pM endothelin-1 (Peptides International), which produced approximately 65% of maximal KCl-induced contraction, followed by relaxation induced by various drugs. Test drugs were dissolved initially in dimethylsulfoxide and diluted to the appropriate concentrations with water. All final dimethylsulfoxide concentrations were less than 1% with no observable effects on the contraction/relaxation of the tissue.
120
Z o
IO0
"~
80
r~
60
F-
WJ 29009 Z r~
40
/
~
20 / 0
~
•
0 "9"
~][ /
•
'
'
..... 10' - 8 . . . . . .
'
10' - f
'
----
Cromakalim
~
Nitroprusside
'
. . . . 10. ' 6"
"
. . . . .
I
10- 5
CONCENTRATION (M)
Figure 1 Vasorelaxant effects of vasodilators in the endothelin-1-precontracted coronary artery
2 (6S)-trans-(-)- 1-(6,7-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-5H-thieno[3,2-b]pyran-7-yl)-2piperidinone
Vol.
52, No.
21,
1993
Vasorelaxant
Effect
Is T i s s u e S e l e c t i v e
PL-235
Analog data from the transducers were amplified and conditioned using preamplifiers (Buxco Electronics), and quantitated using an MI 2 (Modular Instrument Inc.) data acquisition system. Relaxation was expressed as a percent of the initial contracted baseline for each tissue. Means and standard errors for each point were obtained. The slopes of the dose-response curves and the EC50 values (concentration which produces a 50% mean relaxation) and 95% confidence limits were calculated using the EDPLOT and RELPOT programs developed internally. All values reported are means + SEM of at least 6 different experiments. Results The effects of the potassium channel activators and other vasodilators on the endothelin-1 contracted coronary arterial rings are shown in Figure 1. RWJ 29009 was the most potent relaxant, exhibiting an ECs0 of 1.9 nM (Table I). Cromkalim (EC50=220 nM) was 115 times less potent. While nicardipine is a potent vasorelaxant (EC50=16.6 nM), it did not produce 100% relaxation even at a concentration of 1000 nM. Its concentration-relaxation curve had a slope significantly less than that for the potassium channel activators. Nitroprusside (EC50=I09 nM) was somewhat more potent then cromakalim. All agents tested relaxed endothelin- 1 contracted dog femoral artery (Figure 2) and saphenous vein (Figure 3). However, maximal relaxation was no more than 70% at concentrations up to 10 IxM. RWJ 29009 was most potent in both preparations (Table I). Discussion The purpose of the present study was to determine whether vasodilators, and in particular, potassium channel activators, can relax selectively the coronary artery when compared to other vasculatures. The femoral artery, a large peripheral resistance artery, and the saphenous vein were chosen for comparison. Endothelin-1, in our hands, contracted all three canine vascular preparations maximally, thus allowing direct comparison of pharmacologic responses among the preparations against a single agonist.
1oo 80 1 •
13--- RWJ 29009 ~ Cromakalim ~ ~
Nicardipine Nitroprusside
60
5
40
'i
2
-eo ~
10-8
10-7
10-6
10-5
CONCENTRATION (M)
Figure 2 Vasorelaxant effects of vasodilators in the endothelin-1-precontracted femoral artery
PL-236
Vasorelaxant
I oo
Effect
+ ---~~
80
Is T i s s u e S e l e c t i v e
Vol.
52, No.
21,
1993
RWJ 29009 Cromakalim Nicardipine Niuoprusside
60
40
z
20
0 -20
10-8
10-7
10-6
10-5
CONCENTRATION (M) Figure 3 Vasorelaxant effects of vasodilators in the endothelin-l-precontracted saphenous vein
Our results demonstrated the ability of both potassium channel activators to relax maximally endothelin-l-precontracted coronary artery, with RWJ 29009 being 115 fold more potent than cromakalim (Figure 1 and Table I). Nicardipine, at concentrations up to 10 ~tM, could only relax the vessel to about 75% of maximum. Furthermore, the slope of the dose response curve was not parallel to those for RWJ 29009 and cromakalim, indicating differences in mechanisms. Since the endothelin-1 induced contraction is presumably receptor mediated and through IP3-induced calcium release from the sarcoplasmic reticulum, nicardipine, a potent voltage-operated calcium channel blocker, was not expected to be effective. In contrast, potassium channel activators, due to their hyperpolarizing property, are effective against both receptor-operated and voltage-operated calcium channels (12), and thus were able to relax the coronary maximally. Nitroprusside, a guanylate cyclase stimulator, relaxes smooth muscle by increasing directly the intracellular cGMP levels. Its action is independent of membrane events that are necessary for the receptor-operated or voltageoperated contractions. Thus, nitroprusside was able to relax maximally the coronary artery. Indeed, Imai (7) found that nitroprusside increased blood flow to the ischemic myocardium and reduced infarct size. In the femoral artery and saphenous vein, the patterns of relaxation produced by the vasodilators were essentially similar to that in the coronary artery. RWJ 29009 was the most potent vasorelaxant while nicardipine was the least. One significant difference is the inability of these agents to relax the endothelin-l-precontracted vessels maximally. Even with RWJ 29009, the maximum relaxation achieved was 75%. It thus appears that endothelin-1 contracted these two vasculatures, in part, by a mechanism that was not antagonized by a potassium channel activator, a calcium channel blocker, or by a guanylate cyclase stimulator. The nature of this contraction is not known.
Vol.
52, No.
21,
1993
Vasorelaxant
Effect
Is T i s s u e
Selective
PL-237
TABLE I Potencies of Vasodilators in Relaxing Endothelin- 1-precontracted Vascular Preparations
Coronary artery
Mean EC50 (laM) [95% confidence limit] Femoral artery Saphenous vein
RWJ 29009
0.0019 [0.0013-0.0026]
0.54 [0.35-0.86]
1.21 [0.8-1.9]
Cromakalim
0.22 [0.16-0.30]
6.4 [3.6-14.5]
3.7 [2.9-4.8]
Nicardipine
0.0166 [0.01-0.027]
34.5 [12-158]
> 10
Nitroprusside
0.109 [0.07-0.157]
5.4 [3.6-9.2]
16.1 [7.3-60]
Potassium channel activators were more effective in relaxing the coronary artery than the femoral artery and the saphenous vein precontracted with endothelin-1. This was evidenced by the EC50 values and the maximal relaxation achieved (Table I). One possible explanation is the existence of a greater population of potassium channels in the coronary artery compared to the other two vessels. Using 86Rb efflux assay, Masuzawa (13) showed that the preferential responsiveness of the coronary artery compared to the mesenteric and middle cerebral arteries was due to a greater population of ATP-sensitive potassium channels in the coronary. Alternatively, the potassium channels in the coronary artery may be of a different subtypes and may have a higher conductance. In conclusion, we found that, using endothelin-1 as the contracting agent, the coronary artery is more sensitive than the femoral artery and the saphenous vein to the relaxing effects of vasodilators, and in particular, to potassium channel activators. It must be pointed out that the effects observed here is limited to one agonist, i.e. endothelin, only. Since both potassium channels (8) and endothelin-1 (14) had been implicated in the pathogenesis of coronary vasospasm, potassium channel activators may prove to be efficacious in treating variant angina. References 1. 2. 3. 4. 5. 6. 7.
S.D. LONGMAN and T.C. HAMILTON, Med. Res. Rev. 12 73-148 (1992). G. EDWARDS and A.H. WESTON, Trends Pharmscol. Sci. 11 417-422 (1990). J. AUCHAMPACH, M. MARUYAMA, I. CAVERO and G. GROSS, The Pharmacologist 32 147 (1990). M. MARUYAMA and G. GROSS, FASEB J. 4A320 (1990). G. GROSS and Z. YAO, The Pharmacologist 3.A4145 (1992). G. GROVER, P. SLEPH and S. DZWONCZYK, J. Cardiovasc. Pharmacol. 1__66853-864 (1990). N. IMAI, C.S. LEUNG, C.K. STONE, S. SAKAMOTO and W.B. HOOD, Jr., Circulation 7_.7_7 705-711 (1988).
PL-238
8. 9. 10. 11. 12. 13. 14.
Vasorelaxant
Effect
Is T i s s u e
Selective
Vol.
52, No. 21,
1993
M. IWAKI, S. MIZOBUCHI, Y. NAKAYA, K. KAWANO, T. NIKI and H. MORI, Cardiovasc. Res. 2__!_1130-139 (1987). J.M. KITZEN, J.D. McCALLUM, C. HARVEY, M.E. MORIN, G.T. OSHIRO and T.J. COLATSKY, Pharmacology 45 71-82 (1992). H.I. JACOBY, J. MOORE, K. TOMKO, W. MILLER, C. SMITH and D.K.H. LEE, FASEB J. 6 A1291 (1992). E.C. GIARDINO, L.B. KATZ, B. HAERTLEIN, J.A. BARRETT and R. FALOTICO, FASEB J. 6 A1291 (1992). N.S. COOK, Trends Pharmacol. Sci. 9 21-28 (1988). K. MASUZAWA and M. ASANO, Jpn. J. Physiol. 4__0.0(Suppl.) $258 (1990). H. KURIHARA, M. YOSHIZUMI, T. SUGIYAMA, K. YAMAOKI, R. NAGAI, F. TAKAKU, H. SATOH, J. INUI, M. YANAGISAWA, T. MASAKI and Y. YAZAKI, J. Cardiovasc. Pharmacoh 13 (Suppl. 5) S132-S137 (1989).
Pergamon Press
PHARMACOLOGY LETTERS Accelerated
Communication
VASORELAXANT EFFECT OF THE POTASSIUM CHANNEL ACTIVATOR, RWJ 29009, IS TISSUE SELECTIVE Henry I. Jacoby, Karen A. Tomko 1 , Catherine Steffler, and David K.H. Lee
Drug Discovery, The R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 194770776, U.S.A. (Submitted February 19, 1993; accepted March i, 1993; received in final form March 15, 1993)
Abstract. Potassium channel activators have potential cardioprotective properties, in part due to their ability to increase coronary blood flow. We compared the vasorelaxant properties of potassium channel activators, a calcium channel blocker (nicardipine) and a direct smooth muscle relaxant (sodium nitroprusside) in the canine coronary artery, the femoral artery and the saphenous vein precontracted with 0.03 ~tM endothelin-1. In the circumflex coronary artery, RWJ 29009, a novel and potent potassium channel activator, maximally relaxed the precontracted rings with an EC50 of 1.9 nM. Cromakalim (EC50=220 nM) and nitroprusside (EC50=109 nM) were also active. Nicardipine (EC50=16.6 nM) produced only a 70% relaxation at 1 I~M concentration. In both femoral artery and saphenous vein, all agents relaxed the precontracted rings only at much higher concentrations, and the relaxations were only 75% of maximal relaxation. The results show that while all vasodilators preferentially relax the coronary artery, potassium channel activators appear to be the most selective and potent of these agents. Inmoducfion Potassium channel activators are a recently defined class of drugs with potential use for treating hypertension, peripheral vascular diseases, and coronary vasospasm (1,2). In the vascular smooth muscle cell, these agents open potassium channels leading to an efflux of potassium ions out of the cell and hyperpolarization of the membrane potential. This hyperpolarization opposes the opening of the voltage-sensitive calcium channels, reduces the frequency of depolarization of cells and thus reduces the vascular smooth muscle tone. Recent studies have shown that potassium channel activators reduce myocardial infarct size and attenuate myocardial stunning in the canine (3-5). Cromakalim and pinacidil have been shown to improve postischemic dysfunction in the globally ischemic rat heart (6). The cardioprotective effects of these agents were deemed to be a direct action on the myocardium; however, one cannot rule out the contribution, at least in part, by their ability to improve coronary blood flow (3,4,7). Consistent with this observation, Iwaki provided evidence suggesting that coronary spasm is the result of a decrease in potassium permeability of the smooth muscle cell (8). It must be pointed out, however, that recent studies also showed that cromakalim and celikalim may not be effective in protecting the myocardium from ischemic injury (9). The reason for the different observations is not clear. The present study explored the relaxant effects of various vasodilators in the coronary artery as compared to peripheral vasculature. If selectivity for the coronary artery was observed, then treatment of coronary vasospasm and ischemic heart diseases with these agents may be relatively free
1Author~ whomrepfintrequestshouldbe~&essed.
0024-3205/93 $ 6 . 0 0 + .00 Copyright © 1993 Pergamon Press Ltd All rights reserved.
PL-234
Vasorelaxant
Effect
Is T i s s u e
Selective
Vol.
52, No.
21,
1993
of undesirable cardiovascular side effects. Vasodilators tested were RWJ 290092 (10,11) and cromakalim (1,2) (potassium channel activators), nicardipine (a calcium channel blocker) and sodium nitroprusside (a guanylate cyclase stimulator). The femoral artery and the saphenous vein were used for comparison. The results demonstrated that the endothelin-l-contracted coronary artery is preferentially relaxed by all agents, and in particular, by the potassium channel activators. Methods Mature male or female beagles weighing 8-16 kg were obtained from Marshall Farms or Hazelton Laboratories. The dogs were anesthetized with pentobarbital (35 mg/kg iv) and the heart, femoral artery and saphenous vein were quickly removed and placed in chilled Kreb's bicarbonate (118.4 mM NaC1; 1.18 mM MgSO4.7H20; 4.75 mM KC1; 2.5 mM CaCI2.2H20; 1.18 mM KH2PO4; 25 mM NaHCO3; and 11 mM dextrose) solution. The circumflex coronary artery was carefully dissected away from the heart, cleaned, and cut into rings approximately 3-5 mm long. The femoral artery and saphenous veins were treated similarly. Each ring was mounted in a heated (37oc) tissue bath containing 15 mL of oxygenated Kreb's bicarbonate buffer. Each ring was attached to a tissue holder below and to a Grass FT03 isometric transducer above. The tissues were allowed to equilibrate for at least 1 hr with frequent changes of Kreb's solution and adjustment of tension. Final resting tension was set at 1 g for femoral artery and saphenous vein and 0.5 g for the coronary artery. Tissues were precontracted with 0.03 pM endothelin-1 (Peptides International), which produced approximately 65% of maximal KCl-induced contraction, followed by relaxation induced by various drugs. Test drugs were dissolved initially in dimethylsulfoxide and diluted to the appropriate concentrations with water. All final dimethylsulfoxide concentrations were less than 1% with no observable effects on the contraction/relaxation of the tissue.
120
Z o
IO0
"~
80
r~
60
F-
WJ 29009 Z r~
40
/
~
20 / 0
~
•
0 "9"
~][ /
•
'
'
..... 10' - 8 . . . . . .
'
10' - f
'
----
Cromakalim
~
Nitroprusside
'
. . . . 10. ' 6"
"
. . . . .
I
10- 5
CONCENTRATION (M)
Figure 1 Vasorelaxant effects of vasodilators in the endothelin-1-precontracted coronary artery
2 (6S)-trans-(-)- 1-(6,7-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-5H-thieno[3,2-b]pyran-7-yl)-2piperidinone
Vol.
52, No.
21,
1993
Vasorelaxant
Effect
Is T i s s u e S e l e c t i v e
PL-235
Analog data from the transducers were amplified and conditioned using preamplifiers (Buxco Electronics), and quantitated using an MI 2 (Modular Instrument Inc.) data acquisition system. Relaxation was expressed as a percent of the initial contracted baseline for each tissue. Means and standard errors for each point were obtained. The slopes of the dose-response curves and the EC50 values (concentration which produces a 50% mean relaxation) and 95% confidence limits were calculated using the EDPLOT and RELPOT programs developed internally. All values reported are means + SEM of at least 6 different experiments. Results The effects of the potassium channel activators and other vasodilators on the endothelin-1 contracted coronary arterial rings are shown in Figure 1. RWJ 29009 was the most potent relaxant, exhibiting an ECs0 of 1.9 nM (Table I). Cromkalim (EC50=220 nM) was 115 times less potent. While nicardipine is a potent vasorelaxant (EC50=16.6 nM), it did not produce 100% relaxation even at a concentration of 1000 nM. Its concentration-relaxation curve had a slope significantly less than that for the potassium channel activators. Nitroprusside (EC50=I09 nM) was somewhat more potent then cromakalim. All agents tested relaxed endothelin- 1 contracted dog femoral artery (Figure 2) and saphenous vein (Figure 3). However, maximal relaxation was no more than 70% at concentrations up to 10 IxM. RWJ 29009 was most potent in both preparations (Table I). Discussion The purpose of the present study was to determine whether vasodilators, and in particular, potassium channel activators, can relax selectively the coronary artery when compared to other vasculatures. The femoral artery, a large peripheral resistance artery, and the saphenous vein were chosen for comparison. Endothelin-1, in our hands, contracted all three canine vascular preparations maximally, thus allowing direct comparison of pharmacologic responses among the preparations against a single agonist.
1oo 80 1 •
13--- RWJ 29009 ~ Cromakalim ~ ~
Nicardipine Nitroprusside
60
5
40
'i
2
-eo ~
10-8
10-7
10-6
10-5
CONCENTRATION (M)
Figure 2 Vasorelaxant effects of vasodilators in the endothelin-1-precontracted femoral artery
PL-236
Vasorelaxant
I oo
Effect
+ ---~~
80
Is T i s s u e S e l e c t i v e
Vol.
52, No.
21,
1993
RWJ 29009 Cromakalim Nicardipine Niuoprusside
60
40
z
20
0 -20
10-8
10-7
10-6
10-5
CONCENTRATION (M) Figure 3 Vasorelaxant effects of vasodilators in the endothelin-l-precontracted saphenous vein
Our results demonstrated the ability of both potassium channel activators to relax maximally endothelin-l-precontracted coronary artery, with RWJ 29009 being 115 fold more potent than cromakalim (Figure 1 and Table I). Nicardipine, at concentrations up to 10 ~tM, could only relax the vessel to about 75% of maximum. Furthermore, the slope of the dose response curve was not parallel to those for RWJ 29009 and cromakalim, indicating differences in mechanisms. Since the endothelin-1 induced contraction is presumably receptor mediated and through IP3-induced calcium release from the sarcoplasmic reticulum, nicardipine, a potent voltage-operated calcium channel blocker, was not expected to be effective. In contrast, potassium channel activators, due to their hyperpolarizing property, are effective against both receptor-operated and voltage-operated calcium channels (12), and thus were able to relax the coronary maximally. Nitroprusside, a guanylate cyclase stimulator, relaxes smooth muscle by increasing directly the intracellular cGMP levels. Its action is independent of membrane events that are necessary for the receptor-operated or voltageoperated contractions. Thus, nitroprusside was able to relax maximally the coronary artery. Indeed, Imai (7) found that nitroprusside increased blood flow to the ischemic myocardium and reduced infarct size. In the femoral artery and saphenous vein, the patterns of relaxation produced by the vasodilators were essentially similar to that in the coronary artery. RWJ 29009 was the most potent vasorelaxant while nicardipine was the least. One significant difference is the inability of these agents to relax the endothelin-l-precontracted vessels maximally. Even with RWJ 29009, the maximum relaxation achieved was 75%. It thus appears that endothelin-1 contracted these two vasculatures, in part, by a mechanism that was not antagonized by a potassium channel activator, a calcium channel blocker, or by a guanylate cyclase stimulator. The nature of this contraction is not known.
Vol.
52, No.
21,
1993
Vasorelaxant
Effect
Is T i s s u e
Selective
PL-237
TABLE I Potencies of Vasodilators in Relaxing Endothelin- 1-precontracted Vascular Preparations
Coronary artery
Mean EC50 (laM) [95% confidence limit] Femoral artery Saphenous vein
RWJ 29009
0.0019 [0.0013-0.0026]
0.54 [0.35-0.86]
1.21 [0.8-1.9]
Cromakalim
0.22 [0.16-0.30]
6.4 [3.6-14.5]
3.7 [2.9-4.8]
Nicardipine
0.0166 [0.01-0.027]
34.5 [12-158]
> 10
Nitroprusside
0.109 [0.07-0.157]
5.4 [3.6-9.2]
16.1 [7.3-60]
Potassium channel activators were more effective in relaxing the coronary artery than the femoral artery and the saphenous vein precontracted with endothelin-1. This was evidenced by the EC50 values and the maximal relaxation achieved (Table I). One possible explanation is the existence of a greater population of potassium channels in the coronary artery compared to the other two vessels. Using 86Rb efflux assay, Masuzawa (13) showed that the preferential responsiveness of the coronary artery compared to the mesenteric and middle cerebral arteries was due to a greater population of ATP-sensitive potassium channels in the coronary. Alternatively, the potassium channels in the coronary artery may be of a different subtypes and may have a higher conductance. In conclusion, we found that, using endothelin-1 as the contracting agent, the coronary artery is more sensitive than the femoral artery and the saphenous vein to the relaxing effects of vasodilators, and in particular, to potassium channel activators. It must be pointed out that the effects observed here is limited to one agonist, i.e. endothelin, only. Since both potassium channels (8) and endothelin-1 (14) had been implicated in the pathogenesis of coronary vasospasm, potassium channel activators may prove to be efficacious in treating variant angina. References 1. 2. 3. 4. 5. 6. 7.
S.D. LONGMAN and T.C. HAMILTON, Med. Res. Rev. 12 73-148 (1992). G. EDWARDS and A.H. WESTON, Trends Pharmscol. Sci. 11 417-422 (1990). J. AUCHAMPACH, M. MARUYAMA, I. CAVERO and G. GROSS, The Pharmacologist 32 147 (1990). M. MARUYAMA and G. GROSS, FASEB J. 4A320 (1990). G. GROSS and Z. YAO, The Pharmacologist 3.A4145 (1992). G. GROVER, P. SLEPH and S. DZWONCZYK, J. Cardiovasc. Pharmacol. 1__66853-864 (1990). N. IMAI, C.S. LEUNG, C.K. STONE, S. SAKAMOTO and W.B. HOOD, Jr., Circulation 7_.7_7 705-711 (1988).
PL-238
8. 9. 10. 11. 12. 13. 14.
Vasorelaxant
Effect
Is T i s s u e
Selective
Vol.
52, No. 21,
1993
M. IWAKI, S. MIZOBUCHI, Y. NAKAYA, K. KAWANO, T. NIKI and H. MORI, Cardiovasc. Res. 2__!_1130-139 (1987). J.M. KITZEN, J.D. McCALLUM, C. HARVEY, M.E. MORIN, G.T. OSHIRO and T.J. COLATSKY, Pharmacology 45 71-82 (1992). H.I. JACOBY, J. MOORE, K. TOMKO, W. MILLER, C. SMITH and D.K.H. LEE, FASEB J. 6 A1291 (1992). E.C. GIARDINO, L.B. KATZ, B. HAERTLEIN, J.A. BARRETT and R. FALOTICO, FASEB J. 6 A1291 (1992). N.S. COOK, Trends Pharmacol. Sci. 9 21-28 (1988). K. MASUZAWA and M. ASANO, Jpn. J. Physiol. 4__0.0(Suppl.) $258 (1990). H. KURIHARA, M. YOSHIZUMI, T. SUGIYAMA, K. YAMAOKI, R. NAGAI, F. TAKAKU, H. SATOH, J. INUI, M. YANAGISAWA, T. MASAKI and Y. YAZAKI, J. Cardiovasc. Pharmacoh 13 (Suppl. 5) S132-S137 (1989).