Relaxing effect of nicorandil (N-2-(hydroxyethyl)-nicotinamide nitrate), a new anti-angina agent, on the isolated vascular smooth muscle

Shibata, Shoji; Satake, Nobuhiro; Takagi, Takuji; Kerfoot, Florence; Suh, Tae Kyu

doi:10.1016/0014-2999(84)90244-9

Cited by 21 publications

(11 citation statements)

References 8 publications

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“…It was previously shown that nicorandil had a greater inhibitory effect on the con tractile response to noradrenaline than on the response to potassium in rabbit aorta, cat coronary artery and rabbit basilar artery [Shibata et al, 1984], In the present experi ments, nicorandil had much greater inhibi tory effects on the responses to CL and BHT than the response to MO in isolated rabbit femoral and renal arteries as previously re ported in rabbot aorta [Shibata et al, 1985],…”

Section: Discussionsupporting

confidence: 56%

“…It was reported that the vasorelaxing action of nicorandil may be, at least in part, due to an increase in produc tion of PGL [Neichi et al, 1980], cGMP [Holzmann, 1983] or membrane potassium conductance Karashima et al, 1982] of vascular smooth muscle. This mode of action differed from Ca2+ entry blockers, nitrate, papaverine or dipyrida mole [Taira, 1979;Nabata et al, 1981;Sakai et al, 1981], Furthermore, it was suggested that in isolated vascular smooth muscles the suppression of Ca2+ mobilization in the cell and agonist-induced Ca2+ entry may play an important role in the vasorelaxing action of nicorandil Karashima et al, 1982;Itoh et al, 1981;Shibata et al, 1984;Hester, 1985].…”

Section: Introductionmentioning

confidence: 99%

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Differential Inhibitory Effects of Nicorandil, a New Antiangina Agent, on the Contractile Responses to Alpha-1- and Alpha-2-Adrenoceptor Agonists in Isolated Rabbit Renal and Femoral Arteries

Shibata¹,

Satake²

1987

Pharmacology

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In the renal and femoral artery, nicorandil (10^–6–10^–4 mol/l) had a much greater inhibitory effect on the responses to clonidine (CL) and BHT-920 than on the response to methoxamine (MO) but the inhibitory action of nifedipine on the responses was not different. In the presence of nifedipine, nicorandil further inhibited the responses to all agonists. In the tissue pretreated with phenoxybenzamine, nicorandil inhibited the residual maximum response to MO in the femoral artery but not in the renal artery. Nicorandil had no effect on the residual response to high concentrations of MO in the renal artery pretreated with phenoxybenzamine and nifedipine. Relationship between maximum contraction and percent-receptor occupancy was found to be nonlinear for MO but was close to linear for CL. The inhibitory effect (PA2) of prazosin on MO and CL was much greater than that of yohimbine. In both preparations, nicorandil had only a slight inhibitory effect on the responses to potassium and Ca²⁺. It is concluded that the responses induced by MO, CL and BHT are due to activation of α₁-adrenoceptors and that the differential effect of nicorandil on the responses to α₁ and α₂-agonists may be the result of differences in the amount of receptor reserves and/or efficacy of receptor-contraction coupling that exists for MO, CL and BHT.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Differential Inhibitory Effects of Nicorandil, a New Antiangina Agent, on the Contractile Responses to Alpha-1- and Alpha-2-Adrenoceptor Agonists in Isolated Rabbit Renal and Femoral Arteries

Shibata¹,

Satake²

1987

Pharmacology

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“…Moreover, it has recently been reported that agents which possibly interfere with the mobilization of intracellular Ca2 , such as nitroglycerin, nitroprusside, nicorandil and MDI (2-substituted methylenedioxindenes) inhibited the NA-induced contraction observed in a Ca24-free medium (Rahwan et al, 1977;Hester et al, 1979;Ozaki et al, 1981;Heaslip & Rahwan, 1984;Weishaar et al, 1983;Shibata et al, 1984;Hester, 1985). The present results also demonstrate that AQ, like nitroglycerin, resulted in further inhibition of NA-induced contraction in a Ca2 -free medium containing a high concentration of EGTA (2mM), whereas nifedipine and diltiazem failed to affect similar NA responses.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, diltizaem at 10-5M had no significant inhibitory effect on the response to NA. Noradrenaline-induced contraction in a Ct2+-free medium plus high EGTA Incubation oftissues for 30 min in a Ca2+-free medium with EGTA (2 mM) has usually been used to characterize agonist-induced Ca2' release in vascular smooth muscle (van Breemen et al, 1972;Weiss, 1977;Karaki et al, 1979;Ishida et al, 1980;Shibata et al, 1984).…”

Section: Contractile Responses To Noradrenaline and Potassiummentioning

confidence: 99%

The mode of vasorelaxant action of 2‐ aminoisoquinoline, 1.3 (2H.4H)‐dione, a novel ‘intracellular calcium inhibitor’

Hester

Satake

Shibata

et al. 1986

British J Pharmacology

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In rabbit aorta, pretreatment with 2‐aminoisoquinoline, 1.3 (2H.4H)‐dione (AQ, 10−5 M and 10−4 M) shifted the concentration‐response relationship to noradrenaline (NA, 10−9 M to 10−4 M) in a parallel manner whereas the agent (10−4 M) failed to affect the response to potassium and only slightly depressed Ca2+‐induced contractions in a Ca2+‐free medium in the presence of K+ (40 mM). Ca2+‐entry blockers such as nifedipine and diltiazem (10−6 M and 10−5 M) had very weak or no apparent effects on the response to NA but markedly attenuated or abolished the K+‐ and Ca2+‐induced contractions. Following incubation of tissues for 15 min in a Ca2+‐free medium with low EGTA (0.01 mM) and methoxyverapamil (D600, 10−5 M), NA (3 × 10−7 M) caused a phasic (transient) contraction and the subsequent application of Ca2+ (2mM) resulted in a tonic contraction. This NA‐induced, Ca2+‐dependent, D600‐insensitive contraction was inhibited by AQ (10−5 M and 10−4 M) in a concentration‐dependent manner. This suggests that the inhibitory action of AQ may be related to Ca2+ entry through specific receptor activated pathways. Following incubation of tissues for 30 min in a Ca2+‐free medium with high EGTA (2.0 mM), NA (10−5 M) caused a contraction of rabbit aorta which is dependent upon release of intracellular Ca2+, but the response was 50% to 60% less than that in a normal medium. This contraction was inhibited by AQ (10−5 M and 10−4 M) and nitroglycerin (10−5 M) but not by nifedipine or diltiazem. The inhibitory action of combined treatment with AQ and nitroglycerin (10−5 M) on the response to NA was not different from that of either agent alone. These results suggest that AQ may have inhibitory actions on the release of intracellular Ca2+ and also on Ca2+‐entry through D600‐insensitive, receptor‐activated Ca2+ pathways in rabbit aorta.

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“…It has been reported that the residual nor epinephrine-induced contraction in Ca2+-free medium is inhibited by agents which presumably interfere with the mobilization of intracellular Ca2+ [Ozaki et al, 1981;Weishaar et al, 1983;Shibata et al, 1984;Hester, 1985]. In the present study, NG markedly inhibited the residual response to MO or CL in the renal and femoral arteries in a Ca2+-free medium containing EGTA, whereas nifedipine was ineffective in inhib iting the residual response [Shibata and Sa take, 1987], These results demonstrate that NG interferes with the response due to the mobilization of intracellular Ca2+, regardless of an inhibition of voltage-dependent Ca2+-influx.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Nitroglycerin on Contractile Responses to Methoxamine and Clonidine in Isolated Rabbit Renal and Femoral Arteries

Ito¹,

Satake²,

Anno³

et al. 1988

Pharmacology

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The inhibitory effect of nitroglycerin (NG) on contractile responses to methoxamine (MO) and clonidine (CL) was investigated in isolated rabbit renal and femoral arteries. NG (10^–7–10^–5 mol/l) inhibited the responses to MO and CL in a noncompetitive manner and its inhibitory effect on CL-responses was much greater than that on the MO-responses. In the presence of phenoxybenzamine, however, NG (10^–5 mol/l) markedly inhibited the residual response to MO. Contractile responses to KCl or added Ca²⁺ in a Ca²⁺-free medium containing KCl were slightly inhibited by NG. In the presence of nifedipine, NG (10^–5 mol/l) markedly inhibited residual responses to CL but it only slightly inhibited the response to MO. In a Ca²⁺-free medium with EGTA, MO (10”⁵ mol/l) or CL (10^–5 mol/l) induced a phasic contraction. NG had a greater inhibitory effect on the response to CL than MO. In a Ca²⁺-free medium with EGTA, nifedipine and MO (10^–5 mol/l) or CL (10^–5 mol/l), Ca²⁺ induced a tonic contraction. NG inhibited the Ca²⁺-response in the presence of CL, but it had little or no effect on the Ca²⁺-response in the presence of MO. These results suggest that in rabbit renal and femoral arteries, the potent inhibitory effect of NG on the responses to CL as compared to MO may be due to differences in the amount of receptor reserves that exist for both the agonists. In addition, the inhibition of voltage-dependent Ca²⁺ channels may not play a major role in the vasoinhibitory action of NG. Further, NG inhibits contractile responses due to mobilization of intracellular Ca²⁺ much more than the responses due to receptor-activated, nifedipine-insensitive Ca²⁺-movement.

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Relaxing effect of nicorandil (N-2-(hydroxyethyl)-nicotinamide nitrate), a new anti-angina agent, on the isolated vascular smooth muscle

Cited by 21 publications

References 8 publications

Differential Inhibitory Effects of Nicorandil, a New Antiangina Agent, on the Contractile Responses to Alpha-1- and Alpha-2-Adrenoceptor Agonists in Isolated Rabbit Renal and Femoral Arteries

Differential Inhibitory Effects of Nicorandil, a New Antiangina Agent, on the Contractile Responses to Alpha-1- and Alpha-2-Adrenoceptor Agonists in Isolated Rabbit Renal and Femoral Arteries

The mode of vasorelaxant action of 2‐ aminoisoquinoline, 1.3 (2H.4H)‐dione, a novel ‘intracellular calcium inhibitor’

Inhibitory Effects of Nitroglycerin on Contractile Responses to Methoxamine and Clonidine in Isolated Rabbit Renal and Femoral Arteries

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