Hiroyuki Nabata

Cardiovascular effects of a new coronary vasodilator N-(2-hydroxyethyl)nicotinamide nitrate (SG-75): comparison with nitroglycerin and diltiazem.

Summary: The cardiovascular effects of a newly developed nicotinamide derivative. N-(2-hydroxyethy1)nicotinamide nitrate (SG-75). were examined in anesthetized, open-chest or closed-chest dogs and compared with those of nitroglycerin and diltiazem. When administered intra-arterially. SG-75 (0.003–1 mg) increased coronary, renal, mesenteric, and femoral blood flows in a dose-dependent fashion, without affecting systemic blood pressure or cardiac function. The coronary vasodilator response to SG-75 was not influenced by intra-arterial administration of propranolol, atropine, diphenhydramine, or dipyridamole. SG-75 (0.03–1 mg/kg) administered intravenously decreased systemic blood pressure and peripheral (coronary, renal, mesenteric, and femoral) vascular resistance and increased peripheral blood flow in a dose-dependent manner. In doses of 0.03–0.3 mg/kg. this drug did not significantly affect pulse pressure, heart rate, right atrial pressure, aortic blood flow, left ventricular (LV) pressure, LV dP/dt, or myocardial oxygen consumption. The results indicate that SG-75 has desirable characteristics as an antianginal agent.

The neuroprotective effect of a potent and selective inhibitor of type I NOS (L-MIN) in a rat model of focal cerebral ischaemia.

OUR newly synthesized δ-(S-methylisothioureidoJ-L-norvaline (L-MIN) was shown to have potent inhibitory effects on Ca2+-dependent and constitutively expressed neuronal nitric oxide synthase (type I NOS) when compared to other commonly recognized NOS inhibitors and produced an IC50 value of 5.7 nM. By contrast, this compound exhibited more than 40-fold weaker inhibitory effects on the other NOS isoforms. Administration of L-MIN (0.1, 0.3 and lmg kg-1, i.p.) to rats immediately after 2 h middle cerebral artery occlusion and 2 h reperfusion reduced infarct size in a dose-dependent manner. These results suggest that type I NOS activation has a crucial role in the pathogenic cellular mechanisms underlying cerebral ischaemia.

Spasmolytic Action of Nicorandil in Canine Conductive Coronary Arteries In Vivo Is Not Modified by Glibenclamide

The spasmolytic effects of nicorandil, cromakalim, and nitroglycerin on coronary arteries were investigated by angiographic technique in anesthetized dogs. With intracoronary arterial (i.a.) U 46619, a thromboxane A2 mimetic, the diameter of coronary arteries decreased in a sustained manner by 36.1 +/- 1.6% from control levels (coronary spasm). With a successive i.a. injection of nicorandil (300 micrograms), cromakalim (30 micrograms), or nitroglycerin (3 micrograms), the diameter recovered control levels (102.9 +/- 3.9, 96.8 +/- 5.6, and 100.1 +/- 4.3%, respectively). In dogs treated intravenously (i.v.) with glibenclamide, a pharmacologic antagonist of K-channel openers, the spasmolytic effect of cromakalim was significantly reduced, whereas the activity of nicorandil or nitroglycerin remained unaffected. We also investigated a possible modification by glibenclamide of the increase in coronary blood flow (CBF) induced by i.a. nicorandil and cromakalim in anesthetized dogs. The dose-dependent blood flow responses to cromakalim and nicorandil were significantly attenuated by glibenclamide, whereas the response to nitroglycerin remained unaffected. These results suggest that the spasmolytic effect of nicorandil on canine conductive coronary vessels is not mediated by K-channel opening but by a nitroglycerin-like action and that the dilatation of resistive coronary vessels induced by nicorandil may be largely due to its action as a K-channel opener.

Actions of CP-060S on veratridine-induced Ca2+ overload in cardiomyocytes and mechanical activities in vascular strips.

CP-060S, (-)-(S)-2-[3,5-bis(1, 1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N-methyl-N-[2-(3, 4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin- 4-one hydrogen fumarate, is a novel cardioprotective drug which is designed to prevent Ca2+ overload and cause vasorelaxation. The effects of this compound were evaluated and compared with those of CP-060R (enantiomer of CP-060S,) and diltiazem (Ca2+ channel antagonist) in a veratridine-induced model of Ca2+ overload and vasorelaxation. After 5-min superfusion of veratridine (74 microM), intracellular free calcium concentrations ([Ca2+]i) of rat single cardiomyocytes, as measured with the fura-2 procedure, were greatly elevated, from 44 +/- 5 nM to 3705 +/- 942 nM, and subsequently generated cell contracture. Pretreatment of cardiomyocytes with more than 300 nM of CP-060S or CP-060R for 30 min provided almost complete protection against the veratridine-induced cell contracture; in CP-060S(1 microM)-treated myocytes, [Ca2+]i were minimal and partially elevated from 42 +/- 5 nM to 72 +/- 14 nM after 5 min of veratridine superfusion. In comparison, diltiazem showed no protection below 1 microM and only partial protection at 10 microM. CP-060S, CP-060R and diltiazem all shifted the concentration-response curve for CaCl2 to the right in a competitive manner in depolarized rat thoracic aorta. The pA2 values of CP-060S, CP-060R and diltiazem were 9.16 +/- 0.18, 8.24 +/- 0.14 and 7.66 +/- 0.09, respectively. Our results indicate that CP-060 behaves stereoselectively as a Ca2+ channel antagonist and non-stereo-selectively to protect against veratridine-induced contracture. The latter effect suggests that Ca2+ entry blockade is not the mechanism by which CP-060S exerts cardioprotection.

Regional and species differences in glyburide-sensitive K+ channels in airway smooth muscles as estimated from actions of KC 128 and levcromakalim

1 The purpose of the present experiments was to elucidate the differences in actions of two K+ channel openers, KC 128 and levcromakalim, on the carbachol‐induced contraction, membrane potential and 86Rb+ efflux of the dog tracheal and bronchial smooth muscles. Furthermore, we compared the effects of these agents on guinea‐pig and human airway smooth muscles. 2 In the dog tracheal and bronchial smooth muscle tissues, levcromakalim induced a concentration‐dependent relaxation of the carbachol‐induced contraction. The IC50 values were 0.35 μm (pIC50: 6.46 ± 0.10, n = 9) and 0.55 μm (pIC50: 6.26 ± 0.07, n = 5), respectively. KC 128 relaxed bronchial smooth muscles precontracted by carbachol with an IC50 value of 0.19 μm (pICso: 6.73 ± 0.10, n = 7). However, KC 128 had almost no effect on the contraction evoked by carbachol in the trachea (IC50 > 10 μm). The relaxations induced by levcromakalim and KC 128 were antagonized by glyburide (0.03‐1 μm) but not by charybdotoxin (100 nm). 3 Levcromakalim (1 μm) hyperpolarized the membrane of both dog tracheal and bronchial smooth muscle cells, whereas KC 128 (1 μm) hyperpolarized the membrane of bronchial but not of tracheal smooth muscle cells. 4 Levcromakalim (10 μm) increased 86Rb+ efflux rate from both tracheal and bronchial smooth muscle tissues but KC 128 (10 μm) increased 86Rb+ efflux rate only from bronchial and not tracheal smooth muscle tissues. Glyburide (1 μm) prevented the hyperpolarization and the 86Rb+ efflux induced by these agents at the same concentration as observed for mechanical responses. 5 Both KC 128 and levcromakalim relaxed the guinea‐pig isolated tracheal smooth muscles precontracted by carbachol (100 nm), histamine (3μm) or U46619 (10 nm). KC 128 was approximately 10 times more potent than levcromakalim for each agonist. 6 In human bronchial smooth muscles, levcromakalim but not KC 128 induced a concentration‐dependent relaxation of the carbachol‐induced contraction. 7 It is concluded that KC 128 has relaxant and hyperpolarizing effects in the dog bronchial and guinea‐pig tracheal smooth muscles, but not in the dog tracheal and human bronchial smooth muscles. On the other hand, levcromakalim acts consistently on all the above airway smooth muscle tissues. These results indicate that there are regional and species differences in distribution of K+ channels, and at least two different K+ channel opener‐ and glyburide‐sensitive K+ channels are present in the dog airway smooth muscles.

Benzopyran-4-carboxamide K+ channel openers

Abstract N -Substituted benzopyran-4-carboxamides 5 have been synthesized. Some of these compounds exhibited potent vasorelaxant activity.

Synthesis and antihypertensive activity of KC-399, a benzopyran K+ channel opener with long duration of action and less tachycardia

Abstract Synthesis and antihypertensive activity of KC-399 (5) have been described. KC-399 (5) showed a highly potent, slow and long-lasting antihypertensive effect with reduced reflex tachycardia.

Structure-activity relationships of 6-substituted benzopyran-4-carbothioamide potassium channel openers.

Abstract QSAR study of 6-substituted benzopyran-4-carbothioamides 1 showed that vasorelaxant activity is linearly correlated with the electronic parameter (σ m ) and parabolically correlated with steric ( L ) and hydrophobic (π) parameters of the 6-substituent.

Vasorelaxant activity of 2-fluoroalkyl-6-nitro-2H-1-benzopyran-4-carbothioamide and -carboxamide K+ channel openers

Abstract Synthesis and vasorelaxant activity of 2-fluoroalkyl-6-nitro-2 H -1-benzopyran-4-carbothioamides 4 and 6 and -carboxamides 5 and 7 are described. Potent smooth muscle relaxant activity was displayed by 6c .

The effect of a novel benzopyran derivative, KC 399, on the isolated guinea-pig trachealis and human bronchi.

1. In isolated guinea-pig trachealis, KC 399, BRL 38227 and salbutamol suppressed the spontaneously generated tone in a concentration-dependent manner with pD2 values of 8.89 +/- 0.09 (n = 14), 6.18 +/- 0.07 (n = 11) and 7.72 +/- 0.12 (n = 8), respectively. 2. The bronchodilator effects of KC 399 and BRL 38227 were antagonized by glibenclamide but not by charybdotoxin or apamin. The effect of salbutamol was antagonized by charybdotoxin but not by glibenclamide or apamin. 3. KC 399 and BRL 38227 failed to inhibit the tone evoked by 90 mM K+ in guinea-pig trachealis, whereas salbutamol did inhibit it, in a concentration-dependent manner. 4. These bronchodilators also relaxed the tone of isolated guinea-pig trachealis supported by histamine, carbachol, U46619 or leukotriene D4. Their order of potency was always KC 399 > salbutamol > BRL 38227. 5. KC 399 and BRL 38227 relaxed isolated human bronchi contracted with histamine or carbachol. 6. We conclude that KC 399 is a potent relaxant of isolated guinea-pig trachealis and human bronchi in vitro. The relaxant action of KC 399 could be due to the opening of glibenclamide-sensitive K+ channels.