Kohei Kikkawa

Prevention of cerebral vasospasm by a novel endothelin receptor antagonist, TA-0201

This study was designed to examine the preventive effect of a novel endothelin (ET)-receptor antagonist TA-0201 on the cerebral vasospasm in a canine double-hemorrhage model. TA-0201 (10(-9)-10(-7) M) inhibited ET-1-induced vasoconstriction in the isolated canine basilar artery without endothelium in a concentration-dependent manner. Its pA2 value was 9.2 (ET(A) antagonism). In a canine double-hemorrhage model, intravenous treatment with TA-0201 (3 mg/kg, twice a day for 7 days) ameliorated the basilar artery narrowing significantly on day 7 compared with that in nontreated dogs. The reductions of the basilar artery diameter were 26.1+/-3.9% and 40.5+/-4.1% with and without TA-0201 treatment, respectively (p<0.05). Histologic study on day 7 indicated that treatment with TA-0201 inhibited vessel-wall damage such as disintegration of endothelium architecture and degeneration of medial smooth-muscle cells. We conclude that intravenous treatment with TA-0201 prevents the development of cerebral vasospasm and accompanying pathologic changes of the vessel wall, probably through blockade of ET(A) receptors.

Endothelium‐dependent calcium‐induced relaxation in the presence of Ca2+ ‐antagonists in canine depolarized coronary arteries

1 We examined the mechanisms underlying Ca2+‐induced relaxation in the presence of clentiazem, a new Ca2+‐antagonist, in depolarized coronary arteries of the dog. 2 Ca2+ (3 × 10−5−3 × 10−3m) caused an unexpected relaxation in the presence of a high concentration of clentiazem (10−6m) in coronary, but not in mesenteric or renal arteries. 3 The Ca2+‐induced relaxation was also observed in the presence of established Ca2+‐antagonists such as diltiazem (3 × 10−6m), nifedipine (3 × 10−8m) and verapamil (3 × 10−6m). 4 The Ca2+‐induced relaxation was inhibited by removal of the endothelium, treatment with oxyhaemoglobin (1.5 × 10−6m) or methylene blue (10−5m), but not by treatment with indomethacin (5 × 10−6m). 5 The Ca2+‐induced relaxation was observed in an endothelium‐denuded coronary artery segment when closely apposed to an endothelium‐containing segment of coronary or mesenteric artery. 6 These results suggest that Ca2+‐induced relaxation in the presence of high concentrations of Ca2+‐antagonists is mediated through endothelium‐derived relaxing factor (EDRF). In addition, Ca2+‐antagonists do not affect the Ca2+‐influx necessary for the release and/or synthesis of EDRF.

Cloning of hamster preproendothelin-1 cDNA and its expression in the heart

To elucidate the pathophysiologic roles of endothelin-1 (ET-1) in the heart, we first cloned and sequenced a part of hamster preproET-1 cDNA from the heart of the CHF146 hamsters. The amino acid sequence has 89% homology to that of rat preproET-1 in the cloned part. The deduced hamster 21-residue mature ET-1 is identical to human, rat, canine, and mouse ET-1. In the next step we investigated the expression of preproET-1 mRNA in the failing heart of CHF146 hamsters. For this purpose, we used 46-week-old CHF146 hamsters and age-matched control healthy hamsters. Left ventricular (LV) + dP/dtmax was significantly lower in CHF146 hamsters than in control hamsters. LV end-diastolic pressure was significantly higher in CHF146 hamsters than in control hamsters, as was central venous pressure. These results suggested that the CHF146 hamsters developed congestive heart failure. The expression of preproET-1 mRNA was greatly enhanced in the LV of the CHF146 hamsters. Because it has been reported that ET-1 induces cardiac hypertrophy and injury to cardiac myocytes in addition to its potent positive inotropic and chronotropic actions, the present findings suggest that endogenous ET-1 plays pathophysiologic roles in the failing heart of CHF146 hamsters.

Effect of clentiazem (TA-3090) with posttreatment on neurologic and histologic disorders of stroke-prone spontaneously hypertensive rats with history of stroke.

Summary After stroke-prone spontaneously hypertensive rats (SHRSP) received a salt-loaded diet to accelerate onset of stroke, the therapeutic effect of clentiazem, a benzothiazepine Ca antagonist, on neurologic and histologic disorders was examined. Treatment with clentiazem (3, 15, and 30 mg/kg) orally twice daily (b.i.d.) for 28 days after the occurrence of stroke reduced neurologic symptoms and histologic changes of brain and kidney in a dose-dependent manner. Acute treatment with clentiazem (15 mg/kg, b.i.d.) administered immediately after stroke for 1 week not only almost completely abolished neurologic symptoms during treatment, but partially improved them even after treatment. Subacute treatment with clentiazem starting 10 days after stroke and continuing for 18 days also suppressed the neurologic signs. Both acute and subacute treatment improved cerebral histology. These results suggest that clentiazem treatment in the acute and subacute phases of stroke is beneficial After stroke-prone spontaneously hypertensive rats (SHRSP) received a salt-loaded diet to accelerate onset of stroke, the therapeutic effect of clentiazem, a benzothiazepine Ca antagonist, on neurologic and histologic disorders was examined. Treatment with clentiazem (3, 15, and 30 mg/kg) orally twice daily (b.i.d.) for 28 days after the occurrence of stroke reduced neurologic symptoms and histologic changes of brain and kidney in a dose-dependent manner. Acute treatment with clentiazem (15 mg/kg, b.i.d.) administered immediately after stroke for 1 week not only almost completely abolished neurologic symptoms during treatment, but partially improved them even after treatment. Subacute treatment with clentiazem starting 10 days after stroke and continuing for 18 days also suppressed the neurologic signs. Both acute and subacute treatment improved cerebral histology. These results suggest that clentiazem treatment in the acute and subacute phases of stroke is beneficial.