Leukotriene D4（LTD4）の冠動脈攣縮誘発作用—冠動脈造影およびProstanoids代謝からの検討

Coronary vasoconstrictory action of LTD4:Angiographical documentation of coronary spasm and the evaluation of its mechanism in relation to prostanoids metabolism

　虚血性心疾患（以下IHD）の病態発生と進展・増悪に対するアラキドン酸代謝の関与が注目され，cyclooxy—genase系に由来するthromboxane A₂（以下TXA₂）の冠血管収縮作用，血小板凝集促進作用が明らかになってきた。さらに近年，アラキドン酸代謝のもう一方の経路であるlipoxygenase系に由来する1eukotriene （以下LT）が，強力な冠血管収縮作用を有する事が指摘され，IHDとりわけ冠動脈攣縮（以下coronary spasm）の発生因子のひとつとして注目されている^1〜4。しかし，その詳細な作用機序ならびにLTとTXA₂やprostacyclin （以下PGI₂）などの血管作動性prostanoidsとの関連性についてはいまだ明らかでない。

　そこで今回著者は，強力な冠血管収縮作用を有するleukotriene D₄（以下LTD₄）を用い，その冠循環に対する作用特にcoronary spasm誘発作用を，血行動態面，冠動脈造影（以下CAG）およびprostanoids代謝から実験的に検討したので報告する。

We evaluated the coronary vasoconstrictory action of leukotriene D₄ (LTD₄) in anesthetized mongrel dogs (n=20). LTD₄ (0.33,μg or 0.66/μg) was directly admi-nistered into the left anterior descending coronary artery (LAD) from the cannulated first diagonal branch.

Dogs were chosen randamly to receive i.e. admini-stration of either LTD₄ 0.33,μg one bolus (n=10) or 0.66 μg one bolus (n=10). Coronary blood flow (CBF), coronary arterial pressure (CAP), left ventricular end-diastolic pressure (LVEDP), aortic flow (AoF), coro-nary vascular resistance (CVR) and ST deviation on epicardial ECG were measured before and 15 sec intervals until 60 sec after LTD₄, administration. In addition, in the other 10 dogs, to clarify whether the vasoconstrictory action of LTD₄, is primary or mediated by TXA₂, LTD₄ were administered after intravenous infusion of OKY-046 (a selective TXA₂ synthetase inhibitor). Futhermore, to confirm the LTD₄-induced coronary spasm, coronary arteriography (CAG) was performed (n=5).

In results, LTD₄ 0.33/μg i.c. administration caused a significant dose-dependent reduction of CBF (from 0.85±0. 05 to 0.66±0. 06ml/kg/min, P<0.01) and a significant elevation of CVR (from 4.7±0.4 to 7.3±0.9 mmHg/ml/min, P<0.01) concomitant with a marked elevation of ST segment on epicardial ECG (peak voltage 1.8±0. 2 mV, duration 46±6 sec).

And LVEDP elevated significantly from 8.7+0.6 to 9.7±0.7mmHg (P<0.01), meanwhile, AoF and thromboxane B₂ (TXB₂) level in coronary sinus were not changed. OKY-046 did not influence these changes induced by LTD₄.Furthermore, LTD₄-induced coronary spasm was directly documented by CAG.

It was concluded that LTD₄ is extremely a potent coronary vasoconstrictor and may play an important role in the pathogenesis of coronary spasm and is chemic heart disease.