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Investigation of vascular relaxations produced by thalidomide A common adverse effect of thalidomide when used clinically is postural hypotension, but the mechanism of action has not been established. We have found that thalidomide produces hypotension in conscious rats, and have investigated the mode of action. In male Wistar rats (250g), telemetry probes were placed under pentobarbitone anaesthesia, and conscious blood pressure was recorded one week later. In other studies, male Wistar rats (250g) were killed by CO2 overdose, and the tail artery was removed and rings were set up in small vessel myographs. In telemetry experiments, thalidomide (50 mg/kg) produced significant falls in both systolic and diastolic pressures in conscious rats. In rat tail artery, thalidomide (10-100 uM) produced significant relaxations of phenylephrine contracted tissues. In calcium re-addition studies, in which calcium is restored in the presence of KCl or phenylephrine, thalidomide (100 uM) inhibited contractions to calcium restoration only in the presence of phenylephrine (59.6±9.0% of control, n=8). Hence, thalidomide did not act as an L-type calcium channel blocker. Like thalidomide, the T-type calcium channel blocker NNC 55-0396 (100 uM) inhibited contractions to calcium restoration only in the presence of phenylephrine (25.2±5.8% of control, n=5). In combination with NNC 55-0396, thalidomide failed to produce any further inhibition of the contraction to calcium restoration in the presence of phenylephrine. It is concluded that thalidomide produces vascular relaxations by a mechanism distinct from L-type calcium channel block. However, thalidomide mimicked the effects of the T-type calcium channel blocker NNC 55-0396, and the combination had no more effect than the T-type antagonist alone. Hence, thalidomide may act as a T-type calcium channel blocker or at least at another step in the pathway. |
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