Systemic and regional hemodynamic effects of leukotrienes D4 and E4 in the conscious rat.

Abstract

The effect of leukotrienes (LTs) D4 and E4 on systemic and regional hemodynamic variables were studied in the conscious rat (n = 5-9). Renal (R), mesenteric (M), and hindquarter (HQ) blood flow (BF) were monitored by directional pulsed Doppler velocimetry, and mean arterial blood pressure (MAP) and heart rate were recorded through a catheter in the femoral artery. In a separate series of experiments, cardiac index (CI) was measured by the thermodilution method. Systemic injection of LTD4 or LTE4 (0.1-10 micrograms/kg) produced dose-dependent pressor responses; BF in the M, HQ, and R vessels declined, due to increased vascular resistance (VR) at the following order: M much greater than HQ greater than R. Low doses of LTD4 or LTE4 produced vasodilation in the HQ area. Infusion of LTD4 (3 micrograms X kg-1 X min-1) for 10 min produced progressive and pronounced vascular constriction in the M and HQ regions along with reduction in BF. The LTD4 infusion also markedly decreased CI with a concomitant rise in total peripheral resistance index (TPRI). Indomethacin (5 mg/kg iv) pretreatment did not modify any of the hemodynamic effects of LTD4 or LTE4. FPL 55712 (10 mg/kg iv) and LY 171883 (30 mg/kg iv), two different LT-receptor antagonists, partially blocked the constriction effects of these LTs. LY 171883, but not FPL 55172, blocked the HQ vasodilation produced by LTE4. LY 171883 alone increased HQ-BF and reduced HQ-VR. These data indicate that LTD4 and LTE4 are potent constrictors of the M vascular bed, but at low doses they also produce dilation of the HQ blood vessels. Furthermore, no escape from the effects of prolonged infusion of the LTs was demonstrated in this species. Finally, the hemodynamic responses to LTD4 and LTE4 in the conscious rat are independent of cyclooxygenase products of LTs and are only partially blocked by FPL 55712 or LY 171883. These studies taken together suggest a differential distribution of multiple LT receptors in the rat vasculature.