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

Abstract

regional hemodynamic effects of leukotrienes D .. and E 4 in the conscious rat. Am. J. Physiol. 251 (Heart Circ. Physiol. 20): H700-H709, 1986.-The effect of leukotrienes (L Ts) D4 and E 4 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 LTD 4 or LTE 4 (0.1-10 ~g/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 >> HQ > R. Low doses of L TD4 or L TE4 produced vasodilation in the HQ area. Infusion ofLTD4 (3 /J.g· kg-1 ·min-1 ) for 10 min produced progressive and pronounced vascular constriction in the M and H Q regions along with reduction in BF. The LTD 4 infusionalso 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 L Y 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 H Q vasodilation produced by L TE ... L Y 171883 alone increased HQ-BF and reduced HQ-VR. These data indicate that LTD 4 and L TE 4 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 L Ts was demonstrated in this species. Finally, the hemodynamic responses to L TD 4 and LTE 4 in the conscious rat are independent of cyclooxygenase products of L Ts and are only partially blocked by FPL 55712 or L Y 171883. These studies taken together suggest a differential distribution of multiple L T receptors in the rat vasculature.indomethacin; blood pressure; renal blood flow; mesenteric blood flow; leukotriene antagonists; anaphylactic shock THE PEPTIDOLEUKOTRIENES (LTs) are 5-lipoxygenase metabolites of arachidonic acid, which have been shown to be the active constituents of the slow reacting substance of anaphylaxis (SRS-A) (27). The potent vasoactive properties of the LTs are well established, but major differences occur between various in vitro vs. in vivo preparations and among diverse species (9). Although most normal vascular preparations constrict in response to in vitro LTs (for review see Ref. 9), some reports show H700 the opposite (14,18,19). In most species studied, in vivo L Ts produce a pressor response, but hypotension is the dominant outcome in guinea pigs and rabbits (9). Furthermore, L Ts were shown to produce renal vascular constriction in the anesthetized pig (24) but to produce dilation in the dog (4,8). Thus conflicting results on hem...

Directed Vascular Expression of Human Cysteinyl Leukotriene 2 Receptor Modulates Endothelial Permeability and Systemic Blood Pressure

“…Although the endothelium usually contributes to CysLT-mediated relaxation and smooth muscle to direct contractile responses, the resolution of these actions as a change in BP has been difficult to predict. For instance, intravenous injection of LTD 4 exerts a pressor effect in conscious rats, 34 whereas both LTC 4 and LTD 4 decrease arterial pressure in anesthetized guinea pigs. However, high doses of the CysLTs paradoxically increase BP for a period of time, followed by transient hypotension in unanesthetized guinea pigs.…”

Interdependence of contractile responses of rat small mesenteric arteries on nitric oxide and cyclo‐oxygenase and lipoxygenase products of arachidonic acid

“…They found the combined actions of meclofenamate and BW755C could be partially reversed by addition of prostaglandin E2, but not by leukotriene C4 or leukotriene D4 (products of 5-lipoxygenase) neither of which had any effect on vascular tone in this preparation. Conversely Eimerl et al (1986) andChapnick (1984) have demonstrated that leukotriene C4 and leukotriene D4 are potent vasoconstrictors in the mesenteric vascular bed. These intermediates cannot therefore be discounted from mediating the responses seen in this study.…”

“…The main vasoactive products of the 5-lipoxygenase enzyme are leukotriene C4 and leukotriene D4. A number of workers have shown that these two leukotrienes constrict mesenteric arteries from rats and dogs (Feigen, 1983;Chapnick, 1984;Eimerl et al, 1986) although this is not a universal finding (Stanton & Coupar, 1986). Hydroxyeicosatetraenoic (HETE) acids, (products of the lipoxygenase system) are also potent vasoactive compounds with a variety of actions.…”

Mesenteric vascular responses to i.v. administration of lipoxin A4 and lipoxin B4 in the conscious rat

“…Low doses (0. l-l pug/kg) of leukotrienes DJE4 produced short lasting vasodilation of hindquarter blood vessels, mesenteric constriction and change in renal vascular tone; higher doses (lo-100 pug/kg) pro-duced a significant vasoconstriction of all vascular beds along with elevated blood pressure [8].…”

“…In this latter reaction, we have recently shown a marked decrease in splanchnic organ blood flow which persisted beyond the systemic hypotension [7]. A systematic search for the potential arachidonate mediator(s) of blood flow derangements in acute anaphylaxis yielded only partial information indicating that cysteinyl-leukotrienes (LTCJDJE4) might be involved in the prolonged mesenteric vasoconstriction [8]. Yet other lipoxygenase products of arachidonate might play a role in this shock syndrome since LTs cannot reproduce all the hemodynamic responses of acute anaphylaxis nor can 5-lipoxygenase inhibitors completely reverse these phenomena [9].…”