Contribution of prostaglandin EP₂receptors to renal microvascular reactivity in mice

Abstract

The present studies were performed to determine the contribution of EP 2 receptors to renal hemodynamics by examining afferent arteriolar responses to PGE 2, butaprost, sulprostone, and endothelin-1 in EP 2 receptor-deficient male mice (EP2Ϫ/Ϫ). Afferent arteriolar diameters averaged 17.8 Ϯ 0.8 m in wild-type (EP 2ϩ/ϩ) mice and 16.7 Ϯ 0.7 m in EP2Ϫ/Ϫ mice at a renal perfusion pressure of 100 mmHg. Vessels from both groups of mice responded to norepinephrine (0.5 M) with similar 17-19% decreases in diameter. Diameters of norepinephrinepreconstricted afferent arterioles increased by 7 Ϯ 2 and 20 Ϯ 6% in EP 2ϩ/ϩ mice in response to 1 M PGE2 and 1 M butaprost, respectively. In contrast, afferent arteriolar diameter of EP 2Ϫ/Ϫ mice decreased by 13 Ϯ 3 and 16 Ϯ 6% in response to PGE 2 and butaprost. The afferent arteriolar vasoconstriction to butaprost in EP 2Ϫ/Ϫ mice was eliminated by angiotensin-converting enzyme inhibition. Sulprostone, an EP 1 and EP3 receptor ligand, decreased afferent arteriolar diameter in both groups; however, the vasoconstriction in the EP 2Ϫ/Ϫ mice was greater than in the EP2ϩ/ϩ mice. Endothelin-1-mediated afferent arteriolar diameter responses were enhanced in EP 2Ϫ/Ϫ mice. Afferent arteriolar diameter decreased by 29 Ϯ 7% in EP 2Ϫ/Ϫ and 12 Ϯ 7% in EP2ϩ/ϩ mice after administration of 1 nM endothelin-1. These results demonstrate that the EP2 receptor mediates a portion of the PGE 2 afferent arteriolar vasodilation and buffers the renal vasoconstrictor responses elicited by EP 1 and EP3 receptor activation as well as endothelin-1.prostaglandins; endothelin; kidney; microcirculation THE REGULATION OF WATER and electrolyte homeostasis is dependent on the renal hemodynamic and tubular transport actions of PGE 2 (5,14,25,42). PGE 2 is the major renal cyclooxygenase (COX)-derived metabolite in the kidney and the PGE 2 receptors (EP) are abundantly expressed in the kidney (5,7,8). Four seventransmembrane-spanning domain, G protein-coupled EP receptors have been identified (5,7,8). The intracellular signaling mechanisms for the EP receptors have been characterized and activate mechanisms that would either relax or contract smooth muscle (5, 14). Overall, PGE 2 has been demonstrated to increase renal blood flow and glomerular filtration rate but the contribution of EP receptors to the control of renal hemodynamics remains unresolved.An important role for the EP 2 receptors in regulating fluid and electrolyte homeostasis has been suggested by studies in mice with targeted disruption of these receptors (21,38,43). Disruption of the EP 2 receptor in mice does not alter renal blood flow but does unmask a systemic vasoconstriction in response to PGE 2 (3, 43). These mice lacking EP 2 receptors develop salt-sensitive hypertension (20). Thus further investigation of the renal microvascular actions of PGE 2 is of extreme interest in these mice. The purpose of the present study was to determine the contribution of EP 2 receptors to renal hemodynamics by examining afferent arteriolar responses to PGE 2 , selec...

Direct vasoconstrictor effect of prostaglandin E2on renal interlobular arteries: role of the EP3 receptor

“…In hydronephrotic kidneys, we mapped the PGE 2 response along the preglomerular tree, finding vasoconstriction of proximal ILAs, while distal ILAs and AAs only manifested PGE 2 -induced vasodilation. This latter observation is consistent with the response of AAs observed in most other studies (4,8,24), although PGE 2 -induced vasoconstriction of these vessels has also occasionally been reported (9,24). In addition, we found that intermediate ILAs displayed a biphasic response to increasing concentrations of PGE 2 , i.e., vasodilation followed by vasoconstriction.…”

“…By contrast, EP1 receptor labeling was predominantly found at the level of the endothelium. Tang et al (24), who in contrast to our and various other studies (4,8), observed afferent arteriolar constriction to high PGE 2 concentrations, also found that this response was mediated via EP3 receptors. We observed that when isolated proximal ILAs were pretreated with a selective EP1 receptor antagonist, PGE 2 -induced vasoconstriction was not inhibited but rather potentiated, indicating that EP1 receptor activation stimulates a vasodilator process.…”

“…So far, the effects of PGE 2 on smaller pre-and postglomerular arterioles have mainly received attention. The postglomerular efferent arterioles were found to be insensitive to PGE 2 (4,23), while for the preglomerular afferent arterioles (AAs) and distal interlobular arteries (ILAs) most studies indicated vasodilation (4,8,23), although vasoconstriction in certain instances has been reported as well (9,23). Whether larger vessels further upstream of the glomerulus are also sensitive to PGE 2 is currently unknown.…”

Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

“…The perfused juxtamedullary nephron preparation was used to assess renal microvascular reactivity as described previously (54). Male C57BL/6 mice weighing 20-25 g were used.…”

“…Mice were anesthetized with thiobutabarbital (inactin; 100 mg/kg i.p.). The kidney was removed and immediately isolated and perfused in vitro with a physiological salt solution and mixture of l-amino acids (54). The juxtamedullary vasculature was isolated for study, and an afferent arteriole was monitored continuously by videomicroscopy.…”