Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I(2) receptor IP

Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the renin-angiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI(2) in renovascular hypertension in vivo, employing mice lacking the PGI(2) receptor (IP(–/–) mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP(–/–) mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP(–/–) mice than in WT mice. All these parameters were measured in mice lacking the four PGE(2) receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI(2) is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP(–/–) mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP(–/–) mice. These results indicate that PGI(2) derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo

Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I 2 receptor IP

Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the reninangiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI 2 in renovascular hypertension in vivo, employing mice lacking the PGI 2 receptor (IP -/-mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP -/-mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP -/-mice than in WT mice. All these parameters were measured in mice lacking the four PGE 2 receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI 2 is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP -/-mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP -/-mice. These results indicate that PGI 2 derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo

Thromboxane A(2) and prostaglandin F-2 alpha mediate inflammatory tachycardia

authorSystemic inflammation induces various adaptive responses including tachycardia. Although inflammation-associated tachycardia has been thought to result from increased sympathetic discharge caused by inflammatory signals of the immune system^1, definitive proof has been lacking. Prostanoids-including prostaglandin (PG) D_2, PGE_2, PGF_, PGI_2, and thromboxane (TX) A_2-exert their actions through specific receptors: DP, EP (EP_1, EP_2, EP_3, EP_4), FP, IP, and TP, respectively^2. Here we have examined the roles of prostanoids in inflammatory tachycardia with the use of mice lacking each of these receptors individually. The TXA_2 analog I-BOP and PGF_ each increased the beating rate of the isolated atrium of wild-type (WT) mice in vitro through interaction with TP and FP, respectively. The cytokine-induced increase in beating rate was markedly inhibited in atria from mice lacking either TP or FP. The tachycardia induced in WT mice by injection of lipopolysaccharide (LPS) was greatly attenuated in TP-/- or FP-/- mice and was completely absent in mice lacking both TP and FP. Propranolol failed to block the LPS-induced increase in heart rate in WT animals. Our results show that inflammatory tachycardia is caused by a direct action on the heart of TXA_2 and PGF_ formed under systemic inflammatory conditions