Angiotensin II, acting through type 1 angiotensin (AT 1 ) receptors, has potent effects that alter renal excretory mechanisms. Control of sodium excretion by the kidney has been suggested to be the critical mechanism for blood pressure regulation by the renin-angiotensin system (RAS). However, since AT 1 receptors are ubiquitously expressed, precisely dissecting their physiological actions in individual tissue compartments including the kidney with conventional pharmacological or gene targeting experiments has been difficult. Here, we used a cross-transplantation strategy and AT 1A receptor-deficient mice to demonstrate distinct and virtually equivalent contributions of AT 1 receptor actions in the kidney and in extrarenal tissues to determining the level of blood pressure. We demonstrate that regulation of blood pressure by extrarenal AT 1A receptors cannot be explained by altered aldosterone generation, which suggests that AT 1 receptor actions in systemic tissues such as the vascular and/or the central nervous systems make nonredundant contributions to blood pressure regulation. We also show that interruption of the AT 1 receptor-mediated short-loop feedback in the kidney is not sufficient to explain the marked stimulation of renin production induced by global AT 1 receptor deficiency or by receptor blockade. Instead, the renin response seems to be primarily determined by renal baroreceptor mechanisms triggered by reduced blood pressure. Thus, the regulation of blood pressure by the RAS is mediated by AT 1 receptors both within and outside the kidney.

IntroductionProstaglandin E2 (PGE 2 ) is produced during inflammatory responses, and increased levels of PGE 2 help mediate some of the cardinal features of inflammation, including pain, edema, and fever (1, 2). PGE 2 exerts its effects through interactions with EP receptors, termed EP1-4 (3). Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting cyclooxygenase (COX) enzymes and thereby inhibiting prostaglandin production. In the context of this putative mechanism of action, direct cause-and-effect relationships between interruption of specific receptor-mediated signaling pathways and therapeutic actions have not been firmly established. While NSAIDs are effective analgesic agents, certain NSAIDs have a number of troublesome side effects that are due in part to their broad inhibition of a variety of COX products (4,5).Defining the molecular mechanisms underlying both the therapeutic and adverse actions of NSAIDs should provide useful targets for new, more specific therapeutic strategies. Therefore, we focused on a receptor for one of the prostaglandins (PGE 2 ), the EP1 receptor (6). We generated EP1-deficient mice by gene targeting and compared their physiological responses to genetically matched wild-type controls. We find that EP1 -/-animals have reduced nociceptive pain perception as well as altered cardiovascular homeostasis. These results demonstrate the critical actions of EP1 receptors in two physiological functions: pain perception and blood pressure regulation. Methods EP1 targeting vector construction and production of EP1 -/-mice.Mouse genomic clones containing Ptgerep1, mouse gene symbol for EP1 receptor, were isolated from a DBA/1lacJ genomic λ-phage library (Stratagene, La Jolla, California, USA). Long-template PCR was used to amplify 5′and 3′ fragments of the clone using T3 or T7 and EP1-specific primers. A 4.5-kb 5′ fragment and 6.0-kb 3′ fragment were cloned into pCRII vector (Invitrogen Corp., San Diego, California, USA). These fragments were sequence confirmed and subcloned into pHok, a plasmid containing PGK-neo and PGK-thymidine kinase cassettes. The EP1 targeting vector was designed to replace 671 bp of coding sequence with the PGK-neo cassette. This 671-bp coding region was Received for publication March 9, 1999, and accepted in revised form December 6, 2000.The lipid mediator prostaglandin E2 (PGE 2 ) has diverse biological activity in a variety of tissues. Four different receptor subtypes (EP1-4) mediate these wide-ranging effects. The EP-receptor subtypes differ in tissue distribution, ligand-binding affinity, and coupling to intracellular signaling pathways. To identify the physiological roles for one of these receptors, the EP1 receptor, we generated EP1-deficient (EP1 -/-) mice using homologous recombination in embryonic stem cells derived from the DBA/1lacJ strain of mice. The EP1 -/-mice are healthy and fertile, without any overt physical defects. However, their pain-sensitivity responses, tested in two acute prostaglandin-dependent models, were reduced by approximately ...

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Angiotensin II, acting through type 1 angiotensin (AT 1 ) receptors, has potent effects that alter renal excretory mechanisms. Control of sodium excretion by the kidney has been suggested to be the critical mechanism for blood pressure regulation by the renin-angiotensin system (RAS). However, since AT 1 receptors are ubiquitously expressed, precisely dissecting their physiological actions in individual tissue compartments including the kidney with conventional pharmacological or gene targeting experiments has been difficult. Here, we used a cross-transplantation strategy and AT 1A receptor-deficient mice to demonstrate distinct and virtually equivalent contributions of AT 1 receptor actions in the kidney and in extrarenal tissues to determining the level of blood pressure. We demonstrate that regulation of blood pressure by extrarenal AT 1A receptors cannot be explained by altered aldosterone generation, which suggests that AT 1 receptor actions in systemic tissues such as the vascular and/or the central nervous systems make nonredundant contributions to blood pressure regulation. We also show that interruption of the AT 1 receptor-mediated short-loop feedback in the kidney is not sufficient to explain the marked stimulation of renin production induced by global AT 1 receptor deficiency or by receptor blockade. Instead, the renin response seems to be primarily determined by renal baroreceptor mechanisms triggered by reduced blood pressure. Thus, the regulation of blood pressure by the RAS is mediated by AT 1 receptors both within and outside the kidney.

Gains in corn (Zea mays L.) grain yield over time are well documented, but corresponding changes in forage and stover yield and quality have received less attention. Our objective was to describe yield and quality changes of representative cultivars used by farmers in the northern Corn Belt. Six open‐pollinated cultivars used prior to 1930, 24 cultivars representing four 15‐yr eras between 1931 and 1990, and six modern cultivars, for a total of 36 cultivars, were divided into early‐ and late‐maturity trials. Each trial was grown at three locations in Wisconsin during 1997 and 1998. Since 1930, corn forage dry matter yield has increased at the rate of 0.128 to 0.164 Mg ha−1 yr−1 with stover dry matter yields increasing at the rate of 0.043 to 0.054 Mg ha−1 yr−1 Forage crude protein has not changed significantly with time. Forage neutral detergent fiber concentration has decreased 0.825 to 0.948 g kg−1 yr−1, while forage in vitro digestibility increased 0.538 to 0.612 g kg−1 yr−1 Stover neutral detergent fiber concentration and in vitro digestibility have not changed over time. Since 1930 forage, stover, and ear yield have increased 1.4, 0.7, and 2.4% yr−1, respectively. This trend will no doubt continue, but greater progress might be made if corn forage breeding improvement concentrates on yield and quality changes in stover.