The renal medulla plays an important role in maintaining body fluid and electrolyte balance and long-term blood pressure homeostasis through its unique structural and functional properties. Among several The renal medulla plays an important role in maintaining body fluid and electrolyte balance and long-term blood pressure homeostasis through its unique structural and functional properties. Among several humoral, paracrine factors or autocoids, angiotensin II (Ang II) has been implicated in the regulation of renal medullary function, including the medullary/papillary microcirculation, urine concentration, and blood pressure, but the mechanisms by which Ang II exerts influences in the renal medulla are largely unknown. The purpose of this review is to summarize the cellular localization, regulation, and functional properties of Ang II AT₁ receptors in the kidney, with special emphasis on type I renomedullary interstitial cells (RMICs) in the renal medulla and cultured RMICs. High densities of AT₁ receptors have been localized in type I RMICs in the inner stripe of the outer medulla by high resolution light and electron microscopic autoradiography following in vitro or in vivo labelling, or in cultured RMICs. Furthermore, reverse transcription polymerase chain reaction and Southern blot analysis now confirm that AT₁ receptors in cultured RMICs are exclusively of the AT_1A subtype. In cultured RMICs, Ang II markedly increases intracellular inositol 1, 4, 5-triphosphate (IP₃) concentration, and stimulates cell proliferation and extracellular matrix synthesis, and these cellular responses are exclusively mediated by AT₁ receptors. Considering the co-occurrence of high levels of renin, renin substrate angiotensinogen, and Ang II in the interstitial fluid compartment, and AT₁ receptors in type I RMICs of the renal medulla, the AT₁ receptor-bearing RMICs may be more responsive to the locally formed interstitial Ang II than to the circulating peptide. Since RMICs also contain the receptors for other vasoactive peptides, such as endothelin (ET_A and ET_B), natriuretic peptides (NPR_A and NPR_B), and bradykinin (B₂), and synthesize prostaglandins and medullipins, they may serve as an important site for functional interactions between Ang II and other vasoactive peptides in modulating renal medullary function. More studies using different experimental approaches are therefore required to explore and elucidate the functional role of renal interstitial Ang II and AT₁ receptors in RMICs in the physiological control of renal medullary function and in the pathophysiology of hypertension and progressive renal diseases. (Hypertens Res 1997; 20: 233-250)

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Interactions between nitric oxide (NO) and angiotensin (ANG) II in renal vascular beds were examined in anesthetized dogs. The renal blood flow (RBF) response to an intrarenal arterial injection of ANG II was significantly augmented by intrarenal infusion of the NO synthase inhibitor N^G-nitro-L-arginine (LNA, 50μg/kglmin). The simultaneous intrarenal infusion of L-arginine (1mg/kg/min) prevented the potentiating action of LNA. Similar potentiation was also seen in phenylephrine-induced renal vasoconstriction. Moreover, during simultaneous intrarenal infusion of sodium nitroprusside (SNP), an NO donor, the potentiating action of LNA on the renal vasoconstrictor action of ANG II disappeared. Under these conditions, the released NO stimulated by ANG II was still inhibited by LNA, if present, but basally released NO was resupplied by SNP, as indicated by the return of the RBF. During an infusion of phenylephrine, which produced an increase in renal vascular tone similar to that observed during the infusion of LNA, the renal vasoconstrictor action of ANG II was not augmented. These data suggest that basally released NO plays an important role in the regulation of renal hemodynamics by modulating the renal vasoconstrictor actions of ANG II and phenylephrine. (Hypertens Res 1997; 20: 251-256)

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To examine the role of autonomic nervous dysfunction in postprandial hypotension (PPH) in elderly persons, we non-invasively assessed autonomic nervous function in 50 elderly subjects with or without PPH, defined as a reduction of more than 20mmHg in systolic blood pressure (SBP) after a meal. The heart rate response to the reduction of SBP during head-up tilt was less and the coefficient of variation of R-R intervals was smaller in subjects with PPH than in those without PPH. The responses to cold pressor test, hyperventilation test, and mental arithmetic test were normal in all subjects. The magnitude of ΔSBP after meal ingestion closely correlated with ΔSBP during tilt-table examination, but did not correlate with the results of the cold pressor test, hyperventilation test, or mental arithmetic test. Stepwise multiple regression analysis revealed that the magnitude of the BP reduction and heart rate increase during the tilt-table test were independent predictors of the magnitude of ΔSBP after meal ingestion. The results indicate that impaired afferent pathways of baroreflexes, including baroreceptors, may play an important role in the pathogenesis of postprandial hypotension in the elderly and that the magnitude of the fall in SBP during tilt-table testing may be related to the degree of the postprandial reduction in BP in elderly persons. (Hypertens Res 1997; 20: 257-261)

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To determine whether angiotensin II participates in the pathogenesis of cardiac hypertrophy and impairs coronary circulation in DOCA/salt hypertension, DOCA hypertensive rats were treated with candesartan cilexetil for 8wk. DOCA/salt hypertension was induced in Wistar rats by removing the right kidney and subcutaneously injecting deoxycorticosterone acetate once a week. Control rats were given subcutaneous injections of saline and maintained on a normal diet. After 4wk of observation, the angiotensin II receptor antagonist candesartan cilexetil was administered by oral gavage for 8wk to 14 rats. Systolic blood pressure was measured weekly with the tail-cuff method. After 12wk, the rats were killed and prepared. The isolated hearts were perfused by a Langendorff apparatus at constant flow. Perfusion pressure was measured by a small-volume transducer, and perfusion flow was recorded by a drop counter. Development of hypertension was not prevented by candesartan cilexetil treatment, but development of cardiac hypertrophy was inhibited. Minimum coronary vascular resistance (MCVR) obtained upon infusing adenosine into the isolated hearts was significantly higher in DOCA/salt hypertensive rats than in sham-operated controls. The elevated MCVR in DOCA/salt hypertensive rats was decreased by the administration of candesartan cilexetil for 8wk. Thus, candesartan cilexetil regressed cardiac hypertrophy and improved coronary vascular resistance without affecting high blood pressure. These findings suggest that angiotensin II plays an important role in the pathogenesis of cardiac hypertrophy in DOCA/salt hypertension and that cardiac hypertrophy increases coronary vascular resistance. (Hypertens Res 1997; 20: 263-267)

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Adrenomedullin (ADM) is a potent vasoactive peptide. In this study, we explored the effects of a continuous supply of ADM by somatic gene delivery on spontaneously hypertensive rats (SHR). DNA constructs containing the human ADM cDNA fused to either the cytomegalovirus promoter (CMV-cADM) or Rous Sarcoma virus 3′-long terminal repeat (RSV-cADM) were intravenously injected into SHR through the tail vein. Expression of human ADM in SHR was identified in the kidney, adrenal gland, heart, and lung by radioimmunoassay and reverse transcription-polymerase chain reaction followed by Southern blot analysis. A single injection of ADM plasmid DNA in young adult SHR (7wk old) caused a significant reduction in systolic blood pressure for up to 5wk (p<0.05). A second injection of CMV- cADM 5wk after the first delivery resulted in a further reduction in blood pressure for another 3wk (p <0.001). A maximal blood pressure reduction of 22mmHg in SHR was observed 7wk after injection of CMV-cADM plasmid DNA (185±1.7mmHg, n=6, p<0.001), and a reduction of 15mmHg was observed after injection of RSV-cADM (192±2.7mmHg, n=6, p<0.001), as compared with control rats given vector DNA (207±2.4mmHg, n=6). Similarly, injection of CMV-cADM plasmid DNA in adult SHR (10wk old) resulted in a significant reduction in blood pressure for up to 6wk. Antibodies to either human ADM or its plasmid DNA were not detected in rat sera after the second injection. These studies indicate that intravenous injection of the human ADM gene in hypertensive rats results in expression of the foreign gene and induces a long-lasting reduction in blood pressure. (Hypertens Res 1997; 20: 269-277)

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To clarify the relationship between blood pressure and insulin resistance, we studied the role of glucose transporter 4 (GLUT4) in skeletal muscle and the effect of angiotensin-converting enzyme inhibitor on insulin resistance. Blood pressure and plasma glucose and plasma insulin responses to glucose loading (2 g/kg, ip) were measured in spontaneously hypertensive rats (SHRs), Wistar-Kyoto rats (WKYs), and Wistar rats at 8, 12, and 20wk of age. GLUT4 gene expression and plasma membrane protein content were also determined in the gastrocnemius muscle. SHRs and WKYs at the age of 8wk had significantly higher plasma glucose levels than did age-matched control Wistar rats. Insulin response also tended to be higher. Glucose intolerance was also present in 12-wk-old SHRs, but normalized at the age of 20wk. In contrast, WKYs were glucose intolerant at 12 and 20wk. Gene expression and plasma membrane content of GLUT4 were augmented in both 8-wk-old SHRs and WKYs, indicating a compensatory increase in these variables. Effects of captopril (20-30mg/kg/d from 8 to 20wk) on GLUT4 were also investigated in these three strains. Captopril improved steady state plasma glucose levels in association with 1.2- to 2.5-fold higher GLUT4 gene expression and a 1.4-fold increase in skeletal muscle GLUT4 protein in SHRs and WKYs. Our results suggest that (1) not only SHRs but also WKYs may have glucose intolerance and hence insulin resistance; (2) gene expression and protein synthesis of skeletal muscle GLUT4 are probably increased compensatorily, indicating that abnormalities in GLUT4 do not have a pivotal role in the development of insulin resistance in SHRs and WKYs; and (3) captopril stimulates skeletal muscle gene expression and synthesis of GLUT4, providing further evidence of its beneficial effect on glucose metabolism. (Hypertens Res 1997; 20: 279-286)

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To evaluate the effects of prolonged intake of a high-sodium diet on glucose and lipid metabolism, we examined the relation of daily urinary sodium excretion to blood pressure, glucose metabolism, and lipid metabolism in 140 Japanese adults who lived in a region where the average daily consumption of sodium was high and stable during the past 15yr; no subject had received any treatment for hypertension or metabolic disorders. Each subject was admitted to our health examination center for 2d for measurement of blood pressure, sampling of blood, and glucose tolerance testing. A 24-h urine specimen was collected by each subject after discharge. Multiple regression analysis revealed that urinary sodium excretion was significantly independent of the mean blood pressure and was unrelated to the area under the serum glucose curve after glucose administration. The urinary sodium level was also unrelated to low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. The prevalence of hypertension in the group with a daily sodium excretion below 140mEq (low sodium group) was 0%, while that in the group with a daily sodium excretion above 280mEq (high sodium group) was 44%; this difference was significant (p<0.01). No significant difference was observed in the prevalence of metabolic disorders between the two groups. Our results suggest that sodium intake has little influence on glucose and lipid metabolism but has a significant influence on blood pressure in normotensive and untreated hypertensive subjects who reside in an area with a relatively high sodium intake. (Hypertens Res 1997; 20: 287-293)

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We and others have demonstrated the existence of two isoforms or subtypes of the angiotensin type 1 (AT1) receptor, named the AT1a and AT1b receptors. In this study we examined if both types of mouse AT1 receptors are internalized after agonist stimulation and whether protein kinase C (PKC) is involved in this process. To directly visualize the cellular localization of the receptors, an antigenic epitope was engineered onto the amino-terminal of the receptors, and stable cell lines specifically expressing each receptor subtype were isolated. Treatment of these cells with angiotensin II (Ang II) resulted in translocation of surface receptors to intracellular vesicles, together with a reduction in surface binding of Sar¹Ile⁸-Ang II. The agonist-induced internalization of AT1a and AT1b receptors was not inhibited by the PKC inhibitor staurosporine, nor mimicked by the phorbol ester phorbol 12-myristate 13-acetate. Similar results were obtained with cultured rat vascular smooth muscle cells expressing predominantly wild-type AT1a receptors. These results suggest that both AT1a and AT1b receptors are internalized after agonist stimulation by a PKC-independent mechanism. (Hypertens Res 1997; 20: 295-300)

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