Sodium intake, large artery stiffness, and proteoglycans in the spontaneously hypertensive rat.

Although the role of sodium in hypertension has been documented extensively, its effect on large arteries has not been well documented. We examined the effect of high-sodium (8%) diet and the diuretic indapamide (IND) on systemic hemodynamics and aortic wall structure and composition in collagen, elastin, and hyaluronan. Four groups of spontaneously hypertensive rats (SHR) were studied after 8 weeks: those on a normal diet (SHR), a high-sodium diet (SHR+NaCl), a normal diet with IND (SHR+IND), and a high-sodium diet with IND (SHR+NaCl+IND). Mean BP, which was not normalized with IND, was comparable for all groups. Systemic arterial compliance averaged 3.8, 2.5, 4.9, and 3.3 mL/mm Hg. 10(-3), respectively, for the SHR, SHR+NaCl, SHR+IND, and SHR+NaCl+IND groups (P<0.003 and <0.05 for NaCl and IND effects). Wall thickness increased only in the SHR+NaCl group (P<0.01). Aortic wall COL decreased from 16 116 in the SHR to 12 382 micrometer(2)/mm in the SHR+NaCl+IND (P<0.005) group. IND alone had no effect on elastin, but the elastin/collagen ratio was increased significantly. Aortic hyaluronan averaged 2343, 266, 3243, and 1052 micrometer(2)/mm, respectively, for the SHR, SHR+NaCl, SHR+IND, and SHR+NaCl+IND groups (P<0.0001 for NaCl and IND effects). Changes in systemic arterial compliance were significantly and positively correlated with aortic hyaluronan contents. Thus, high-sodium diet affects the structural and functional characteristics of large arteries independently of BP. A high-sodium diet, in addition to a diuretic regimen with IND, affects simultaneously aortic hyaluronan contents and large artery mechanical properties through pressure-independent mechanisms that remain to be defined.

Effects of tranexamic acid and aprotinin, two antifibrinolytic drugs, on PAF-induced plasma extravasation in unanesthetized rats.

Two antifibrinolytic drugs, tranexamic acid (TXA), and aprotinin (APR), are currently used to improve the recovery of patients following major surgery while reducing blood loss. Their mechanisms of action have yet to be fully understood. Here, we examined (1) the effects of TXA or APR on basal vascular permeability (VP) and (2) the effects of TXA or APR on platelet-activating factor (PAF)-induced increase of VP in normal unanesthetized rats. Evans blue dye (EB) bound to albumin was used as the marker of extravasation in selected tissues. In normal rats, PAF (1 microg/kg i.v.) increased VP in most selected tissues including bronchi, aorta, duodenum and pancreas without affecting blood pressure. TXA (up to 300 mg/kg i.v.) had no significant effect on basal VP in any tissues, while APR (30000 KIU/kg i.v.) decreased basal VP in 5 out of 8 tissues. Pre-treatment with TXA decreased PAF-induced increases of VP in the microcirculation of the thoracic and abdominal aorta, the duodenum and the pancreas, from 35% to 41%. TXA was mostly effective at an i.v. dose of 100 mg/kg with a 2 h of pre-treatment period. Pre-treatment with APR also reduced PAF-induced increases of VP in selected tissues by 35 to 61%. The i.v. dose of 30000 KIU/mg was optimal when injected at least 30 min before the administration of PAF + Evans blue. These results suggest that the beneficial effect of APR and TXA, following cardiopulmonary bypass (CPB) and other type of surgeries, may be attributed to the inhibition of plasma exudation mediated, at least in part, by PAF. Thus, TXA and APR may improve patients recovery by reducing the capillary leakage of albumin, associated with interstitial edema formation, and maintaining intravascular fluid volume.

The blood vessel, linchpin of diabetic lesions.

The morbidity and mortality associated with diabetes mellitus are essentially related to the vascular lesions that develop over time in this condition. Both the macrocirculation and microcirculation are involved, and as a consequence, vital organs such as the brain, retina, heart, and kidney and the limbs become damaged. Because microalbuminuria represents the earliest and probably most sensitive indication of endothelial dysfunction in diabetes mellitus, the results of pharmacologic intervention with angiotensin-converting enzyme inhibitors, which treat glomerular hypertension were the first indication of potential beneficial effects in reducing diabetic nephroplasty. The nature of endothelial dysfunction related to diabetes is probably not homogeneous, since microcirculation networks are affected at different periods and with variable intensity. This appears to be the case for the aorta, the heart, segments of the digestive tract, the skin, and the skeletal muscle, the largest consumer of insulin. Although the aorta and large arteries contain a small portion of the total blood volume, their distribution of blood flow (pulse pressure) to peripheral organs may affect endothelial function in the microcirculation. Changes in the structure of conduit arteries, partly responsible for the alteration in compliance characteristics, could well be related to the way these arteries are fed by the vasa vasorum system. This report describes a new in vitro approach to examine capillary permeability in normal and alloxan-induced diabetic rabbits. Preliminary results indicate that the size of terminal arterioles of the vasa vasorum (increased diameter) and the capillary permeability to albumin (markedly enhanced) in this specialized network are profoundly affected in the thoracic aorta obtained from diabetic animals. Albumin extravasation into the interstitial fluid compartment of the aorta is likely to lead to structural and physicochemical changes: in fact, removal of interstitial macromolecules via lymphatic drainage is poor in the blood vessel wall of large arteries. This experimental approach is likely to be useful in the exploration of medications affecting the structure and function of conduit vessels.

Reduction of capillary permeability in the fructose-induced hypertensive rat.

Impaired insulin transcapillary transport and the subsequent decrease in insulin delivery to target organs have been suggested to play a role in insulin resistance. These defects were studied in fructose-fed rats, an animal model with insulin resistance. For this study, male Sprague-Dawley rats were fed with either a 60% fructose enriched (F) or a standard chow diet (N) for a total of 2, 4, or 8 weeks. Capillary permeability to albumin was assessed at the end of each dietary period by quantifying the extravasation of albumin-bound Evans blue (EB) dye in different organs. Unanesthetized animals were injected with Evans blue dye (20 mg/kg) in the caudal vein 10 min before being killed and EB dye was extracted by formamide from selected organs collected after exsanguination. As expected, rats had an increase in blood pressure upon feeding with fructose at 4 and 8 weeks (F, 149 +/- 3 mm Hg; N, 139 +/- 3 mm Hg; P < .05). Using this technique, we showed a 56% and a 51% reduction in capillary permeability in skeletal muscles at 4 and 8 weeks of fructose feeding, respectively (4 weeks: N, 44.5 +/- 5.0 microg/g of dry tissue; F, 19.8 +/- 4.2 microg/g of dry tissue; P < .01 and 8 weeks: N, 23.3 +/- 3.7 microg/g of dry tissue; F, 11.3 +/- 4.0 microg/g of dry tissue; P < .05). Similar changes were observed at 4 weeks in the thoracic aorta (N, 82.8 +/- 8.8 microg/g of dry tissue; F, 53.0 +/- 5.1 microg/g of dry tissue; P < .02) and skin (N, 36.0 +/- 5.3 microg of dry tissue; F, 15.0 +/- 2.3 microg/g of dry tissue; P < .02) and at 8 weeks in the liver (N, 107.5 +/- 4.3 microg/g of dry tissue; F, 80.9 +/- 3.2 microg/g of dry tissue; P < .01). In conclusion, fructose feeding is accompanied by a significant and selective reduction of Evans blue leakage primarily in skeletal muscle and liver, and transiently in the skin and aorta, consistent with a role for decreased tissue insulin delivery in insulin resistance.

Aprotinin, an antifibrinolytic drug, attenuates bradykinin-induced permeability in conscious rats via platelets and neutrophils.

Two antifibrinolytic drugs, tranexamic acid (TXA) and aprotinin (APR), are used to improve the recovery of patients following cardiac surgery while reducing blood loss. Their mechanisms of action have yet to be fully understood. To investigate their possible mechanisms of action during cardiopulmonary bypass, we examined (i) the effects of TXA and APR on bradykinin (BK) induced vascular permeability (VP) in conscious rats, (ii) the roles of platelets and neutrophils in this reaction, and (iii) the effects of TXA or APR on BK responses in platelet- or neutrophil-depleted rats. Evans blue dye (EB) was used as the marker of extravasation. The animals were treated with antiplatelet serum for platelet depletion or with methotrexate for neutrophil depletion. In normal rats, BK increased VP in most tissues. Thrombocytopenia and neutropenia also increased basal VP. TXA had no significant effect whereas APR decreased basal VP. In the second series of experiments, APR significantly attenuated BK-induced increases in VP, whereas TXA was completely ineffective. Platelet depletion did not affect BK-induced increases of VP, except for a massive plasma exudation in the lung parenchyma. Neutrophil depletion also had no effect on BK-induced increases of VP, except for an attenuation in the duodenum. In the third and last series of experiments, TXA potentiated the effect of BK in the upper and lower bronchi of platelet-depleted rats, compared with the effects of TXA on BK in normal animals, except in the lung parenchyma, where TXA blocked the increase of VP induced by BK. APR also potentiated the effect of BK in the lower bronchi of platelet-depleted rats. Overall, the inhibitory effect of APR on the VP induced by BK in normal rats was attenuated in platelet-depleted rats. Like TXA, APR blocked the increase of VP induced by BK in the lung parenchyma of platelet-depleted rats. In neutrophil-depleted rats, TXA did not affect the permeabilizing response to BK. In those rats, the inhibitory effect of APR against BK increases of VP was attenuated. These results show that the beneficial effect of APR, but not TXA, following cardiac surgery may be attributed to the inhibition of plasma exudation mediated, in part, by BK. In addition, platelets and neutrophils do not appear to be involved in BK-mediated plasma exudation. However, both cell types are essential for the regulation of basal VP. Finally, the mechanism underlying the protective inhibitory effect of APR on BK-induced increases of VP involves, at least in part, platelets and neutrophils, since the inhibitory effect of APR is attenuated in thrombocytopenic and neutropenic rats. Both cell types are not involved in the action of TXA on VP. Therefore, maintaining platelet and neutrophil counts following cardiopulmonary bypass could enhance the protective effect of APR.

[Role of neutral endopeptidases in capillary dysfunctions of diabetic origin in rats]. / Rôle des endopeptidases neutres dans les dysfonctions capillaires d'origine diabétique chez le rat.

Among numerous complications associated with diabetes, the alterations of the normal properties of various microcirculation circuits lead to important dysfunctions which may contribute to target organ damage. As the endothelium plays a crucial role in the microcirculatory circuits, it is suggested that diabetes may influence both the physical and endocrine properties of that cell layer. In 1995, we reported an important increase in plasma extravasation in a model of diabetes in rats treated with streptozotocin. The increase of plasma extravasation was particularly significant in the pulmonary, skin and splanchnic areas. In that particular study, it was of interest that inhibitors of neutral endopeptidases, such as thiorphan, phosphoramidon and SQ 28,603 (specific inhibitor of the recombinant neutral endopeptidases2) corrected almost completely the increase of plasma extravasation induced by diabetes when compared with control rats. It is also worthy of note that the three above-mentioned inhibitors failed to normalize in any case the hyperglycaemia associated with the diabetes in these animals. The present document is a summary synthesis of the putative role of neutral endopeptidases and of the beneficial effects of the inhibitors of these enzymes in diabetes-induced plasma extravasation in the rat.

[Contribution of the vascular interstitial matrix to induced contraction by angiotensin II. In vitro studies on the rabbit aorta, mesenteric artery and vein]. / Contribution de la matrice interstitielle vasculaire à la contraction induite par l'angiotensine II. Etudes in vitro sur l'aorte, l'artère et la veine mésentériques du lapin.

This study examines the contribution of hyaluronan, a rich anionic glycoprotein, to angiotensin-II-induced contraction (AII: 10(-11) to 10(-8) M) of endothelium-free strips of aorta, mesenteric artery and vein obtained from normal rabbits. Tissues are treated with hyaluronidase (HYAL: 1 mg/ml) during 60 min before being mounted in organ baths superfused with normal Krebs solution for isotonic contraction. Isotonic contraction of the mesenteric artery to the four highest doses of AII is reduced by 50 to 60% following HYAL treatment, compared to the normal contraction curve (0.01 < p < 0.001). Isotonic contraction of the aorta and mesenteric vein to AII is not influenced by HYAL. Isometric contraction curves of the three tissues to AII are not modified by HYAL. In additional experiments, the Krebs solution was selectively enriched in calcium (3.8 mM/l) and in sodium (160 mEq/l) to verify if the effect of HYAL is associated with interstitial washing in the concentration of these cations, because of the hyaluronan digestion. In fact, the calcium-rich superfusion is associated with complete correction of the HYAL-induced reduction of the mesenteric artery isotonic contraction. The sodium-rich superfusion failed to normalize the depressed mesenteric artery contraction. Since HYAL only affected isotonic contraction of the resistance artery (mesenteric), it is likely that the interstitial space of this tissue contains more hyaluronan than the aortic or mesenteric vein matrix, or that HYAL only affected the smooth muscle cell population involved in the circular tonus of the resistance vessel. Correction of the abnormality by calcium enrichment of the Krebs solution suggests that a relative diminution and/or a redistribution of this important cation, obtained following the interstitial degradation of hyaluronan.

Comparison of the pre- and post-capillary vascular reactivity in the rat and guinea pig perfused mesenteric bed.

The present study reports the development and optimization of a new model by which the vasoactive properties of various agents can be monitored in the endothelium-intact pre- and post-capillary mesenteric vasculatures of the guinea pig. In contrast with the rat, the guinea pig pre-capillary mesenteric circulation responds to neurokinins via an endothelium-dependent vasodilation (ED50 for the NK-1 selective agonist, 20.2 pmol). In addition, in the rat as in the guinea pig mesenteric vasculature, kinins induced an endothelium-dependent vasodilation in the venous and arterial circuits. ED50 values for rat were arterial, 1.0 nmol, venous, 100 pmol; ED50 values for guinea pig were arterial, 5.5 pmol, venous, 1.9 pmol. The pharmacology of the receptors for these vasoactive agents (and others) as well as the localization of these entities is discussed. In addition, an interspecies comparison is made between the pre- and post-capillary vascular reactivity in the mesenteric circuit of the rat and guinea pig. Our studies should elucidate the pharmacodynamic properties of vasoactive agents in the pre- and post-capillary circulation and shed further light on the contribution of these agonists in hydrostatic force changes and in plasma extravasation phenomena.

Consequences of alteration in capillary permeability.

In this review paper, three aspects related to alteration in capillary permeability, based on a series of recent observations from this laboratory, are examined. Firstly, the determinants of capillary extravasation, which include pre- and post-capillary resistances in different microcirculation networks, as well as endothelial permeability per se, are described with particular reference to the heterogeneous character of both regulatory components, reported by this and other groups. Secondly, the endothelium-interstitium relationship, responsible in part for the maintenance of the interstitial compartment physicochemical characteristics, is introduced as an important factor in regulating the traffic of vital nutrients delivered to the cell mass, and the removal of waste products from the cellular compartment to the microcirculation, for ultimate excretion. Examined in this manner, it appears that modulation of capillary permeability is essential for the maintenance of cellular life, yet the neurohumoral mechanisms involved in the control of microcirculation networks are just starting to be identified. A number of morbid conditions characterized by multiorgan involvement exhibit a common pathophysiological denominator which involves endothelium-interstitium relationships, as illustrated in experimental animal models of arterial hypertension, diabetes mellitus, heart failure, and degenerative renal diseases. Enhanced capillary permeability associated with local interstitial edema in specific organs, such as the heart and the kidney, in arterial hypertension and diabetes mellitus, as well as decreased permeability in peripheral tissues, such as the skeletal muscle and the skin, in congenital cardiomyopathy, have been documented. It is likely that alteration in the characteristics of interstitial matrix composition contributes to target organ damage in these examples of systemic disorders from different etiologies. Thirdly, the recent identification of autocoids and hormones involved in the direct and indirect control of capillary permeability has led to the development of pharmacological tools capable of modulating pre- and post-capillary vascular tonus, as well as endothelial permeability. Angiotensin II antagonism, bradykinin B1-receptor inhibition, and modulation of eicosanoid production, in particular thromboxane A2, are associated in some of the above-described disorders, with normalization of capillary permeability defects, and occasionally with improvement in organ function. The eventual development of agents capable of directly controlling the physicochemical characteristics of the interstitial matrix should be of interest, not only for preventing the development of irreversible matrix structural alterations but also for facilitating the traffic of metabolites between capillaries and the cell mass of vital organs.

Indapamide is superior to thiazide in the preservation of renal function in patients with renal insufficiency and systemic hypertension.

The long-term effects of indapamide or hydrochlorothiazide on blood presssure and renal function were examined in patents with impaired renal function and moderate hypertension. Both drugs controlled hypertension and blood pressure remained normal during the 2 years of the study. Despite this comparable control of hypertension, indapamide therapy was associated with a 28.5 +/- 4.4% increase in creatinine clearance, whereas treatment with hydrochlorothiazide was associated with a 17.4 +/- 3.0% decrease in creatinine clearance. The results of the study indicate that indapamide is superior to hydrochlorothiazide in the treatment of patients with impaired renal function and moderate hypertension.

Drug-induced alteration of endothelial permeability in the rat aorta. Potential consequences on the vessel wall.

UNLABELLED: We recently reported that some diuretics affect capillary permeability in the normotensive rat. In the present study, we explore the effect of selected antihypertensive drugs administered orally during 10 days, on Evans blue (EB) extravasation within the wall of the thoracic (TA) and abdominal aorta (AA) obtained from spontaneously hypertensive rats (SHR). Description of the EB method has been previously reported. Daily doses (mg/kg) of captopril (CAP: 3.0), perindopril (PER: 0.3), nifedipine (NIF: 1.0), clentiazem (CLE: 0.1), hydralazine (HYD: 0.5), furosemide (FUR: 0.5), cicletanine (CIC: 2.0), hydrochlorothiazide (HCZ: 0.5), and indapamide (IND: 0.04) resulted in comparable blood pressure reduction. Percent changes in EB tissue concentration (measured in ug/g dry tissue) was increased by 24% in both the TA and AA in the untreated SHR. CAP reduced by half EB leakage in the TA, while PER decreased EB extravasation 16% below baseline values. Both angiotensin converting enzyme inhibitors failed to normalize EB leakage in the AA. The calcium channel blockers also normalized EB extravasation in the two segments of the aorta, except that CLE was without effect in the AA. HYD normalized EB leakage in the TA, but not in the AA. All diuretics tested reduced EB extravasation by 48 to 58% below baseline values in the TA, whereas CIC only normalized EB leakage. None of the diuretics affected EB extravasation in the AA of the SHR. IN CONCLUSION: 1-the two segments of the aorta were similarly affected in the SHR; 2-despite comparable effect on blood pressure, treatment of the SHR was associated with different responses in the TA and AA; 3-within a given class of drugs, different effects are observed on EB.

Endothelial dysfunction in diabetes mellitus.

In the present study, we examined the pattern of Evan's blue (EB) extravasation over time and we verified the effect of two inhibitors of aldose reductase (sorbinil and ARI 509) as well as aminoguanidine, which modulate nitric oxide (NO) production, on streptozotocin-induced capillary extravasation abnormalities in the upper bronchi, heart, kidney, duodenum, pancreas, skeletal muscle and skin. Albumin extravasation was measured using the EB technique (20 mg/kg). On the third day, a transient decrease in EB leakage was observed in the lung (-49%), heart (-29%) and skeletal muscle (-64%). These early changes in EB were transient, and values returned to normal there after. Later on, EB extravasation was significantly enhanced in the skin (+358, +680, +580, +525 and +365, respectively, at 2, 4, 5, 6 and 7 weeks of diabetes), the duodenum (+101, +160, +92, +124 and +76%), the upper bronchus (+70, +113, +70, +41 and +25%) and the pancreas (+43, +102, +46, +15 and +78%). In the kidney, the increase of EB extravasation was significant at 2 weeks (26%), and from 5 to 7 weeks (+12, +22, +36%). The chronic treatment of diabetic rats with aminoguanidine normalized capillary permeability in most tissues, suggesting that NO is involved in the development of endothelium dysfunction in this streptozotocin-induced diabetic model. Treatment with aldose reductase inhibitors selectively normalized EB extravasation in the kidney.

Antihypertensive drugs and endothelial cell function.

Arterial hypertension is associated with increased capillary permeability, a possible contributor to the vascular remodeling process which could be involved in certain pathological conditions arising from elevated blood pressure. This study evaluated the effects of various antihypertensive drugs on capillary permeability in the normal rat, using Evan's blue dye (EB) as a marker of albumin extravasation. The results reveal that acute injection of certain diuretics (furosemide, indapamide, hydrochlorothiazide) increase while others (amiloride, cicletanine) decrease capillary permeability via stimulation of the cyclooxygenase pathway. 10 day gavage with indapamide, amiloride and cicletanine, as well as angiotensin-converting enzyme (ACE) inhibitor perindopril and calcium channel blockers nifedipine and verapamil decreases capillary permeability, whereas furosemide, hydrochlorothiazide, ACE inhibitor captopril and calcium channel blocker clentiazem do not modify or increase EB extravasation. Hence, selected antihypertensive agents reduce capillary permeability and could therefore have a supplemental protective vascular effect, in addition to their lowering arterial pressure.

Disorders of body fluid balance: a new look into the mechanisms of disease.

OBJECTIVE: To review the mechanisms of disease on the basis of dysfunction in body fluid distribution secondary to abnormalities in capillary permeability and plasma membrane transport disorders, leading to quantitative and qualitative alterations of the interstitial space, a mainly strategic compartment positioned between the microcirculation and cell mass. DATA SOURCES: The recent literature on the mechanisms involved in the control of body fluid balance, with special reference to microcirculation and interstitial compartment physiology, as well as published and unpublished original data from the authors laboratory. DATA EXTRACTION AND SYNTHESIS: To illustrate the importance of capillary permeability dysfunction in the development of disease, animal (rat and dog) models of chronic renal failure, acute diuretic-induced fluid depletion, diabetes mellitus, arterial hypertension and ischemia-reperfusion of the kidney were used in an attempt to show that in all these experimental models, basic capillary permeability dysfunction (measured by the extravasation of Evans blue, a marker of albumin leakage) develops in specific microcirculation beds. As a consequence, tissue edema (interstitial and/or cellular) develops and likely impairs the traffic of nutrients and waste products to and from the cellular mass, and/or challenges the microcirculation, leading to organ damage. Kidney dysfunction is measured by conventional clearance methods (renal hemodynamics and tubular function). In some models, the eventual mediators of vascular abnormality are examined by use of pharmacological tools. CONCLUSIONS: The critical role of microcirculation dysfunctions, in particular capillary permeability, resulting in interstitial compositional changes is presented as the basis of disease. The apparent specificity of target organ damage may represent the nonspecific result of physicochemical alteration in the strategic interstitial fluid compartment.

Neutral endopeptidase inhibition, a new approach in the exploration of diabetic vasculopathy in rats.

Diabetic complications are mostly vascular and involve alteration in blood vessel reactivity and permeability. The contribution of the latter dysfunction to the development of target organ damage has not been thoroughly examined. In this study, we verify the acute effect of three peptidase inhibitors (phosphoramidon: N-(alpha-rhamnopyranosylhydroxyphosphinyl)-Leu-Trp, thiorphan: 3-mercapto-2-benzyl-propanoylglycine, and SQ 28,603: N-(2-mercaptomethyl)-1-oxo-3-phenylpropyl]- < or = b-alanine; each at a dose of 2 mg/kg), as well as captopril ([2S]-1-[3-mercapto-2-methyl-propionyl]-L-proline; 10 mg/kg), and an aminopeptidase inhibitor (amastatin: ([(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-Val-Val-Asp; 2 mg/kg) on capillary extravasation abnormalities in the streptozotocin-induced diabetic rat using the Evans blue method. Untreated diabetic rats exhibited a significant enhancement of Evans blue extravasation in the duodenum, upper bronchus, pancreas and skin (175 +/- 19, 94 +/- 4, 95 +/- 9 and 47 +/- 10 micrograms/g dry tissue respectively compared to 67 +/- 9, 44 +/- 5, 47 +/- 4, and 6 +/- 2 micrograms/g dry tissue). The three endopeptidase inhibitors normalized capillary permeability in all tissues. Also, treatment with captopril was associated with complete correction of capillary dysfunction in the skin and partially in the duodenum, upper bronchus, and pancreas. These findings indicate for the first time that the use of neutral endopeptidase inhibitors may be beneficial in preventing capillary abnormalities in this diabetic rat model.

Comparison between the effects of indapamide and hydrochlorothiazide on creatinine clearance in patients with impaired renal function and hypertension.

The long-term effects of indapamide or hydrochlorothiazide on blood pressure and renal function were examined in patients with impaired renal function and moderate hypertension. Both drugs controlled hypertension and blood pressure remained normal during the 2 years of the study. Despite this comparable control of hypertension, indapamide therapy was associated with a 28.5 +/- 4.4% increase in creatinine clearance while treatment with hydrochlorothiazide was associated with a 17.4 +/- 3.0% decrease in creatinine clearance. The results of the study indicate that indapamide is superior to hydrochlorothiazide in the treatment of patients with impaired renal function and moderate hypertension.

Regional changes in the extravasation of albumin in the canine kidney: comparison of bradykinin and water diuresis.

This report describes the adaptation of the albumin bound Evans blue dye (EB) extraction technique and its use in identifying regional changes in albumin extravasation rates. We present data to justify our technical approach and highlight the use of this method by describing differences resulting from two different models of induced diuresis and natriuresis. Results observed under control conditions (Group 1) are compared to those obtained following the infusion of bradykinin (BK) into the left kidney (Group 2) or hypotonic saline-induced water diuresis (Group 3). EB and water content of tissue samples of cortex (CTX), outer medulla (OM), inner medulla (IM), and papilla (PAP) regions are reported. Under control conditions a significant heterogeneous distribution of EB and water content (wet/dry tissue weight) between zones was observed. Left kidney EB values for the CTX, OM, IM, and PAP in Group 1 were 125 +/- 11, 398 +/- 56, 763 +/- 51, and 741 +/- 52 micrograms EB/g dry tissue and respective wet/dry tissue ratios were 4.48 +/- 0.05, 5.10 +/- 0.19, 7.13 +/- 0.37, and 6.35 +/- 0.32. In Group 2, BK caused a selective increase in cortex EB content to 201 +/- 7 (P < 0.01) micrograms EB/g dry tissue, without altering water content values. Results of EB extraction in Group 3 revealed no change in the CTX but significant increases in the OM, IM, and PAP regions: 576 +/- 40 (P < 0.01), 910 +/- 60 (P < 0.01), and 850 +/- 69 (P < 0.05) micrograms EB/g dry tissue, respectively. Likewise, tissue water content values were unchanged in the CTX but significantly greater in the OM, IM, and PAP: 6.02 +/- 0.22, 8.90 +/- 0.25, and 8.40 +/- 0.17, respectively (P < 0.01, all three values). This technique clearly shows the regional heterogeneity of the renal microvascular network and allows the localization of intrarenal changes in albumin extravasation. This method provides evidence that BK increases albumin extravasation in the cortex only and that changes in the renal medulla are obtained in hypotonic saline-induced water diuresis.