Effect of Paclitaxel-based Hyperthermic Intraperitoneal Chemotherapy (HIPEC) on colonic anastomosis in a rat model.

BACKGROUND: Paclitaxel has been used frequently for Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for ovarian carcinomatosis. Cytoreductive surgery and HIPEC are associated with high rates of morbidity being anastomotic dehiscence one of the most frequent. The objective of this study is to quantify the effect of Paclitaxel-based HIPEC on colonic anastomosis in an experimental rat model. METHODS: After left colon resection and anastomosis, animals were randomized into four groups: Controls (C); Hyperthermia (H); Normothermic Intraperitoneal Paclitaxel (CP) and Paclitaxel-based HIPEC (HP). On postoperative day four, animals' peritoneal cavities were examined macroscopically, colon anastomosis burst pressures measured and specimens analyzed histologically. RESULTS: Thirty-nine animals were randomized and 36 were included in the analysis. H group presented the highest burst pressure 105.11 ± 22.9 mmHg, which was 27% higher than C (77.89 ± 27.6 mmHg). On the other hand, HP presented the lowest burst pressure 64 ± 26 mmHg, 16% lower than C group and 39% lower than H, being this latter difference statistically significant (p = 0.004). There were no significant differences regarding weight loss, adhesion scores, perianastomotic abscesses and histological findings (inflammation, fibroblasts, neoangiogenesis, and collagen among groups). CONCLUSION: Strength of colonic anastomosis was improved by isolated hyperthermia and negatively affected by Paclitaxel-based HIPEC.

Role of kinins in the control of renal papillary blood flow, pressure natriuresis, and arterial pressure.

The present study evaluated the effects of blocking kinins with the bradykinin B(2) receptor antagonist Hoe140 on the relationship between renal perfusion pressure, papillary blood flow (PBF), and sodium excretion. To determine the relevance of renal kinins in the long-term control of arterial pressure, the effect of a chronic intrarenal infusion of Hoe140 on arterial pressure and sodium balance was also studied. PBF was not autoregulated in volume-expanded rats, and the administration of Hoe140 reduced PBF (-30%) and improved PBF autoregulation. The kinin antagonist also decreased sodium excretion (-35%) and blunted pressure natriuresis with no whole-kidney renal hemodynamic changes. These effects may be mediated through nitric oxide (NO), because in rats pretreated with N(G)-nitro-L-arginine methyl ester, Hoe140 had no additional effects on PBF or pressure natriuresis. A role for NO in mediating the renal response to Hoe140 is also supported by the finding that Hoe140 reduced basal urinary NO(3)(-)/NO(2)(-) excretion (-33%), and it blunted the arterial pressure-induced increase in NO(3)(-)/NO(2)(-) excretion, which is compatible with the idea that the pressure-natriuresis response may be mediated through kinins and NO. The importance of kinins in long-term regulation of arterial pressure is demonstrated by the severe arterial hypertension (172+/-6 mm Hg) induced during the chronic intrarenal infusion of Hoe140 associated with sodium and volume retention. These data suggest that renal kinins and NO may be a part of the renal mechanism coupling changes in arterial pressure with modifications in PBF and sodium excretion, therefore contributing to the long-term control of arterial pressure.

Effect of interactions between nitric oxide and angiotensin II on pressure diuresis and natriuresis.

The present study examined the effect of an angiotensin II AT1 or AT2 receptor antagonist on the impairment of the pressure diuresis and natriuresis response produced by nitric oxide (NO) synthesis blockade. N omega-nitro-L-arginine methyl ester (L-NAME, 37 nmol.kg-1.min-1) lowered renal blood flow and reduced the slopes of the pressure diuresis and natriuresis responses by 44 and 40%, respectively. Blockade of AT1 receptors with valsartan increased slightly sodium and water excretion at low renal perfusion pressure (RPP). Blockade of AT2 receptors with PD-123319 had no effect on renal function. The administration of valsartan or PD-123319 to rats given L-NAME had no effect on the renal vasoconstriction induced by NO synthesis blockade. In addition, in rats given L-NAME, valsartan elevated baseline excretory values at all RPP studied, but it had no effect on the sensitivity of the pressure diuresis and natriuresis response. However, the administration of PD-123319 to L-NAME-pretreated rats shifted the slopes of the pressure diuresis and natriuresis responses toward control values, indicating that the impairment produced by NO synthesis blockade on pressure diuresis is dependent on the activation of AT2 angiotensin receptors.

Interactions between nitric oxide and angiotensin II on renal cortical and papillary blood flow.

This study examined the role of angiotensin II (Ang II) on the effects of nitric oxide (NO) synthesis blockade on renal cortical and papillary blood flow in innervated and denervated kidneys of volume-expanded Munich-Wistar rats with hormonal influences on the kidney that were held constant by intravenous infusion. Cortical (CBF) and papillary (PBF) blood flow were measured by laser-Doppler flowmetry. A low dose of N omega-nitro-L-arginine methyl ester (L-NAME, 3.7 nmol x kg[-1] x min[-1]) reduced CBF only in innervated kidneys, and this effect was abolished by subsequent administration of valsartan (an AT1 antagonist). L-NAME 3.7 nmol x kg(-1) x min(-1) improved PBF autoregulation by lowering PBF to the range of 100 to 140 mm Hg of perfusion pressure, and this effect was attenuated or abolished by valsartan in innervated and denervated kidneys, respectively. These results indicate that the cortical and medullary vasoconstriction induced by a low dose of L-NAME are caused by potentiation of the vasoconstrictor influence of renal sympathetic nerves and Ang II. A higher dose of L-NAME (37 nmol x kg[-1] x min[-1]) lowered CBF and PBF in both innervated and denervated kidneys. This effect of L-NAME on the cortical circulation was abolished by valsartan, but this AT1 antagonist had no effect on the medullary vasoconstriction produced by NO synthesis blockade. Therefore, a higher dose of L-NAME induces a renal cortical vasoconstriction through potentiation of the renin-angiotensin system, whereas the fall of PBF seen after L-NAME 37 nmol x kg(-1) x min(-1) seems to be caused primarily by NO suppression. This Ang II potentiation produced by L-NAME in the renal cortex seems to be mediated by AT1 receptors, because it was unaffected by PD123319 (an AT2 antagonist). The results of the present study indicate that NO is an important modulator of the vasoconstrictor influence of Ang II in the renal cortical circulation of the rat. However, although there are some interactions between NO and renal nerves and Ang II on the medullary circulation, the renal medullary vasoconstriction produced by L-NAME appears to be caused primarily by NO suppression, with little influence of the renal vasoconstrictor systems.

Role of nitric oxide on papillary blood flow and pressure natriuresis.

This study examined whether nitric oxide synthesis blockade or potentiation (with N omega-nitro-L-arginine methyl ester [L-NAME] or N-acetylcysteine, respectively) can shift the relations between sodium excretion, papillary blood flow, and renal perfusion pressure. Papillary blood flow was measured by laser Doppler flowmetry. A low dose of L-NAME (3.7 nmol/kg per minute) reduced papillary blood flow only at high arterial pressure (140 mm Hg), but it had no effect on pressure natriuresis. Infusion of 37 nmol/kg per minute L-NAME reduced cortical blood flow by 9% at all perfusion pressures studied, lowered papillary blood flow by 8% and 19% at 120 and 140 mm Hg, respectively, and blunted the pressure-natriuresis response. The administration of 185 nmol/kg per minute L-NAME reduced cortical blood flow by 30% and decreased papillary blood flow by 25% in the range of 100 to 140 mm Hg of arterial pressure. Blockade of nitric oxide synthesis with L-NAME at all doses studied reduced papillary blood flow only at high renal perfusion pressures, but papillary blood flow remained essentially unchanged at low perfusion pressures, thus restoring papillary blood flow autoregulation. N-Acetyl-cysteine (1.8 mmol/kg) increased papillary blood flow by 9% and shifted the relations between papillary blood flow, sodium excretion, and renal perfusion pressure toward lower pressures. This effect of N-acetylcysteine on papillary blood flow was blocked by subsequent L-NAME administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of chronic infusion of rANP in renal hypertensive rats.

The purpose of this study was to evaluate the hemodynamic effects induced by an infusion of synthetic rat atrial natriuretic peptide (rANP, 0.5 micrograms/h iv) during 5 consecutive days in conscious normotensive and two-kidney, one-clip hypertensive (2K,1C) rats. Changes in plasma ANP (pANP) levels and plasma renin activity (PRA) were also determined. The administration of ANP in 2K,1C rats induced a significant decrease in mean arterial pressure (MAP) from 169 +/- 3 to 138 +/- 3, and 149 +/- 3 mmHg by 2 and 5 days of infusion, respectively. This hypotension was accompanied by a significant fall in cardiac index (CI) from 400 +/- 16 to 348 +/- 14 ml.min-1.kg-1 after 2 days of ANP treatment. However, CI returned to the basal levels at the third day, and a significant decrease in total peripheral resistance (TPR) was observed by 3 and 5 days of ANP infusion. The administration of the same dose of ANP in normotensive rats did not induce changes in MAP, but CI decreased (P less than 0.001) transitorily during the first 2 days and returned to control values thereafter. Basal pANP levels were significantly elevated in the hypertensive animals (176 +/- 40 pg/ml) when compared with the normotensive rats (82 +/- 10 pg/ml). The ANP infusion resulted in lower (P less than 0.05) pANP levels in hypertensive (1,017 +/- 234 pg/ml) than in normotensive rats (3,466 +/- 975 pg/ml). PRA did not change in any group during the administration of ANP.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of hypertonic saline in the conscious rat.

The present study examines the role of vasopressin and the sympathetic nervous system on the hemodynamic effects of an infusion of hypertonic saline (NaCl 1.5 M) in conscious rats. The cardiovascular response to hypertonic saline was similar in both untreated and hexamethonium-pretreated rats. Mean arterial pressure increased by 15 mmHg as a consequence of the elevation of total peripheral resistance, while cardiac index was decreased. The administration of an antagonist to the pressor activity of vasopressin in rats with intact reflexes, partially decreased mean arterial pressure and total peripheral resistance and increased cardiac index toward basal values. In contrast, the hemodynamic response to hypertonic saline was totally reverted when the vasopressin antagonist was injected in the hexamethonium-pretreated rats. The results of the present study indicate that the hypertensive response induced by hypertonic saline in conscious rats is due to the vasoconstrictor effects of both vasopressin and the sympathetic nervous system.