Search

Hyperthyroidism in rats is associated with increased oxidative stress. These animals also show abnormal renal hemodynamics and an attenuated pressure-diuresis-natriuresis (PDN) response. We analyzed the role of oxidative stress as a mediator of these alterations by examining acute effects of tempol, a superoxide dismutase mimetic. The effects of increasing bolus doses of tempol (25–150 μmol/kg) on mean arterial pressure (MAP), renal vascular resistance (RVR), and cortical (CBF) and medullary (MBF) blood flow were studied in control and thyroxine (T4)-treated rats. In another experiment, tempol was infused at 150 μmol·kg−1·h−1 to analyze its effects on the glomerular filtration rate (GFR) and on PDN response in these animals. Tempol dose dependently decreased MAP and RVR and increased CBF and MBF in control and T4-treated rats, but the T4 group showed a greater responsiveness to tempol in all of these variables. The highest dose of tempol decreased RVR by 13.5 ± 2.1 and 5.5 ± 1.2 mmHg·ml−1·min−1 in hyperthyroid ( P < 0.01) and control rats, respectively. GFR was not changed by tempol in controls but was significantly increased in the hyperthyroid group. Tempol did not change the absolute or fractional PDN responses of controls but significantly improved those of hyperthyroid rats, although without attaining normal values. Tempol increased the slopes of the relationship between renal perfusion pressure and natriuresis (T4+tempol: 0.17 ± 0.05; T4: 0.09 ± 0.03 μeq·min−1·g−1·mmHg−1; P < 0.05) and reduced 8-isoprostane excretion in hyperthyroid rats. These results show that antioxidant treatment with tempol improves renal hemodynamic variables and PDN response in hyperthyroid rats, indicating the participation of an increased oxidative stress in these mechanisms.

This study analyzed the contribution of neuronal nitric oxide synthase (nNOS) to the hemodynamic manifestations of hyperthyroidism. The effects on hyperthyroid rats of the chronic administration of 7-nitroindazole (7-NI), an inhibitor of nNOS, were studied. Six groups of male Wistar rats were used: control, 7-NI (30 mg·kg−1·day−1by gavage), T450, T475 (50 or 75 μg thyroxine·rat−1·day−1, respectively), T450+7-NI, and T475+7-NI. All treatments were maintained for 4 wk. Body weight, tail systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, SBP, pulse pressure (PP), and HR were measured in conscious rats, and morphological, metabolic, plasma, and renal variables were determined. Expression of nNOS in the hypothalamus of T475 and control rats was analyzed by Western blot analysis. The response of mean arterial pressure (MAP) to pentolinium (10 mg/kg iv) was used to evaluate the sympathetic contribution to BP in T475 and T475+7-NI rats. T4produced an increased hypothalamic nNOS expression and dose-related increases in blood pressure (BP), HR, and PP vs. control rats. 7-NI did not modify BP or any other hemodynamic variable in normal rats. However, 7-NI produced a marked reduction in BP, HR, PP, and food and water intake in both hyperthyroid groups and improved creatinine clearance in the T475 group. Pentolinium produced a greater MAP decrease in the T475+7-NI than in the T475 group. In conclusion, administration of 7-NI attenuates the hemodynamic and metabolic manifestations of hyperthyroidism, suggesting that nNOS contributes to the hyperdynamic circulation of this endocrine disease by modulating sympathetic activity.

This review focuses on the effects of thyroid hormones in vascular and renal systems. Special emphasis is given to the mechanisms by which thyroid hormones affect the regulation of body fluids, vascular resistance and, ultimately, blood pressure. Vascular function is markedly affected by thyroid hormones that produce changes in vascular reactivity and endothelial function in hyper- and hypothyroidism. The hypothyroid state is accompanied by a marked decrease in sensitivity to vasoconstrictors, especially to sympathetic agonists, alteration that may play a role in the reduced blood pressure of hypothyroid rats, as well as in the preventive effects of hypothyroidism on experimental hypertension. Moreover, in hypothyroid rats, the endothelium-dependent and nitric oxide donors vasodilation is reduced. Conversely, the vessels from hyperthyroid rats showed an increased endothelium-dependent responsiveness that may be secondary to the shear-stress induced by the hyperdynamic circulation, and that may contribute to the reduced vascular resistance characteristic of this disease. Thyroid hormones also have important effects in the kidney, affecting renal growth, renal haemodynamics, and salt and water metabolism. In hyperthyroidism, there is a resetting of the pressure-natriuresis relationship related to hyperactivity of the reninangiotensin system, which contributes to the arterial hypertension associated with this endocrine disease. Moreover, thyroid hormones affect the development and/or maintenance of various forms of arterial hypertension. This review also describes recent advances in our understanding of thyroid hormone action on nitric oxide and oxidative stress in the regulation of cardiovascular and renal function and in the long-term control of blood pressure.

Dahl salt-sensitive (DS) rats seem characterized by a ubiquitous increase in Na-K-Cl cotransport activity. Here, an endogenous inhibitor of the Na-K-Cl cotransport system (cotransport inhibitory factor, CIF) was investigated in inbred Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The animals were orally loaded for 10 days with 2% NaCl. Plasma from salt-loaded DS rats inhibited cotransport with a 50% inhibition concentration value (IC50) of 6.4 +/- 0.6% (% plasma concentration, vol/vol) vs. 24.2 +/- 2.2% in DR rats (P < 0.0001). In urine, IC50 for cotransport inhibition was constantly lower in DS before and all during the whole salt-loading period (after 10 days of salt loading, IC50 was 2.59 +/- 0.11% and 6.00 +/- 0.24% in DS and DR rats, respectively; P < 0.0001). After 3 days of salt loading, higher salt appetite in DS rats magnified the differences in urinary CIF excretion. In erythrocytes from DS rats, increased cotransport activity was strongly correlated with urinary CIF excretion (r = 0.967). In conclusion, DS rats present increased plasmatic and urinary CIF levels. This can be a compensatory phenomenon to reduce cotransport hyperactivity and increased NaCl reabsorption at the thick ascending limb of Henle's loop.

Objectives. This study sought to evaluate the relation, if any, between fluid overload in congestive heart failure (CHF) and a newly discovered endogenous natriuretic factor acting like loop diuretic drugs: contransport inhibitory factor (CIF).Background. The humoral mechanisms regulating volume overload in CHF are not fully understood. Therefore, we investigated whether there is a role for CIF in this pathologic condition.Methods. Plasma and urinary CIF levels were investigated in 23 patients with chronic CHF and compared with changes in plasma atrial natriuretic peptide (ANP). Twelve patients without CHF served as control subjects.Results. CHF was associated with a highly significant threefold increase in both plasma CIF levels (mean ± SD 7.10 ± 3.01 vs. 2.28 ± 0.92 U/ml, p < 0.0001) and urinary CIF excretion (7,849 ± 3,600 vs. 2,351 ± 1,297 U/day, p < 0.0001) with respect to patients without CHF. CIF increased as a function of impairment in left ventricular ejection fraction (r = −0.703, p < 0.0001) and the severity of clinical status. Plasma ANP was also increased in patients with CHF, although to a lesser extent (68%, p = 0.0501) than plasma CIF, and was also significantly correlated with left ventricular ejection fraction (r = −0.552, p = 0.0004).Conclusions. Plasma and urinary CIF activities were strongly and very significantly increased in chronic CHF. In addition to ANP, this long-term natriuretic agent may be of potential importance in reducing fluid overload in CHF.

In pithed rats, the levorotatory (-)-enantiomer of cicletanine reduces the pressor responses to angiotensin II (AII) and also, to a lesser extent, those to arginine-vasopressin (AVP). Here we have attempted to characterize further these inhibitory effects by studies of isolated perfused rat kidney and mesenteric vascular beds. In the isolated rat kidney, (-)-cicletanine behaves as a noncompetitive antagonist of AII- and AVP-receptor stimulation, with Ki values of 9.6 and 208 micromol/L respectively. In the isolated mesenteric vascular bed, (-)-cicletanine antagonized both AII dependent contractions with an inhibitory concentration (IC50) of 54.0 +/- 20.5 micromol/L (n = 6), and AVP dependent contractions with an IC50 of 31.6 +/- 5.0 micromol/L (n = 8). In conclusion, (-)-cicletanine antagonizes AII more effectively in rat kidney than in mesenteric vascular beds. Moreover, in rat kidney vascular beds (-)-cicletanine is more potent in blocking the pressor responses to AII than in blocking those to AVP. A selective blockade of AII induced contractions in kidney vascular beds can be one factor explaining both the greater antagonistic potency of (-)-cicletanine against AII compared with AVP in pithed rats, and the renal protective properties of cicletanine in both hypertensive and aged rats.

Cicletanine [particularly the levorotatory (-)enantiomer] inhibits calcium/calmodulin cyclic GMP phosphodiesterase (PDE) in vascular smooth muscle (VSM) and potentiates the vasorelaxant actions of the guanylate cyclase activators sodium nitroprusside (SNP) and atriopeptin II, but the possible interference with vasopressor mechanisms remains to be determined. We tested racemic (+/-) cicletanine for its ability to modify the vascular responses to vasocontractant agents in pithed rats. The most significant results were obtained with angiotensin II (AII). Therefore, the dose of AII that increased the carotid artery blood pressure (BP) 50 mm Hg was twice as high in cicletanine-pretreated (50 mg/kg orally, p.o.) as that in vehicle-pretreated animals (ED50 = 0.48 +/- 0.012 vs. 0.25 +/- 0.007 microgram/kg, p < 0.05). The displacement by cicletanine represented 47.2% of that obtained with losartan (40 micrograms/kg, intravenously, i.v.). Similar results were obtained with (-)-cicletanine (p.o. or i.v.), but not with (+)-cicletanine. In isolated rat aorta, the contraction induced by AII was reduced by (-)-cicletanine in a noncompetitive manner (the percent reduction was independent of the AII concentration). (-)-Cicletanine reduces the vascular reactivity to AII, which plays a key role in several forms of hypertension. These findings are compatible with an action of (-)-cicletanine at any of the numerous steps that couple the occupation of AII receptors to the final contractile response, such as calcium/calmodulin cyclic GMP PDE.