Increased Pressor Sensitivity to Chronic Nitric Oxide Deficiency in Hyperthyroid Rats

Abstract

Abstract-We studied the effects of a possible interaction between partial nitric oxide deficiency and thyroid hormone excess on the long-term control of blood pressure (BP) and morphological and renal variables and examined the role of the renin-angiotensin system in the increased BP of this interaction. Eight groups (nϭ8 each) of male Wistar rats were used: a control group; 3 groups that were treated with thyroxine (50 g/d), N w -nitro-L-arginine methyl ester (L-NAME; subpressor dose, 1.5 mg · kg, or thyroxine plus L-NAME; and another 4 similarly treated groups that received losartan (20 mg · kg Ϫ1 · d Ϫ1) in their drinking fluid. All treatments were maintained for 3 weeks. The time course of tail systolic BP was recorded once a week. At the end of the experimental period, we measured mean arterial pressure in conscious rats and assessed the morphological, metabolic, plasma, and renal variables. Thyroxine produced a mild BP increase from the second week of treatment and an increase in plasma angiotensin II and plasma nitrates/nitrites by the end of the study. Simultaneous administration of thyroxine and a subpressor dose of L-NAME produced a marked BP increase that reached significance from the first week of treatment. Losartan produced normotension in thyroxine-treated rats and attenuated the BP elevation in thyroxineϩL-NAME-treated rats. Hyperthyroid rats showed relative renal and ventricular hypertrophy, absence of absolute left ventricular hypertrophy, and proteinuria. These alterations were not changed by losartan. We conclude that an impaired nitric oxide system might have a counterregulatory homeostatic role against the prohypertensive effects of thyroid hormone and that the renin-angiotensin system plays an important role in thyroxineϩL-NAME hypertension. Key Words: blood pressure Ⅲ hypertrophy, cardiac Ⅲ losartan Ⅲ nitric oxide Ⅲ hyperthyroidism T he hyperthyroid state is an endocrine disorder associated with important changes in hemodynamic, renal, and cardiac function. 1-3 Hyperthyroidism manifests a hyperdynamic circulation, with increased cardiac output, increased heart rate, and decreased peripheral resistance. 2-4 These characteristic cardiovascular manifestations of hyperthyroidism have been reproduced in rats by thyroid hormone treatment. [1][2][3] Animal studies have reported a dose-and time-related increase in arterial pressure 5,6 and have shown that the hyperthyroid state affects cardiac and renal weight and reduces renal sodium excretion. 2,5,6 It is well known that nitric oxide (NO) plays a major role in the regulation of vascular tone, 7 renal sodium excretion, 8,9 and therefore, of arterial blood pressure (BP). 10 Both acute and chronic administration of NO synthase (NOS) inhibitors increase systemic arterial BP. 11,12 Hyperthyroidism in rats increases the responsiveness of resistance vessels to the endothelium-dependent vasodilator acetylcholine. 13 Fernández et al 14 demonstrated that hyperthyroidism leads to a significant and reversible enhancement in rat liver NOS activity. More rec...

Salt sensitivity in experimental thyroid disorders in rats

“…However, our group did not observe increased sodium excretion in hypothyroid methimazole-treated rats under some of the above conditions (44) or in pressure-diuresis-natriuresis studies (43). On the other hand, thyroxine (T 4 )-treated rats showed changes in renal hemodynamics and sodium resorption (46), increased blood volume (34), polydipsia/polyuria (15), reduced ability to excrete sodium after hypertonic saline loading (44), and a blunted pressure-diuresis-natriuresis response (43).…”

The renin–angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations

“…This disorder appears to be unrelated to RAS activity (Rodríguez-Gómez et al 2003) or BP, given that it is not reduced by antihypertensive therapy (Rodríguez-Gómez et al 2003, Moreno et al 2005. These observations suggest that proteinuria in the hyperthyroid state may be attributable to the direct action of thyroid hormones in increasing the permeability of the glomerular barrier.…”

“…They also reported that thyroid hormone-induced renal hypertrophy is reduced by losartan but not by nicardipine, with a decrease in renal AII levels, suggesting a possible role for intrarenal RAS in the renal hypertrophy of hyperthyroidism. However, renal hypertrophy in hyperthyroid rats is not modified by chronic captopril (García del Río et al 1997) or losartan (Rodríguez-Gómez et al 2003) treatment. The reasons for these discrepancies are not clear.…”

“…Therefore, genomic effects of T 3 in downregulating the AT 1 receptor may be involved in reducing vascular resistance in the hyperthyroid state. It is possible that T 3 may indirectly inhibit vascular AT 1 receptor effects via nitric oxide (NO) production (Rodríguez-Gómez et al 2003) in addition to directly downregulating the AT 1 receptor. However, NO would not participate in modulating AT 1 expression after T 3 administration, because L-NAME, an inhibitor of NO synthase, has no effect on T 3 -induced AT 1 receptor downregulation in VSMCs (Fukuyama et al 2003).…”

Experimental Investigation of Acute and Delayed Renal Effect of Exogenous Thyroxine

“…Later, was experimentally proven leadership PAC stimulation in pathological structural changes in tissues of other internal organs in hyperthyroidism [9,14]. However, experimental results indicate that structural changes of tissues of internal organs, including kidneys, concomitant flow of hyperthyroidism, may play a major role in the pathogenesis of renal dysfunction caused by the disruption of thyroid status of the organism [8,23,24]. However, the prerequisite for the reliability of data recorded structural damage kidney tissue is a long course of experimental hyperthyroidism -about 30 days [14,23].…”