Renal Denervation Abolishes Hypertension in Low-Birth-Weight Offspring From Pregnant Rats With Reduced Uterine Perfusion

Abstract

Abstract-Low birth weight is a risk factor for the subsequent development of hypertension in humans. We previously reported that reduced uterine perfusion in the pregnant rat results in growth-restricted offspring predisposed to the development of hypertension. The purpose of this study was to determine whether the sympathetic nervous system plays a role in mediating hypertension in this model of low birth weight. Key Words: hypertension, pregnancy Ⅲ rats Ⅲ renal nerves Ⅲ denervation Ⅲ sympathetic nervous system H ypertension is a multifactorial disorder thought to result from both genetic and environmental factor interactions. Recent epidemiological studies 1,2 suggest that a predisposition for development of hypertension may be programmed by factors initiated in utero, 3 an observation supported by many animal studies. 4 -7 Fetal malnutrition limits fetal growth and results in small-for-gestational-age newborns. 8,9 Findings from both epidemiological and animal studies suggest that fetal malnutrition may also program or permanently alter fetal structure and physiology, resulting in an increased risk for development of hypertension and cardiovascular disease. 3,10 -12 However, the mechanisms mediating low birth weight (LBW) and hypertension remain to be elucidated.In humans, few studies have examined the relationship between the sympathetic nervous system (SNS) and LBW, and controversy exists with regards to whether LBW individuals are associated with increases [13][14][15] or decreases in sympathetic activity. 16 Evidence for alterations in the SNS is noted in some animal models of intrauterine growth restriction (IUGR), because plasma levels of circulating catecholamines are increased. [17][18][19][20][21] This observation has been noted in growth-restricted offspring from pregnant rats fed a proteinrestricted diet during gestation, 17 in a naturally occurring model of IUGR using piglets, 18,19 and in a model of IUGR induced by placental insufficiency in the rat 20 and in sheep. 21 Additionally, hypoxia during fetal development leads to increased sympathetic innervation. 22,23 However, no further assessment of the SNS in association with IUGR has been examined.Nutrient and oxygen supply limitations are the components of the intrauterine environment that limit fetal growth and result in small-for-gestational-age newborns. Because IUGR within the Western world is more likely the result of reduced uterine perfusion, 24 we have developed a model of fetal programming induced by placental insufficiency caused by hypoxia and fetal undernutrition. 25 Using this model, we previously reported that reduced uterine perfusion initiated at day 14 of gestation in the rat results in growth-restricted offspring that are hypertensive as early as 4 weeks of age. 25 Furthermore, marked elevations in mean arterial pressure (MAP) remain evident in male growth-restricted offspring at 12 weeks of age. Because increased renal sympathetic nerve activity appears to be a causal mechanism in primary hypertension, 26 we determined the ro...

Renal Denervation as a Therapeutic Approach for Hypertension

“…[1][2][3][4][5][6] Studies using radiotracer dilution methodology to measure overflow of norepinephrine (NE) from the kidneys to plasma revealed increased renal NE spillover rates in patients with essential hypertension, 7,8 particularly so in young hypertensive subjects, which, in concert with increased NE spillover from the heart, is consistent with the hemodynamic profile typically seen in early hypertension, characterized by increased heart rate, cardiac output, and renovascular resistance. 9 It is now widely accepted that essential hypertension is commonly neurogenic, both initiated and sustained by sympathetic nervous system overactivity.…”

“…Preclinical experiments in models of hypertension, myocardial infarction, heart failure, chronic kidney disease, and diabetic nephropathy have successfully used renal denervation as both an experimental tool and a therapeutic strategy. [1][2][3][4][5][6] In the absence of appropriate drugs to pharmacologically reduce blood pressure in severely hypertensive patients, therapeutic splanchnicectomy and even radical surgical sympathectomy were used since the 1930s. In patients with end stage renal disease (ESRD) and uncontrollable hypertension, an even more radical approach, such as bilateral nephrectomy, is sometimes considered.…”

Renal and extrarenal mechanisms of perinatal programming after intrauterine growth restriction

“…41 The hypothesis is supported by animal data showing that denervation of renal sympathetic nerve supply leads to a normalization of blood pressure in IUGR rats. 42 Certainly, the mechanism is not exclusively extrarenal as sympathetic nerve activity regulates renin synthesis and salt retention in the kidneys.…”

Developmental origins of obesity: a sympathoadrenal perspective

“…[19][20][21][22] Third, chemicals from the environment, such as ethanol, nicotine, chlorpromazine, diethylstilbesterol, interfere with normal SNS development. [23][24][25][26][27][28][29] Fourth, nutritional factors involving mothers and offspring also affect the developing SNS.…”