Normotensive sodium loading in conscious dogs: regulation of renin secretion during β-receptor blockade

Abstract

Renin secretion is regulated in part by renal nerves operating through beta1-receptors of the renal juxtaglomerular cells. Slow sodium loading may decrease plasma renin concentration (PRC) and cause natriuresis at constant mean arterial blood pressure (MAP) and glomerular filtration rate (GFR). We hypothesized that in this setting, renin secretion and renin-dependent sodium excretion are controlled by via the renal nerves and therefore are eliminated or reduced by blocking the action of norepinephrine on the juxtaglomerular cells with the beta1-receptor antagonist metoprolol. This was tested in conscious dogs by infusion of NaCl (20 micromol.kg(-1).min(-1) for 180 min, NaLoad) during regular or low-sodium diet (0.03 mmol.kg(-1).day(-1), LowNa) with and without metoprolol (2 mg/kg plus 0.9 mg.kg(-1).h(-1)). Vasopressin V2 receptors were blocked by Otsuka compound OPC31260 to facilitate clearance measurements. Body fluid volume was maintained by servocontrolled fluid infusion. Metoprolol per se did not affect MAP, heart rate, or sodium excretion significantly, but reduced PRC and ANG II by 30-40%, increased plasma atrial natriuretic peptide (ANP), and tripled potassium excretion. LowNa per se increased PRC (+53%), ANG II (+93%), and aldosterone (+660%), and shifted the vasopressin function curve to the left. NaLoad elevated plasma [Na+] by 4.5% and vasopressin by threefold, but MAP and plasma ANP remained unchanged. NaLoad decreased PRC by approximately 30%, ANG II by approximately 40%, and aldosterone by approximately 60%, regardless of diet and metoprolol. The natriuretic response to NaLoad was augmented during metoprolol regardless of diet. In conclusion, PRC depended on dietary sodium and beta1-adrenergic control as expected; however, the acute sodium-driven decrease in PRC at constant MAP and GFR was unaffected by beta1-receptor blockade demonstrating that renin may be regulated without changes in MAP, GFR, or beta1-mediated effects of norepinephrine. Low-sodium diet augments vasopressin secretion, whereas ANP secretion is reduced.

Salt feedback on the renin-angiotensin-aldosterone system

“…Because ANP plasma levels are elevated under significant salt load and ANP can suppress renin release, a functional role of ANP in the salt-dependent regulation of PRA appears plausible. However, modest, acute salt loading by NaCl infusion at rates that did not elevate plasma ANP levels suppressed the plasma renin activity in healthy humans or dogs [9,23,82], indicating that inhibition of PRA is not dependent on ANP in this setting. Generally, as has been recently discussed in detail [23], even large changes in salt load, either by infusion or oral salt intake, only evoke rather small increases in plasma ANP levels.…”

“…Thus, slow salt loading by an infusion of saline markedly suppressed PRA without any detectable changes in the arterial blood pressure [82] or even a slight decrease in blood pressure in humans [2]. Similarly, PRC was reduced by a saline infusion in dogs without any detectable changes in MABP [9].…”

“…Moreover, a saline injection did not suppress PRC in A1 adenosine receptor knockout mice, indicating that adenosine plays a role in the acute salt-dependent inhibition of renin release not only in vitro (see above) but also in vivo [61]. The suppression of plasma renin activity by a slow salt infusion in dogs and humans occurred without any detectable changes in blood pressure and ANP plasma concentration, and even under the blockade of ß1-adrenoreceptors, which mediate the regulation of renin secretion by renal sympathetic nerves [9,82]. Thus, these three putative regulators of salt-dependent renin release do not appear to be of major importance in this acute setting.…”

Physiology of Kidney Renin

“…In addition, it was shown that the natriuresis in response to sodium load, which increased blood pressure, was inhibited by the administration of ANG II, suggesting that a decrease in the RAS is a prerequisite for the natriuretic response to sodium load (21, 74). Subsequent elegant studies in humans and laboratory animals further suggest that the suppression of renin release in response to an acute modest sodium load is not only independent of changes in blood pressure, but also independent of cardiac output, GFR, ANP, ␤ 1 -adrenergic receptors, plasma sodium levels, osmolality, renal nerves, and nNOS-derived NO (73,456,593,717). Therefore, the question arises which mechanism(s) mediates natriuresis and suppression of renin in response to an acute modest sodium load.…”

Role of blood pressure in mediating the influence of salt intake on renin expression in the kidney

“…Other candidates that have been considered as possible mediators of salt balance on renin expression are hormones such as atrial natriuretic peptide, which could inhibit renin expression during extracellular volume expansion, or renal nerves, which might stimulate renin expression during salt depletion. However, neither renal innervation, ␤-adrenoreceptors, nor atrial natriuretic peptides appear to be essential for the regulation of renin expression by salt balance (2,16,18,28). Finally, also a mediator function of renal perfusion pressure is conceivable because the perfusion is known to affect renin expression (29) and the metaplastic phenotype switch in preglomerular arteries (13).…”