Renal Effects of α‐Adrenoceptor Blockade During Furosemide Diuresis in Conscious Rats

Abstract

Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non-selective alpha-adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide-induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n = 6) was compared with time control animals (n = 9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n = 9), 0.3 (n = 6), 1.0 (n = 7) and 3.0 mg/kg/hr (n = 6). Phentolamine infusion reduced norepinephrine-induced increase in blood pressure at all three dose levels (n = 5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose-dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose-dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FELi) increased to 65 +/- 3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52 +/- 3% during furosemide alone. At steady-state conditions (120-180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume-depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FELi = 48 +/- 2% versus 39 +/- 1% in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular alpha-adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide-induced volume contraction.

Interactions Between Furosemide and the Renal Sympathetic Nerves

“…The renal vasoconstrictor response and the decrease in GFR were unchanged in rats with AMX. The lack of effect of AMX on the decrease in RPF and GFR during volume depletion is in agreement with the lack of effect of SNX or phentolamine on the renal vasoconstriction and decrease in GFR that we have demonstrated during furosemide-induced volume depletion (IV; Petersen et al 1992). In accordance with the findings of Janssen et ul.…”

“…Thus, increased plasma levels of vasoconstrictor substances and/or decreased plasma levels of hormones with vasodilator actions could mediate arteriolar vasoconstriction. This hypothesis is supported by numerous studies which have demonstrated increased plasma levels of norepinephrine, epinephrine, vasopressin, and angiotensin I1 during acute furosemide administration in both rat (DiPette & Rogers 1988;Petersen et al 1992), dog (Ueno et al 1980;Ueno et al 1983) and humans (Hesse et al 1975;Van Hooff et al 1983;Canella et al 1983;Kelly et al 1983;Francis et al 1985;Kubo et al 1987;Goldsmith et al 1989;Passmore et al 1989;Fujimura & Ebihara 1990;Okaniwa et al 1990;Jespersen et al 1991). The plasma concentration of the vasodilator hormone atrial natriuretic peptide decreases during furosemide diuresis, whereas furosemide produces an increase in both circulating and urinary excretion of prostaglandin E2 Dupont et al 1988;Fujimura & Ebihara 1990;Okaniwa et al 1990;Jespersen et al 1991).…”

“…As reviewed in chapter 2.1, acute furosemide administration is associated with increases in plasma concentrations of catecholamines in both rat, dog and humans (Ueno et al 1980(Ueno et al & 1983Van Hoof et al 1983;Francis et al 1985;DiBona & Sawin 1985;Wilcox et al 1987;Petersen et al 1992). To examine the role of the sympathetic nervous system in the regulation of arterial pressure and renal function during acute furosemide-induced volume contraction, we compared furosemide-induced changes in MAP, renal hemodynamics and renal tubular function in rats with guanethidine-induced peripheral sympathetectomy (SNX) to responses in normal rats (IV).…”

Long-Term Adaptation of Renal Ion Transporters to Chronic Diuretic Treatment

“…Thus, increasing the NHE3 activity probably via the traffic of the NHE3 protein between a cytoplasmic compartment and the apical membrane [62]may contribute to the short-term diuretic tolerance. However, neither the inhibition of angiotensin-converting enzyme nor adrenergic blockade, separately or together, consistently prevents it [63, 64, 65]. Thus, other as yet unidentified mechanisms must also be involved.…”

Diuretic Resistance: Mechanisms and Therapeutic Strategies

“…Co administration of an angiotensin-converting enzyme inhibitor, however, appears to have no effect on braking [9][10][11], Similarly, it may be speculated that sympathoadrenal activa tion would increase proximal tubular reab sorption of sodium and contribute to the braking phenomenon. Studies in man with the cq-adrenoceptor antagonist prazosin have shown no effect on braking [11]; studies in animal models have both supported and re futed a role for the sympathetic nervous sys tem [12][13][14][15], Thus, although the braking sys tem is well characterized and is clearly a short-term modulator of response to loop di uretics, its mechanism is unclear. It is impor tant to emphasize that the trigger for the brak ing phenomenon is contraction of intravascu lar volume.…”