John F. Gerkens

The Effect Of Salt Intake On Cyclosporine-induced Impairment Of Renal Function In Rats

Three groups of rats were fed a low-sodium diet. Groups 1 drank water and was treated with cyclosporine, 100 mg kg-1 48 h-1 p.o. for 3 weeks (low-salt-treated group). Group 2 drank 0.15 M saline and was also treated with cyclosporine (high-salt-treated group). Group 3 drank water and was treated with the vehicle (low-salt-vehicle group). Measurements were made during a control period and weekly during the 3-week treatment period and a 3-week recovery period. Both cyclosporine-treated groups lost weight during treatment but the rises in serum creatinine and blood urea and decrease in creatinine clearance were greater in the low-salt group. The vehicle group gained weight and had no change in the other parameters over the three weeks. There was an increase in urine volume and sodium excretion in the high-salt group associated with cyclosporine treatment. Although the low-salt groups had a higher plasma renin concentration than the high-salt group there were no changes produced by cyclosporine treatment. Histopathological examination showed mild tubular lesions with vacuolar degeneration of proximal tubular cells. This was more prevalent in the low-salt-cyclosporine-treated group. The plasma concentrations of cyclosporine were not different after one-week treatment but were slightly greater after 2 week and 3-week treatment in the low-salt group. We have suggested that the greater impairment of renal function in the low-salt group produced by cyclosporine may be contributed to by an involvement of tubuloglomerular feedback.

Effects of dietary sodium and fish oil on blood pressure development in stroke-prone spontaneously hypertensive rats.

The postulated antihypertensive effect of dietary fish oil and the influence of dietary sodium on this effect were evaluated in young stroke-prone spontaneously hypertensive rats (SHRSP) by direct intra-arterial measurement of blood pressure. Weaning rats were fed synthetic diets containing olive oil or eicosapentaenoic acid-enriched fish oil (5% of dry weight) with normal (0.23%) or high (2.8%) sodium content. Catheters were implanted after 3 months for blood pressure measurement under resting conditions and to sample blood for catecholamine determinations. Effects of fish oil on vascular reactivity were assessed in the in situ blood-perfused mesentery. The overall observation, from a series of experiments, was that feeding diets containing 5% fish oil to young SHRSP resulted in a small but consistent suppression of the development of hypertension. This effect could be counteracted, however, by increasing dietary sodium intake. Observations after ganglion blockade indicate that the antihypertensive effect of fish oil is unlikely to result from a reduction in sympathetic vascular tone.

Inhibition of vasoconstriction by frusemide in the rat

1 Mesenteric blood flow was measured in anaesthetized rats with a non‐cannulating electromagnetic flow probe around the superior mesenteric artery. Reductions in blood flow were produced by intravenous bolus injections of angiotensin II (1–300ng) and noradrenaline (3–300ng) before and after the administration of frusemide (5 mg kg−1, i.v.). Loss of volume after frusemide was prevented by either a urinary bladder‐intravenous shunt or replacement of urinary output by intravenous saline. 2 Frusemide administration caused a small increase in baseline blood pressure of 3.2 ± 1.3 mmHg (P<0.05) but did not change mesenteric blood flow. This dose of frusemide inhibited the vasoconstrictor responses to both angiotensin II and noradrenaline (P<0.01, two way analysis of variance). Responses to angiotensin II were inhibited to a greater extent. 3 Acute bilateral nephrectomy or treatment with indomethacin (2 mg kg−1, i.v.) completely prevented the inhibitory effect of frusemide on the responses to angiotensin II and noradrenaline. 4 To test whether frusemide‐induced increased endogenous levels of angiotensin II may be responsible for the effects of frusemide on the vasoconstrictor responses, a separate group of rats were not given frusemide but were infused with exogenous angiotensin II (12.5–25 ng kg−1 min−1). This produced a small increase in mean blood pressure (4.0± 1.4 mmHg, P<0.05) but did not change baseline mesenteric blood flow. Unlike frusemide, the responses to bolus injections of angiotensin II and noradrenaline were not changed by the infusion of angiotensin II. 5 It is suggested that frusemide may release directly or indirectly a prostanoid from the kidney (or a substance from the kidney which leads to the formation of a prostanoid) which inhibits constrictor responses in the peripheral vasculature.

Does furosemide have vasodilator activity

Abstract Furosemide decreases peripheral resistance in hypertensive patients and dilates veins in patients with congestive heart failure. There is evidence that both these actions are due to an effect on blood vessel tone which requires the presence of the kidneys but is not a result of a diuretic-induced loss of volume. John Gerkens presents experimental evidence which supports his proposal that furosemide may release a hormone from the kidney, possibly from the renal papilla, which leads to an inhibition of vasoconstriction. This inhibition requires an intact endothelium in the blood vessel.

Reproducible vasodilatation by platelet-activating factor in blood-and Krebs-perfused rat kidneys is albumin-dependent

The vasodilator effect of platelet-activating factor (PAF) and its reproducibility was determined in rat kidneys perfused in situ with blood or in isolated kidneys perfused with Krebs solution or Krebs plus 0.25% bovine serum albumin (BSA) at 3 ml/min. Dilatation was measured as inhibition of the increase in perfusion pressure produced by stimulation of the renal nerves or by infusion of noradrenaline. PAF, in saline and 0.25% BSA, was infused into the perfusate at 0.05 ml/min to produce eight incremental consecutive concentrations from 3 x 10(-11) to 10(-7). Two sets of PAF infusions were made during nerve-stimulated responses followed by one set during noradrenaline infusion. With blood perfusion, PAF consistently produced dose-dependent dilatation and 3 x 10(-9) M reduced nerve-stimulated responses to 52% of control. This effect was reproduced by a second infusion. However in Krebs-perfused kidneys the effect of the first PAF infusion was not consistent, with responses either not affected or reduced only at the lower doses so that the mean maximum decrease was only 10% and the vasodilatation was not dose-dependent. The second PAF infusion invariably had no effect. On the other hand perfusion with Krebs and 0.25% BSA produced consistent and dose-dependent inhibition of vasoconstriction which was reproduced by a second infusion. PAF was effective at 10-fold lower doses in Krebs-albumin perfused compared to blood-perfused kidneys. These results indicate that exogenous PAF is a potent and reproducible dilator of the rat renal vasculature perfused with blood or Krebs-albumin solution but not albumin-free Krebs solution.

Chemical renal medullectomy prevents frusemide-induced inhibition of sympathetic vasoconstriction in the in situ blood perfused rat mesentery.

The mesentery of anaesthetized rats was perfused in situ at a constant rate, via the cannulated superior mesenteric artery, with blood drawn from a cannulated carotid artery. Increases in perfusion pressure were produced by peri-arterial electrical stimulation of the mesenteric sympathetic nerves at 3, 6 and 10 Hz before and after the intravenous administration of frusemide 5 mg/kg. Loss of solutes and volume as a result of frusemide-induced diuresis was prevented by a urinary bladder-venous shunt. In control animals the vasoconstrictor responses to mesenteric nerve stimulation were significantly reduced after frusemide administration. However, in animals pretreated 4 weeks previously with bromethylamine (BEA) 200 mg/kg i.p., frusemide had no effect on vasoconstrictor responses. Chemical papillectomy with BEA has been shown by others to prevent the antihypertensive effects attributed to the non-prostanoid lipids produced by the interstitial cells of the renal medulla. Our data suggest that the vasoconstrictor-inhibiting effect of frusemide may be mediated by the release of renomedullary lipids.

Inhibitory effect of frusemide on sympathetic vasoconstrictor responses: dependence on a renal hormone and the vascular endothelium

SUMMARY

FRUSEMIDE INHIBITION OF SYMPATHETIC VASOCONSTRICTION IN THE RAT IN SITU BLOOD PERFUSED MESENTERY

1. Mesenteric perfusion pressure was measured in the in situ blood‐perfused mesentery of anaesthetized rats. Increases in perfusion pressure were produced by mesenteric periarterial electrical stimulation at 3, 6 and 10 Hz before and after the administration of frusemide 5 mg/kg intravenously (i.v.) or vehicle. Loss of volume due to diuresis was prevented by replacement with intravenous saline.

ENDOTHELIUM-DEPENDENT INHIBITION OF SYMPATHETIC VASOCONSTRICTION BY FRUSEMIDE ADMINISTRATION TO RATS

1. Segments of the tail artery of the rat were cannulated at both ends and mounted in an organ bath filled with Krebs solution.

Inhibition of Sympathetic Constriction of the Ex Vivo Tail Artery Perfused with Blood from Rats Given Frusemide

Blood was withdrawn at a constant rate from the cannulated carotid artery of an anaesthetized rat and perfused an ex vivo segment of tail artery cannulated at both ends and contained in an organ bath. Blood returned to the rat via a cannulated jugular vein. The tail artery was constricted and perfusion pressure increased by peri-arterial stimulation at 5 Hz for 5 s every 2 min. Intravenous frusemide (5 mg/kg) decreased the stimulation responses of the tail artery. Diuresis-induced volume losses after frusemide were circumvented by a urinary bladder-intravenous shunt. Frusemide-induced reduction of tail artery vasoconstrictor responses was not seen in nephrectomized rats nor in rats pretreated with indomethacin or saralasin. Indomethacin did not change responses already reduced by frusemide. Exogenous arachidonate or angiotensin II infused into the blood perfusing the tail artery did not alter stimulation responses. We conclude that intravenous frusemide administration to a rat reduces sympathetic vasoconstrictor responses of the ex vivo blood perfused tail artery segment by a diuresis-independent but prostaglandin and angiotensin II dependent release of another hormone from the kidney.