John A. Gagnon

RENAL FUNCTION IN THE NORMOTENSIVE AND HYPOTENSIVE DOG DURING HYPERTONIC MANNITOL AND DEXTROSE INFUSIONS.

Summary Observations were made on the renal clearance of creatinine, inulin and para-aminohippurate with simultaneous measurement of direct renal blood flow in the normotensive and hypotensive dog. The subsequent effects of infusing hypertonic mannitol or dextrose on these measurements were also determined. Good correlation was observed between renal blood flow calculated from clearance and extraction of PAH, and hematocrit and directly measured renal flow in the laterperiods of osmotic diuresis induced during anuric hypotension. Glomerular filtration rate (GFR). calculated from DRPF and EIn, also correlated well with CIn and CCr during this period. The infusion of hypertonic mannitol or dextrose, in the normotensive animal, resulted in a decrease in glomerular filtration subsequent to a fall in the values of creatinine and inulin and a smaller decrease in the value of PAH; in the hypotensive animal these changes were reversed or reduced. These initial responses were followed by a gradual increase in renal blood flow and a simultaneous decrease in hematocrit and plasma total solids. The experiments suggest that multiple extrarenal alterations, resulting from an expansion of the plasma volume, appear to be primarily responsible for the increase in renal perfusion.

Blood Flow Distribution and Tissue Solute Content of the Isolated-Perfused Kidney

SummaryIsolated renal perfusion experiments were performed in the dog kidney to evaluate solute composition of cortex, medulla, and papilla and intrarenal blood flow distribution after 1 to 4 h of normothermic blood perfusion. Tissue slices were assayed for sodium, potassium, urea and water content and external monitoring of133Xe washout and radionuclide-labelled microphere distribution were utilized to determine intrarenal blood flow distribution. Between the first and fourth hours of renal perfusion, total renal blood flow increased secondary to a decrease in renal vascular resistance and urine osmolality decreased. Concurrently there was a reduction in medullary tonicity primarily due to a loss of both urea and sodium. During this same period of time, there was a redistribution of intrarenal blood flow from outer cortex to inner cortex as determined by the microsphere technique. In addition, the distribution of133Xe was significantly altered: radioactivity of Component I decreased from 82±1% to 62±5% while radioactivity increased in Component II from 9±1% to 19±2%. Dissipation of the hypertonic medullary interstitium and alteration of intrarenal blood flow distribution may explain the observed loss of urinary concentration as well as other functional alterations encountered in the isolated perfused kidney.

Plasma kinin levels in acute renovascular hypertension in dogs.

The role of kinins in the hypertensive response to acute renal artery constriction (RAC) was examined in the dog. RAC resulted in an increase in systemic arterial pressure (SAP) from 144 +/- 6 to 155 +/- 4 mm HG (p less than 0.05). Simultaneously, arterial plasma bradykinin decreased from 2.3 +/- 0.2 to 1.4 +/- 0.1 ng/ml (p greater than 0.01), while renal venous bradykinin remained unchanged (2.3 +/- 0.2 to 2.0 +/- 0.4 ng/ml, p greater than 0.05). At the same time urinary kallikrein decreased from 55 +/- 6 to 33 +/- 4 milliesterase units (mEU)/min (p less than 0.05), while urinary kinin decreased from 3.2 +/- 0.4 to 1.9 +/- 0.3 ng/min (p less than 0.05). There was a significant correlation between the decrease in arterial bradykinin and the rise in SAP induced by RAC (p less than 0.01). Administration of the dipeptidyl hydrolase inhibitor SQ20881 during RAC reduced angiotensin-converting enzyme levels from 578 +/- 86 to 10 +/- 0.0 mU/ml (p less than 0.005). There was an associated increase in arterial bradykinin (1.4 +/- 0.1 to 5.8 +/- 0.8 ng/ml, p less than 0.001), renal venous bradykinin (2.0 +/- 0.4 to 5.7 +/- 0.5 ng/ml, p less than 0.005), and urinary kinin (1.9 +/- 0.3 to 5.0 +/- 0.7 ng/min, p less than 0.01) in conjunction with return of SAP to control levels. Urinary kallikrein, however, remained depressed following SQ20881 (33 +/- 4 to 30 +/- 5 mEU/min, p greater than 0.05). These results suggest that (1) decreases in circulating BK may potentiate the vasoconstrictor effect of angiotensin II and contribute to the hypertension induced by RAC, and (2) urinary kallikrein is an unreliable marker of changes in plasma bradykinin in this model of hypertension.

Pyrogenic Renal Hyperemia: The Role of Prostaglandins

The intravenous administration of triple typhoid vaccine to anesthetized dogs resulted in a significant increase in renal blood flow accompanied by a modest decline in systemic blood pressure. This renal hyperemia was associated with elevated renal secretory rates of renin and prostaglandin E and F. Measurements of the intracortical distribution of radiolabeled microspheres revealed a progressive decrease in outer cortical blood flow rates and a progressive increase in inner cortical flow rates. When meclofenamate, an inhibitor of prostaglandin synthetase, was administered concomitantly with triple typhoid vaccine renal hyperemia did not develop. The renal renin secretory rate increased modestly and intracortical renal blood flow was not redistributed. The increased renal blood flow after triple typhoid vaccine administration to unanesthetized dogs was also reversed by meclofenamate. The marked increase in prostaglandin secretion by the kidney during renal hyperemia following triple typhoid vaccine administration (pyrogen), and the effect of meclofenamate, is consonant with a role for increased renal synthesis and release of prostaglandins.

Acute reversible and irreversible renal insufficiency in the dog: A reproducible laboratory preparation

Summary A technique has been described for the experimental production of the clinical syndrome of acute renal insufficiency, reversible or irreversible, which makes use of renal arterial infusion of epinephrine in dogs in known states of hydration. The severity of the clinical syndrome and the degree of pathologic damage were directly related to the length of infusion and less clearly related to the state of hydration. The gross and microscopic pathologic changes have been described.

Intrarenal Kallikrein-Kinin Activity in Acute Renovascular Hypertension in Dogs

The intrarenal kallikrein-kinin system was studied during the acute phase of renovascular hypertension induced by renal artery constriction and during teprotide inhibition of kininase II in the dog. Kallikrein-like activity measured by both kininogenase and esterolytic assays, was increased during renal artery constriction (p less than 0.5) and (p less than 0.01). The administration of teprotide resulted in a further increase of renal cortical kallikrein-like activity and inhibited kininase II activity (p less than 0.01). Following the inhibition of kininase II, the plasma concentration of kininogen was also significantly decreased (p less than 0.01). These results suggest that kininase II inhibition may increase levels of intrarenal and plasma kinins and that decreased degradation of kinin peptides may contribute significantly to the acute hypertensive effect of teprotide.