M. J. Fiksen-Olsen

Effects of NG-monomethyl-L-arginine and L-arginine on acetylcholine renal response.

Intrarenal infusion of acetylcholine in meclofenamate-treated dogs significantly increased renal blood flow, diuresis, and natriuresis. Intrarenal infusions of either NG-monomethyl-L-arginine (inhibitor of endothelium-derived relaxing factor formation), or L-arginine (precursor of endothelium-derived relaxing factor formation) did not modify basal levels of those parameters. However, the infusion of NG-monomethyl-L-arginine inhibited the acetylcholine-induced increases in renal blood flow and diuresis without affecting natriuresis, which increased significantly. The infusion of L-arginine failed to further enhance hemodynamic and excretory effects elicited by acetylcholine. The concomitant infusion of L-arginine and NG-monomethyl-L-arginine did not change renal blood flow, urine flow, or sodium excretion rate. L-Arginine administration prevented the inhibitory effect of NG-monomethyl-L-arginine on acetylcholine-induced renal vasodilatation and diuresis. Glomerular filtration rate and mean arterial pressure did not change throughout the experiment. The results indicate that the vasodilatory and diuretic responses to intrarenal acetylcholine in meclofenamate-treated dogs are largely dependent on endothelium-derived relaxing factor.

Effect of adenosine on the distribution of renal blood flow in dogs.

Previous reports have shown that the intrarenal infusion of adenosine results in a relatively greater fall in superficial nephron glomerular filtration rate (GFR) than whole kidney GFR. This nonuniform decrease in GFR occurred despite a concomitant increase in total renal blood flow (RBF); thus, the present study was undertaken to assess the effect of intrarenally administered adenosine on the distribution of RBF. RBF distribution was measured with radiolabeled microspheres (15 μn) in anesthetized dogs (n = 8) before and during the intrarenal artery infusion of adenosine (0.3 μmol/min). In dogs with elevated plasma renin activities (PRA), adenosine infusion produced no significant change in outer cortical blood flow (4.36 ± 0.50 vs. 4.41 ± 0.63 ml/min per g), whereas absolute inner cortical blood flow increased by 94% (1.54 ± 0.34 vs. 2.99 ± 0.52 ml/min per g). In dogs with low PRA, outer cortical blood flow was only minimally affected by adenosine infusion (6.39 ± 0.44 vs. 5.88 ± 0.33 ml/min per g), whereas inner cortical blood flow was increased from 4.91 ± 0.43 to 6.06 ± 0.38 ml/min per g. Although adenosine resulted in a deep cortical vasodilation in dogs with both high and low PRA (94% vs. 23%), the relative change was greater in the animals with high PRA. Additional experiments were performed in indomethacin- (or meclofenamate-) treated (n = 14) or phenoxybenz-amine-treated (n = 5) dogs to determine whether the deep cortical vasodilation is mediated by increased prostaglandin production or by inhibition of norepinephrine release. The increase in deep cortical flow during adenosine administration was not affected by either the blockade of prostaglandin synthesis or α-adrenergic receptors. We conclude that the effect of adenosine to preferentially dilate vessels of the inner cortex is independent of a prostaglandin-related or sympathetic adrenergic mechanism.

Comparison of the effects of calcium antagonists and converting enzyme inhibitors on renal function under normal and hypertensive conditions

Calcium antagonists decrease the ability of the kidney to autoregulate renal blood flow (RBF) and glomerular filtration rate (GFR). Therefore, when afferent renovascular resistance is elevated, as in essential hypertension, there is a resultant increase in RBF and GFR with the administration of calcium antagonists. These agents also induce a marked natriuresis because of direct tubular action through unknown mechanisms. The natriuresis can be dissociated from renal and systemic hemodynamic actions, indicating that the decreased sodium reabsorption could override other compensatory mechanisms explaining the absence of sodium retention during the treatment. The renal effects of converting enzyme inhibitors (CEIs) can be explained by the reduction of intrarenal formation in angiotensin II. Because the activation of the renin-angiotensin system is mainly responsible for inducing sodium retention during a decrease in systemic blood pressure, CEIs could have a protecting effect without disturbing other homeostatic mechanisms. CEIs decrease efferent glomerular resistance, reducing capillary pressure and thereby reducing GFR. This effect is not translated in sodium retention because the reduction of GFR is mild during captopril administration in kidneys with normal or increased renal perfusion pressure. At low renal perfusion pressure, the reduced glomerular afferent vasoconstriction can compromise GFR, leading to renal insufficiency. Although these situations are not likely to be encountered during the treatment of uncomplicated essential hypertension, in severe hypertension with hypertrophy of pre-glomerular vessels, glomerular perfusion may decrease. Combination therapy of calcium antagonists and CEIs has been reported to be an effective treatment of severe hypertension. Currently, little information is available on the manner in which renal function is affected by simultaneous administration of both drugs.

High-Fructose Feeding Elicits Insulin Resistance Without Hypertension in Normal Mongrel Dogs

This study was undertaken to characterize blood pressure (by continuous blood pressure recording), renal hemodynamics, and excretory function in high-fructose-fed insulin-resistant dogs. We fed 10 mongrel dogs for 28 days with a normal sodium diet containing 60% of the calories either as fructose (n = 6) or dextrose (n = 4). Fructose-fed dogs developed insulin resistance by the 21st day of the experimental diet, as estimated by the mean glucose concentrations (in arbitrary units, AU) during the final hour of the insulin suppression test (640.3 +/- 57 AU fructose-fed dogs upsilon 397.5 +/- 24.7 AU dextrose fed dogs; P < .05). Neither of the groups showed any change in body weight, or in fasting plasma levels of glucose or insulin. There was no difference in mean arterial pressure between the groups before or during either diet, nor did we find any important alterations in renal function in these animals. We conclude that insulin resistance can be induced by a high-fructose diet in the dog. However, it is not accompanied by either hypertension or alteration in renal function. These findings emphasize the importance of continuously recording blood pressure under resting conditions and suggests that in the fructose-fed dog, insulin resistance does not appear to lead directly to hypertension.

Role of prostaglandins in mediating the renal effects of atrial natriuretic factor.

Tbe natriuretk response to the intrarenal administration of atrial natriuretic factor (ANF) is accompanied by an increase in tbe synthesis of prostaglandins and by a redistribution of renal blood flow from the superficial to the deep cortex. This study was undertaken to define whether prostaglandins mediate the ANF-induced redistribution of renal blood flow and if prostaglandins and renal blood flow redistribution contribute to the natriuretic actions of ANF. In anesthetized dogs, the Intrarenal administration of indomethadn (10 μg/kg/min) or the intravenous administration of meclofenamate (5 mg/kg) completely prevented the sixfold and twofold increments in urinary prostaglandin E2 and 6-keto-prostaglandin Fla excretion, respectively; it also abolished the redistribution of renal blood flow to the deep cortex. However, ANF induced a similar natriuresis before (from 53 ± 17 to 281 ± 48 μEq/min) and after (from 45 ± 13 to 273 ± 60 μEq/min) the administration of prostaglandin synthesis inhibitors. It is concluded that the ANF-induced redistribution of renal blood flow to the deep cortex is prostaglandinmediated but that neither redistribution nor increased prostaglandin synthesis Is an important mediator of ANFs natriuretic action.

A comparison of angiotensin II and angiotensin III as vasoconstrictors in the mesenteric circulation of dogs.

Angiotensin II is more potent as a vasopressor than angiotensin III when given intravenously. We tested the hypothesis that differential changes in mesenteric blood flow contribute to this difference in potency. The effects of angiotensin II and angiotensin III on mesenteric blood flow were compared in 31 dogs anesthetized with pentobarbital. These agonists were administered either as bolus injections (10-160 pmol) or as constant infusions (30 pmol/min per kg) directly into the vasculature supplied by the superior mesenteric artery. Approximately equipressor doses of angiotensin II (40 pmol/min per kg) and angiotensin III (80 pmol/min per kg) also were given intravenously. On the basis of duration and graphic integration of the response in mesenteric blood flow, but not on the basis of absolute change in amplitude, angiotensin II was consistently more potent than angiotensin III as a mesenteric vasoconstrictor. The intra-arterial and intravenous constant infusion doses were repeated after the administration of meclofenamate (4 mg/kg, iv). Meclofenamate did not alter any of the responses to angiotensin II or angiotensin III. We conclude that the differential constrictor properties of these compounds in the mesenteric vasculature contribute to the greater potency of intravenously administered angiotensin II on arterial pressure. The results provide no evidence for an interaction between prostaglandins and the vasoconstrictor properties of angiotensin II or III in the intact mesenteric vasculature of the anesthetized dog. Circ Res 46:146-151, 1980

Stimulation of Plasma Renin Activity by Captopril in Renovascular Hypertensive Conscious Dogs

The increase in plasma renin activity induced by captopril is used in the clinical evaluation of renovascular hypertensive patients. This increase in plasma renin activity could result from either the concomitant fall in systemic pressure or other effects of captopril, such as the removal of an angiotensin II inhibitory effect on renin release, the increased production of bradykinin or prostaglandins, etc. To examine the effect captopril has on plasma renin activity, independent of changes in systemic pressure, captopril (5, 10 and 50 micrograms/kg iv) was administered to conscious dogs before and following the development of 1 clip-2 kidney Goldblatt hypertension. Plasma renin activity, under normal conditions remained unchanged, while during hypertension it increased 2.0, 2.8 and 3.5 fold respectively in response to the three doses of captopril. These results suggest that the development of renovascular hypertension sensitized the kidney to release renin when challenged by captopril and that the effect is independent of changes in systemic pressure.

Intrarenal vascular effects of angiotensin II and angiotensin III in the dog

The effects of intrarenal bolus injections of equal molar doses of angiotensin II and angiotensin III on renal blood flow were examined in seven pentobarbital anaesthetized dogs. Renal blood flow was measured with an electromagnetic flow probe. Angiotensin II produced a greater decrease in renal blood flow than angiotensin III at all bolus doses tested when the integral of the renal blood flow response was examined. In 10 other dogs, we compared the molar dose of intrarenal constant infusions of angiotensin II and angiotensin III required to decrease total renal blood flow by approximately 25%. The effect these peptides had on the distribution of renal cortical blood flow was determined with radioactive microspheres. In the constant infusion experiments, more moles of angiotensin III than angiotensin II were required to produce agiven decrease in renal blood flow in each experiment. The average percent decrease in blood flow to each of the four cortical zones produced by angiotensin II was not different from that produced by angiotensin III. Our data demonstrate that angiotensin II is more potent than angiotensin III as a vasoconstrictor in the renal vasculature.

The Use of the Dynamic Spatial Reconstructor to Study Renal Function

It is well known that the discovery of the X-ray represented a major advance in medical science, since it allowed for the first time a non-invasive, direct confirmation of morphological alterations suspected by the physician during physical examination. While the conventional radiograph is a highly valuable method of diagnosis, it is static because fourth-dimensional or dynamic information (i. e., rapid alteration over time) is not provided and third-dimensional information is obscured by the superim- position of anatomic structures. The limitation of the fourth dimension has been solved by following radioopaque tracers through organ systems using rapid-imaging techniques (e. g., cineangiography). However, the problem of superimposition still makes it difficult, and often impossible, to distinguish, unambiguously, one anatomic structure from another, especially when there are only small differences in X-ray density. These kinds of problems are usually overcome by making a number of X-ray pictures from different angles, in which anatomic structures appear in different relationships to one another.

Effect of SQ20881 and Captopril on Pulmonary Angiotensin II Formation and Blood Pressure

The lung is thought to be the major site for conversion of angiotensin l (AI) to angiotensin II (All), although a significant amount of AI conversion is also known to occur in the peripheral circulation. Reports suggest that pulmonary conversion of AI to All is more sensitive to inhibition by specific kininase II inhibitors than extrapulmonary conversion. This latter observation prompted us to seek for a dose of SQ20881 and/or captopril that would suppress the conversion of AI to All in the lung without affecting extrapulmonary conversion of AI and thereby peripheral pressor responses to intravenously administered AI. Experiments were performed on 15 pentobarbital anaesthetized dogs. The All arterial-venous difference across the lung was measured during an intravenous (i.v.) infusion of AI which produced a steady-state rise in blood pressure of 20 mmHg. This protocol was repeated with the same dose of AI following three graded doses of either SQ20881, captopril or vehicle. Results showed that the systemic pressor response to AI cannot be dissociated from pulmonary AI conversion.