S. L. Britton

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.

Intrarenal vascular effects of [des-Asp1] angiotensin I and angiotensin III in the dog.

We determined the effects of direct renal intra-arterial injections of [des-Asp angiotensin I (0.2-3.2 pg) and angiotensin HI (0.00625-0.1 fig) on renal blood flow in 10 dogs anesthetized with pentobarbitaL Both [des-Asp*]angiotensin I and angiotensin HI caused dose-dependent decreases in renal blood flow. The decreases in ipsilateral renal blood flow occurred in the absence of alterations in systemic arterial pressure and flow to the contralateral kidney, suggesting that the response was a local event. The renovascular responses to [des-Aspjangiotensin I were greatly attenuated during the intravenous administration of SQ 20881, a synthetic peptide that competitively inhibits angiotensin converting enzyme., SQ 20881 did not alter the vasoconstrictor responses to angiotensin EH, angiotensin n, or norepinephrine. [UejAngiotenain HI (an angiotensin HI antagonist) abolished decreases in renal blood flow produced by [des-Asplangiotenflin L, angiotensin H angiotensin HL and angiotensin I, whereas the response to norepinephrine was unchanged. These results suggest that the decrease in renal blood flow produced by [des-AspJangiotensin I is due to its local enzymatic conversion to angiotensin HI. About 7% of [des-AspJangiotensin I is converted to angiotensin HI during one transit through the kidney. Circ Res 44:666-671, 1979

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

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.

Renal pressure-flow relationships in severely hypertensive rabbits.

Abstract The relationship between renal perfusion pressure and renal blood flow (RBF) was studied in the contralateral or not-clipped kidneys of seven two-kidney one-clip renovascular severely hypertensive rabbits and in the right kidneys of eight normotensive rabbits. Thirty to forty days after clipping the left renal artery, severely hypertensive rabbits were characterized by blood pressures significantly greater than normotensive (105 vs 80 mm Hg), and plasma renin activities three times greater than in normotensive rabbits. The absolute RBF to the right kidney was greater in hypertensive rabbits, but these kidneys were hypertrophied so that renal blood flow per gram kidney weight was the same (2.4 ml/min) in kidneys of both hypertensive and normotensive rabbits. Sequentially reducing renal perfusion pressure decreased RBF similarly in both groups suggesting hypertensive rabbits required 27% greater perfusion pressure to achieve RBF similar to that of normotensive rabbits. When the competitive angiotensin antagonist [Sar1-Ile8]-angiotensin II was administered to both groups, there was no significant change in the RBF of normotensives. In the hypertensive rabbits, however, blood pressure dropped to a value not different from normotensive while renal vascular resistance decreased such that RBF was maintained at a normal level. These results suggest the contralateral kidneys of severely hypertensive rabbits chronically adapt RBF to normal levels despite elevated renal perfusion pressure.

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.

Intrarenal hemodynamics in nonfiltering, filtering, and compensated kidneys.

Abstract Renal blood flow and intrarenal blood flow distribution were studied in nine nonfiltering and contralateral compensated kidneys and in seven control filtering kidneys. Unilateral ureteral ligation coupled with a 2-hr renal ischemia 4 days prior to the experiment induced the kidney to be nonfiltering and resulted in a marked decrease in renal blood flow (59.2 ± 35.1 ml/min vs 124.7 ± 12.9 ml/min in control, P < 0.05). In contrast, the contralateral kidney demonstrated a compensatory increase in renal blood flow (48%) equal to the reduction in flow to the impaired kidney (52%). Regional blood flows to the four cortical zones were commensurate with the rise in total flow in that they increased markedly in all zones of contralateral kidneys. In nonfiltering kidneys, the decrease in total flow was due to a proportional fall in regional blood flows of zones I, II, and III. Blood flow in zone IV also decreased but not to the extent seen in the other zones. Thus, it may be concluded that the large changes in renal hemodynamics to nonfiltering and compensated kidneys are proportionally distributed throughout the four cortical zones with the exception of an attenuated decrease in blood flow in the innermost zone.

Specificity of angiotensin antagonists in the mesenteric vasculature of dogs.

Abstract Experiments were conducted to assess whether the octapeptide antagonist Sar1-Ile8-angiotensin II or the heptapeptide antagonist Ile7-angiotensin III demonstrates specificity for antagonizing the mesenteric vasoconstrictor properties of angiotensin II or angiotensin III. Experiments were performed on 12 dogs anesthetized with sodium pen-tobarbital. In all dogs, the effects of five graded doses (10, 20, 40, 80, and 160 pmole, bolus injections) of angiotensin II and angiotensin III on superior mesenteric artery blood flow were tested. At all doses tested, angiotensin II was more potent than angiotensin III. Administration of the middle dose (40 pmole) of angiotensin II and angiotensin III was repeated during the infusion of either Ile7-angiotensin III (N = 6) or Sar1-Ile8-angiotensin II (N = 6) at five different dosages into the superior mesenteric artery, Sar1-Ele8-angiotensin II antagonized equally the mesenteric vasoconstrictor effects of both angiotensin II and angiotensin III. Ile7-angiotensin III was not absolutely specific as an antagonist of the mesenteric vasoconstrictor effects of angiotensin III.