Abstract-Increasing renal arterial pressure activates at least 3 antihypertensive mechanisms: reduced renin release, pressure natriuresis, and release of a putative renal medullary depressor hormone. To examine the role of renal medullary perfusion in these mechanisms, we tested the effects of the infusion of norepinephrine, either infusion into the renal medullary interstitium or intravenous infusion, on responses to increased renal arterial pressure in pentobarbital-anesthetized rabbits. We used an extracorporeal circuit, which allows renal arterial pressure to be set to any level above or below systemic arterial pressure. With renal arterial pressure initially set at 65 mm Hg, intravenous and medullary interstitial norepinephrine (300 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) similarly increased mean arterial pressure (by 12% to 17% of baseline) and reduced total renal blood flow (by 16% to 17%) and cortical perfusion (by 13% to 19%), but only medullary norepinephrine reduced medullary perfusion (by 28%). When renal arterial pressure was increased to Ϸ160 mm Hg, in steps of Ϸ65 mm Hg, urine output and sodium excretion increased exponentially, and plasma renin activity and mean arterial pressure fell. Medullary interstitial but not intravenous norepinephrine attenuated the increased diuresis and natriuresis and the depressor response to increased renal arterial pressure. This suggests that norepinephrine can act within the renal medulla to inhibit these renal antihypertensive mechanisms, perhaps by reducing medullary perfusion. These observations support the concept that medullary perfusion plays a critical role in the long-term control of arterial pressure by its influence on pressure diuresis/natriuresis mechanisms and also by affecting the release of the putative renal medullary depressor hormone. Key Words: kidney medulla Ⅲ laser-Doppler flowmetry Ⅲ norepinephrine Ⅲ natriuresis Ⅲ renal circulation I t has been hypothesized that the level of medullary blood flow (MBF) is an important determinant of urinary sodium excretion (U Na ϩ V) and, indeed, may be the key initiating factor in the pressure natriuresis response. 1 In turn, the impact of MBF on the pressure natriuretic mechanism provides an explanation for the effects of chronic changes in MBF on the long-term control of arterial pressure. 1 Thus, in rats, chronic reductions in MBF shift the pressure natriuresis relation toward higher pressures and lead to hypertension in normotensive animals. Conversely, chronic increases in MBF shift the pressure natriuresis relation toward lower pressures and ameliorate hypertension in spontaneously hypertensive rats. 1 From studies using an extracorporeal circuit in anesthetized rabbits, 2 we recently obtained preliminary evidence indicating that influences on the release and/or actions of the putative renal medullary depressor hormone might also contribute to the impact of MBF on the long-term control of arterial pressure. In this model, 3 major renal antihypertensive mechanisms can be studied simultaneously. Thus, when renal arterial ...

We tested methods for delivery of drugs to the renal medulla of anesthetized rabbits. Outer medullary infusion (OMI) of norepinephrine (300 ng ⋅ kg−1 ⋅ min−1), using acutely or chronically positioned catheters, reduced both cortical (CBF; 15%) and medullary perfusion (MBF; 23–31%). Inner medullary infusion (IMI) did not affect renal hemodynamics, whereas intravenous infusion reduced CBF (15%) without changes in MBF. During OMI of [3H]norepinephrine, much of the radiolabel (∼40% with chronically positioned catheters) spilled over systemically. Nevertheless, autoradiographic analysis showed the concentration of radiolabel was about fourfold greater in the infused medulla than the cortex. In contrast, during IMI, only ∼5% of the infused radiolabel spilled over into the systemic circulation and ∼64% was excreted by the infused kidney. The resultant intrarenal levels of radiolabel were considerably less with IMI compared with OMI. In rabbits, OMI therefore provides a useful method for targeting agents to the renal medulla, but given the considerable systemic spillover with OMI, its utility is probably limited to substances that are rapidly degraded in vivo.

V1-AG reduced MBF but did not significantly affect juxtamedullary arteriolar diameter. Our results therefore do not support a role for juxtamedullary arterioles in producing V1-receptor-mediated reductions in MBF, suggesting that downstream vascular elements (e.g. outer medullary descending vasa recta) might be involved.

Increasing renal artery pressure (RAP) activates pressure diuresis/natriuresis and inhibits renal renin release. There is also evidence that increasing RAP stimulates release of a putative depressor hormone from the renal medulla, although this hypothesis remains controversial. We examined the relative roles of these antihypertensive mechanisms in the acute depressor responses to increased RAP in anaesthetized rabbits and rats. In rabbits, an extracorporeal circuit was established which allows RAP to be set and controlled without direct effects on systemic haemodynamics. When RAP was maintained at ∼65 mmHg, cardiac output (CO) and mean arterial pressure (MAP) did not change significantly. In contrast, when RAP was increased to ∼160 mmHg, CO and MAP fell 20 ± 5 % and 36 ± 5 %, respectively, over 30 min. Urine flow also increased more than 28‐fold when RAP was increased. When compound sodium lactate was infused intravenously at a rate equal to urine flow, neither CO nor MAP fell significantly in response to increased RAP. In 1 kidney‐1 clip hypertensive rats, MAP fell by 54 ± 10 mmHg over a 2 h period after unclipping. In rats in which isotonic NaCl was administered intravenously at a rate equal to urine flow, MAP did not change significantly after unclipping (−14 ± 9 mmHg). Our results suggest that the depressor responses to increasing RAP in these experimental models are chiefly attributable to hypovolaemia secondary to pressure diuresis/natruresis. These models therefore appear not to be bioassays for release of a putative renal medullary depressor hormone.

1. We tested the effects of intravenous infusions of angiotensin II (AngII; 300 ng/kg per min) and the vasopressin V1 receptor agonist [Phe2,Ile3,Orn8]-vasopressin (30 ng/kg per min) on regional kidney perfusion in an extracorporeal circuit model in anaesthetized rabbits in which renal artery pressure (RAP) can be set independently of systemic mean arterial pressure. To test whether the level of RAP can influence the renal vascular response to [Phe2,Ile3,Orn8]-vasopressin, we compared its effects when RAP was initially set at approximately 65 mmHg with those when RAP was set at approximately 130 mmHg. 2. When RAP was initially set at approximately 65 mmHg, a 20min infusion of AngII increased RAP (13%) and reduced renal blood flow (RBF; 50%) and cortical perfusion (CBF; 43%). Medullary perfusion (MBF) transiently increased during the first 10 min of infusion, but was not significantly different from control levels during the final 5 min of infusion. 3. When RAP was initially set at approximately 65 mmHg, a 20 min infusion of [Phe2,Ile3,Orn8]-vasopressin increased RAP (9%) and reduced RBF (21%); MBF was reduced by 57%, but CBF was reduced by only 15%. In contrast, when RAP was initially set at approximately 130 mmHg, infusion of [Phe2,Ile3,Orn8]-vasopressin reduced RAP (7%) and increased RBF (13%). In these experiments, MBF was reduced by 38%, but CBF increased by 6%. 4. Our experiments show that AngII preferentially reduces CBF, while [Phe2,Ile3,Orn8]-vasopressin preferentially reduces MBF. The renal vascular responses to [Phe2,Ile3,Orn8]-vasopressin appear to be profoundly affected by the level of RAP, because increasing RAP from approximately 65 to approximately 130 mmHg transforms its cortical vasoconstrictor effect into cortical vasodilatation while leaving the response of the medullary microvasculature relatively unchanged. Whether renal vascular responses to other vasoactive agents (e.g. AngII) are similarly affected by the level of RAP remains to be determined.