Dynamic autoregulation in the in vitro perfused hydronephrotic rat kidney.

Renal autoregulation is mediated by tubuloglomerular feedback, operating at 0.03-0.05 Hz, and a faster system, operating at 0.1-0.2 Hz, that has been attributed by exclusion to myogenic vasoconstriction. In this study, we examined dynamic autoregulation in the hydronephrotic rat kidney, which lacks tubuloglomerular feedback but exhibits pressure-induced afferent arteriolar vasoconstriction. Kidneys were harvested under anesthesia from Sprague-Dawley rats and perfused in vitro using defined, colloid-free medium. Renal perfusate flow was assessed during forced pressure fluctuations at mean pressures of 60-140 mmHg. Transfer function analysis revealed passive behavior at 60 mmHg and active, pressure-dependent responses at higher pressures. In all cases, coherence was high (0.89 +/- 0.03 between 0.01 and 0.9 Hz). There was a resonance peak in admittance gain at approximately 0.3 Hz and an associated broad peak in phase angle. Below this frequency, gain declined progressively. The minimum gain achieved at 0.01-0.05 Hz was pressure sensitive, being 1.08 +/- 0.02 at 60 mmHg and 0.71 +/- 0.04 at 140 mmHg. These findings are consistent with in vivo results and with model-based predictions of the dynamics of myogenic autoregulation, supporting the postulate that the rapid component of autoregulation reflects operation of a myogenic mechanism.

In situ studies of renal arteriolar function using the in vitro-perfused hydronephrotic rat kidney.

A method of examining arteriolar function in situ using the in vitro-perfused hydronephrotic rat kidney is described. This approach facilitates direct visualization of arteriolar contractile responses in a well-controlled experimental environment while avoiding the consequences of traumatic microdissection and the accompanying exposure to ischemia, hypothermia, or hypoxia. The preparation has a remarkably well-preserved myogenic reactivity, exhibiting precisely graded vasoconstriction over the range in perfusion pressure subtending normal renal autoregulatory responses (i.e., 80-180 mm Hg). Using this preparation, the inhibitory effects of hypoxia on arteriolar myogenic reactivity have been demonstrated. The range over which reduced pO2 affected arteriolar reactivity in this model corresponded closely to that reported to alter vascular tone in vivo. A technique of adapting the model to incorporate simultaneous monitoring of arteriolar fluorescence measurements and contractile responses is also described. This approach has been used to examine the relationship between arteriolar contractility and NADH autofluorescence during the hypoxia-induced activation of ATP-sensitive K channels. Future applications may include the use of intravital fluorescent dyes to examine, for example, microvascular endothelial calcium signaling in an intact, functioning arteriole.

Hypoxia inhibits myogenic reactivity of renal afferent arterioles by activating ATP-sensitive K+ channels.

Recent findings implicate K+ channels as important modulators of myogenic tone and possible mediators of the vasodilatory effects of hypoxia. In the present report, we examined the effects of hypoxia on myogenic vasoconstriction of renal afferent arterioles. Using the in vitro perfused hydronephrotic rat kidney model, we observed precisely graded decreases in arteriolar diameter when renal perfusion pressure was increased. Normal myogenic reactivity was observed over PO2 levels of 150 to 80 mm Hg. Reducing PO2 to 60, 40, and 30 mm Hg resulted in a significant progressive inhibition of myogenic reactivity. At approximately 20 mm Hg, myogenic vasoconstriction was essentially abolished, whereas the vasoconstriction induced by 30 mmol/L KCl was unaffected. The addition of 1.0 mumol/L glibenclamide completely restored myogenic vasoconstriction during hypoxia. In contrast, 1.0 mmol/L tetraethylammonium did not alter the effects of hypoxia. To investigate the relation between hypoxia-induced vasodilation and smooth muscle oxidative phosphorylation, we monitored changes in arteriolar levels of reduced NADH during exposure to hypoxia. Arterioles preconstricted by elevated pressure were optically isolated for simultaneous monitoring of vessel diameter and NADH fluorescence (360-nm excitation, 450-nm emission). Reducing perfusate PO2 from 150 to 20 mm Hg resulted in progressive loss of myogenic tone with no change in arteriolar NADH. These findings indicate that lowering PO2 within a physiological range attenuates myogenic reactivity of the renal afferent arteriole by causing the activation of ATP-sensitive K+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium antagonists and the kidney.

Recently, attention has focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonist exhibit consistent actions permitting characterization of their renal effects. Calcium antagonists do not affect the vasodilated isolated perfused kidney, but they do dramatically alter the response of the kidney to vasoconstrictor agents. In the presence of norepinephrine, calcium antagonists markedly augment glomerular filtration rate but produce only a modest improvement in renal perfusion. Utilizing the isolated perfused hydronephrotic rat kidney model that permits direct visualization of afferent and efferent arterioles, we have demonstrated that this preferential augmentation of glomerular filtration rate is primarily attributable to a selective vasodilation of pre-glomerular vessels. Although the clinical implications of such observations are not yet clear, preliminary studies in experimental animal models indicate that calcium antagonists may exert salutary effects on renal function in clinical settings that are characterized by impaired renal hemodynamics. The possible benefits of calcium antagonists in ameliorating the development of renal dysfunction in patients in whom there is increased risk for the development of acute renal insufficiency remain to be evaluated.

Effects of calcium antagonists on renal hemodynamics.

Recent attention has been focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonists exhibit consistent actions permitting characterization of actions permitting characterization of their renal effects. Calcium antagonists do not affect the vasodilated isolated perfused kidney, but they do markedly alter the response of the kidney to vasoconstrictor agents. In the presence of norepinephrine, calcium antagonists markedly augment the glomerular filtration rate but produce only a modest improvement in renal perfusion. Studies using the isolated perfused hydronephrotic rat kidney model, which permits direct visualization of afferent and efferent arterioles, have demonstrated that the augmentation of the glomerular filtration rate is attributable to a preferential vasodilation of preglomerular vessels. Although the clinical implications of such observations are not fully delineated, preliminary studies in experimental animal models indicate that calcium antagonists might exert salutary effects on renal function in clinical settings characterized by an acute impairment of renal hemodynamics. It is apparent, however, that the renal hemodynamic effects of calcium antagonists commend their use in the management of essential hypertension.

Effects of amlodipine on renal hemodynamics.

Recently, attention has focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonists exhibit consistent actions permitting characterization of their renal effects. Calcium antagonists do not affect the vasodilated isolated perfused kidney, but they do dramatically alter the response of the kidney to vasoconstrictor agents. This study examined the effects of the novel dihydropyridine amlodipine on the hemodynamic response of the isolated perfused kidney to angiotensin II. Amlodipine completely reversed the angiotensin II-induced decrement in glomerular filtration rate of this model (0.72 +/- 0.15, 0.26 +/- 0.10 and 0.73 +/- 0.12 ml/min/g for control, angiotensin II and angiotensin II plus 0.1 microM amlodipine respectively). In contrast, amlodipine only partially restored renal perfusate flow (35.8 +/- 2.7, 14.7 +/- 1.9 and 23.7 +/- 2.5 ml/min/g for control, angiotensin II and angiotensin II plus amlodipine), thereby increasing filtration fraction. These findings are consistent with previous observations from this laboratory indicating that dihydropyridines predominantly vasodilate preglomerular renal resistance vessels and through this mechanism exert a preferential augmentation of glomerular filtration rate.

Renal hemodynamic effects of calcium antagonists.

Recently, attention has focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonists exhibit predictable actions allowing for characterization of their renal effects. Calcium antagonists do not affect the vasodilated isolated perfused kidney; however, they do dramatically alter the response of the kidney to vasoconstrictor agents. In the presence of norepinephrine, calcium antagonists markedly augment the glomerular filtration rate but produce only a modest improvement in renal perfusion. A study using the postischemic hydronephrotic rat kidney model that permits direct visualization of afferent and efferent arterioles, this study demonstrated that this preferential augmentation of the glomerular filtration rate is primarily attributable to a selective vasodilation of pre-glomerular vessels. Although the clinical implications of such observations are not yet clear, preliminary studies in experimental animal models indicate that calcium antagonists might exert salutary effects on renal function in clinical settings characterized by impaired renal hemodynamics. The possible benefits of calcium antagonists in ameliorating the development of renal dysfunction in patients in whom there is increased risk of acute renal insufficiency remain to be evaluated.

Calcium antagonists and the kidney.

Recently, attention has focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonists exhibit consistent actions, permitting characterization of their renal effects. Calcium antagonists do not affect the vasodilated isolated perfused kidney, but they do dramatically alter the response of the kidney to vasoconstrictor agents. In the presence of norepinephrine, calcium antagonists markedly augment the glomerular filtration rate, but produce only a modest improvement in renal perfusion. By use of the postischemic, hydronephrotic rat kidney model, which permits direct visualization of afferent and efferent arterioles, it can be demonstrated that the above-mentioned preferential augmentation of glomerular filtration rate may be attributable to a selective vasodilation of preglomerular vessels. Although the clinical implications of such observations are not yet clear, preliminary studies in experimental animal models indicate that calcium antagonists might exert salutary effects on renal function in clinical settings characterized by impaired renal hemodynamics. There is a need to carry out prospective studies to determine the benefits of calcium antagonists in ameliorating the development of renal dysfunction in patients at risk of acute renal insufficiency.

Renal hemodynamic effects of calcium antagonists.

Recently, attention has focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonists exhibit consistent actions permitting characterization of their renal effects. Calcium antagonists do not affect the vasodilated isolated perfused kidney, but they do dramatically alter the response of the kidney to vasoconstrictor agents. In the presence of norepinephrine, calcium antagonists markedly augment glomerular filtration rate but produce only a modest improvement in renal perfusion. This preferential augmentation of glomerular filtration rate may be attributable to a selective vasodilation of preglomerular vessels. Although the clinical implications of such observations are not yet clear, preliminary studies in experimental animal models indicate that calcium antagonists may exert salutary effects on renal function in clinical settings that are characterized by impaired renal hemodynamics. The possible benefits of calcium antagonists in ameliorating the development of renal dysfunction in patients in whom there is increased risk for the development of acute renal insufficiency remain to be evaluated.

Renal hemodynamic effects of calcium antagonists.

Although the cardiovascular actions of calcium antagonists have been studied extensively, it is only recently that attention has focused on the effects of calcium antagonists on renal function. Variable actions of calcium antagonists on renal hemodynamics have been observed when these agents are used in experimental animal models. In contrast, when administered in vitro to the isolated perfused kidney, calcium antagonists demonstrate more predictable actions. Calcium antagonists do not affect the vasodilated isolated kidney, but they do dramatically alter the response of the kidney to vasoconstrictor agents. In the presence of norepinephrine, calcium antagonists produce a modest improvement in renal perfusion and significantly augment glomerular filtration rate. This preferential augmentation of glomerular filtration rate may be attributable to a selective vasodilation of pre-glomerular vessels. Although the clinical implications of such observations are not yet clear, preliminary studies indicate that calcium antagonists may exert salutary effects on renal function in clinical settings that are characterized by impaired renal hemodynamics. The possible benefits of calcium antagonists in ameliorating the development of renal dysfunction in patients in whom there is increased risk for the development of acute renal insufficiency remain to be evaluated.

Increases in circulating atrial natriuretic factor during immersion-induced central hypervolaemia in normal humans.

The role of atrial natriuretic factor (ANF) in modulating volume and circulatory homeostasis remains uncertain, and there has been as yet no systematic analysis of the factors promoting ANF release in humans. Since immersion in water to the neck provides a 'volume stimulus' identical to that induced by 2 litres of saline, without plasma compositional change, immersion to the neck was used to assess the ANF response to acute central blood-volume expansion. Using a radio-immunoassay that reliably detected ANF in human plasma extracts, more than 80% of plasma immunoreactive (ir) ANF was shown to elute as a single peak on reverse-phase high performance liquid chromatography, with a retention time identical to that of the synthetic 28-residue alpha-human (alpha-h) ANF. The response of plasma irANF to 3 h of immersion in water to the neck was evaluated in four sodium-replete normal subjects; the immersion produced a prompt and marked increase in irANF in each subject, and recovery was associated with a prompt return to pre-study levels. Concurrently, there was a marked natriuresis and a profound suppression of plasma renin and aldosterone. These findings support the hypothesis that an increase in plasma ANF contributes to the hormonal and renal effects of immersion in water to the neck, suggesting that ANF has an important physiological role in modulating volume homeostasis in humans.

Effects of vasopressin administration on diuresis of water immersion in normal humans.

Although previous studies have demonstrated that water immersion to the neck (NI) results in a significant diuresis, the mechanisms are incompletely delineated. Because recent studies in our laboratory have demonstrated that NI is associated with a suppression of antidiuretic hormone (ADH), it is possible that such a suppression mediates the encountered diuresis. The present study was undertaken to assess more directly the relative role of ADH suppression by determining the effects of vasopressin administration. Six hydrated normal subjects were studied on two occasions while undergoing 6 h of NI. During the second NI study, aqueous vasopressin (20 mU/h) was infused for the initial 4 h of study (NI + vasopressin). NI resulted in a significant increase in urinary flow rate beginning during hour 1 and persisting throughout NI. In contrast, during NI + vasopressin, the anticipated diuresis was abolished throughout the 4 h of vasopressin administration. Cessation of vasopressin administration during the final 2 h of NI + vasopressin resulted in a marked and prompt diuresis. The present observations are consistent with the formulation that ADH suppression participates importantly in mediating the diuresis of NI in hydrated normal subjects.