Impaired myogenic autoregulation in kidneys of Brown Norway rats.

The Brown Norway (BN) rat is normotensive and has an extended lifespan but is extremely sensitive to hypertension-induced renal injury. Relative impairment of autoregulation has been implicated in the progression of renal failure whereas absence of myogenic autoregulation is associated with early renal failure. Therefore, we tested the hypothesis that there is conditional failure of renal autoregulation in BN rats. In isoflurane-anesthetized BN rats, the pressure-flow transfer function was normal when pressure fluctuated spontaneously. External forcing increased pressure fluctuation and exposed weakness of the myogenic component of autoregulation; the component mediated by tubuloglomerular feedback was less affected. In the presence of vasopressin to raise renal perfusion pressure, myogenic autoregulation was further impaired during forcing in BN rats but not in Wistar rats. Compensation by the myogenic system was rapidly restored on cessation of forcing, suggesting a functional limitation rather than a structural failure. Graded forcing in Wistar rats and in spontaneously hypertensive rats revealed that compensation due to the myogenic system was strong and independent of forcing amplitude. In contrast, graded forcing in BN rats showed that compensation was reduced when fluctuation of blood pressure was increased but that the reduction was independent of forcing amplitude. The results demonstrate conditional failure of myogenic autoregulation in BN rats. These acute studies provide a possible explanation for the observed sensitivity to hypertension-induced renal injury in BN rats.

Nitric oxide, atrial natriuretic factor, and dynamic renal autoregulation.

Inhibition of nitric oxide (NO) synthase by N(omega)-nitro-L-arginine methyl ester (L-NAME) increases arterial pressure (PA) and profoundly reduces renal blood flow (RBF). Here we report that L-NAME causes changes in the PA-RBF transfer function which suggest augmentation of the approximately 0.2 Hz autoregulatory mechanism. Attenuation of PA fluctuations from 0.06 to 0.11 Hz was enhanced, indicating increased efficacy of autoregulation. Also, the rate of gain reduction between 0.1 and 0.2 Hz increased while the associated phase peak became > or = pi/2 radians, indicating emergence of a substantial rate-sensitive component in this system so that autoregulatory responses to rapid PA changes become more vigorous. Infusion of L-arginine partly reversed the pressor response to L-NAME, but not the renal vasoconstriction or the changes in the transfer function. The ability of atrial natriuretic factor (ANF), which also acts via cGMP, to replace NO was assessed. ANF dose dependently reversed but did not prevent the pressor response to L-NAME, indicating additive responses. ANF did not restore RBF or reverse the changes in the transfer function induced by L-NAME. The rate-sensitive component that was enhanced by L-NAME remained prominent, suggesting that either ANF did not adequately replace cGMP or provision of a basal level of cGMP was not able to replace cGMP generated in response to NO. It is concluded that NO synthase inhibition changes RBF dynamics with the most notable change being increased contribution by a rate-sensitive component of the myogenic system.

Incommensurate frequencies of major vascular regulatory mechanisms.

The dynamic relationship among three major vascular control mechanisms that operate on large fractions of cardiac output: arterial baroreflex and renal and mesenteric autoregulation, was investigated in conscious rats. Wistar and spontaneously hypertensive rats were studied in their home cages 10 days after implantation of pulsed Doppler flow probes. There was an oscillation of blood pressure centered at 0.45 Hz that is associated with operation of arterial baroreflexes. Hindquarters blood flow displayed a featureless, "1/f' power spectrum, in which no autoregulatory or baroreflex signatures could be discerned, although active control of resistance over a wide range of frequencies was evident. The renal pressure - flow transfer function was dominated by an autoregulatory mechanism with a resonance peak at 0.25 +/- 0.01 Hz. In the mesenteric circulation an autoregulatory mechanism was seen with a resonance peak at 0.15 +/- 0.01 Hz and another active mechanism was seen above 0.2 Hz that appeared from its negative admittance phase to be a baroreflex. The center frequencies of mesenteric and renal autoregulation and of the arterial baroreflex were related in a ratio of 1 : 1.7 +/- 0.1 : 3.0 +/- 0.2 (approximately 4:7:12). Such relatively high order ratios can be expected to minimize the possibility of phase locking and (or) entrainment among the various control mechanisms.

Responses of mesenteric and renal blood flow dynamics to acute denervation in anesthetized rats.

Previous studies have shown that renal autoregulation dynamically stabilizes renal blood flow (RBF). The role of renal nerves, particularly of a baroreflex component, in dynamic regulation of RBF remains unclear. The relative roles of autoregulation and mesenteric nerves in dynamic regulation of blood flow in the superior mesenteric artery (MBF) are similarly unclear. In this study, transfer function analysis was used to identify autoregulatory and baroreflex components in the dynamic regulation of RBF and MBF in Wistar rats and young spontaneously hypertensive rats (SHR) anesthetized with isoflurane or halothane. Wistar rats showed effective dynamic autoregulation of both MBF and RBF, as did SHR. Autoregulation was faster in the kidney (0.22 +/- 0.01 Hz) than in the gut (0.13 +/- 0.01 Hz). In the mesenteric, but not the renal bed, the admittance phase was significantly negative between 0.25 and 0. 7 Hz, and the negative phase was abrogated by mesenteric denervation, indicating the presence of an arterial baroreflex. The baroreflex was faster than autoregulation in either bed. The presence of sympathetic effects unrelated to blood pressure was inferred in both vascular beds and appeared to be stronger in the SHR than in the Wistar rats. It is concluded that a physiologically significant baroreflex operates on the mesenteric, but not the renal circulation and that blood flow in both beds is effectively stabilized by autoregulation.

Pharmacological modulation of spontaneous renal blood flow dynamics.

Two mechanisms contribute to renal autoregulation. The faster system, which is thought to be myogenic, operates at 0.1-0.2 Hz (i.e., 5-10 s/cycle), while the slower one, tubuloglomerular feedback, operates at 0.03-0.05 Hz (i.e., 20-30 s/cycle). Both attenuate spontaneous or induced fluctuations of blood pressure, but it has proven difficult to separate their individual contributions because there is potential for interaction between the two. The present study was designed to examine the dynamics of the faster system during pharmacological blockade of tubuloglomerular feedback. Normotensive and hypertensive rats were studied under isoflurane or halothane anesthesia. Administration of the loop diuretic furosemide plus the angiotensin II (ANGII) AT1 receptor antagonist losartan caused a 10-fold or greater natriuresis, indicating profound inhibition of ascending limb salt transport, and also produced characteristic changes in the transfer function relating blood pressure (input) to renal blood flow (output). Operation of the 0.1-0.2 Hz mechanism was essentially unaltered, as shown by the presence of a peak in phase angle at 0.1-0.2 Hz and reduction of gain at frequencies slower than 0.15 Hz. The 0.03-0.05 Hz mechanism was markedly inhibited, as shown by loss of the second phase angle peak at 0.03-0.05 Hz, loss of the local maximum in gain at 0.05 Hz, and loss of the second gain reduction below 0.05 Hz. Both during control and after inhibition of tubuloglomerular feedback, the 0.1-0.2 Hz system attenuated = 50% of the effects of spontaneous blood pressure fluctuations, suggesting that this mechanism, operating alone, can significantly stabilize renal blood flow in the face of spontaneous fluctuations of blood pressure.

Spontaneous blood pressure fluctuations and renal blood flow dynamics.

Two mechanisms operating at 0.03-0.05 and 0.1-0.2 Hz are involved in autoregulation of renal blood flow (RBF). To examine the behavior of the faster system, the response of RBF to spontaneous fluctuations of arterial pressure was assessed in Sprague-Dawley rats anesthetized by isoflurane or halothane. During halothane anesthesia, autonomous oscillation of total RBF was observed at 0.10-0.15 Hz, and normalized admittance gain became negative at 0.11 +/- 0.01 Hz. During isoflurane anesthesia, there was autonomous power in blood flow in a broad peak between 0.15 and 0.25 Hz, and gain became negative at 0.15 +/- 0.01 Hz. Increasing inspired isoflurane concentration from 1.4 +/- 0.1% to 2.2 +/- 0.1% reduced pressure by 22 +/- 2 mmHg but did not alter blood flow or the transfer function, indicating that the operating frequency was not changed. In another experiment, changing from isoflurane to halothane increased peak power in the autonomous blood flow oscillation fivefold and reduced its frequency from 0.18 +/- 0.01 to 0.14 +/- 0.01 Hz. Gain became negative at a higher frequency (0.16 +/- 0.01 Hz) during isoflurane than halothane anesthesia (0.12 +/- 0.01 Hz). The results show that the 0.1-0.2 Hz system is reliably detected under unforced conditions and provides modest attenuation of pressure fluctuations at < or = 0.1 Hz. Its operating frequency under isoflurane anesthesia is consistent with previous estimates from barbiturate-anesthetized rats, whereas it operates significantly slower under halothane anesthesia.

Haemodynamic and metabolic consequences of aortic occlusion during abdominal aortic surgery.

We have studied the haemodynamic and metabolic effects of application and removal of the infrarenal aortic crossclamp in 20 patients during aortic reconstructive surgery for repair of aneurysmal or occlusive disease. A highly significant positive correlation was detected between the change in systemic vascular resistance (SVR) associated with application of the aortic crossclamp and the change in base deficit (BD) associated with its removal (r = 0.851; P = 0.001). There was no difference in regression analysis (P = 0.21) or mean change of SVR and BD (P = 0.73) in patients with either aneurysmal or occlusive disease. In addition, the maximum increase in mixed venous serum lactate concentration correlated positively with the duration that the aortic crossclamp was applied (r = 0.717, P = 0.0297). These observations suggest the importance of the collateral circulation in the development of metabolic acidosis during aortic surgery.

Epidural epinephrine and the systemic circulation during peripheral vascular surgery.

This study was designed to determine the haemodynamic effects of epidural epinephrine, 5 micrograms.ml-1, added to bupivacaine, 0.75 per cent, in elderly patients with cardiac disease undergoing peripheral vascular surgery (PVS). The effect of epidural epinephrine on the plasma concentration of bupivacaine was also measured. Twenty patients with a history and/or ECG evidence of myocardial ischaemia requiring PVS were randomly assigned to two groups. The patients were monitored with a modified V5 ECG, oscillometric BP monitor and a PA catheter. After control haemodynamic measurements, 12 ml of bupivacaine, 0.75 per cent, +/- epinephrine, 5 micrograms.ml-1, was injected over five minutes into the epidural space at L3-4. Supine haemodynamic measurements were repeated at 15 and 45 min after injection. At 15 min after epidural injection, compared with control values, patients receiving epidural epinephrine showed a significantly greater decrease in mean blood pressure and systemic vascular resistance, and a significantly greater increase in cardiac output than patients receiving plain epidural bupivacaine (79.3 +/- 11.6 per cent vs 94.6 +/- 16.8 per cent, 61.6 +/- 9.0 vs 91.6 +/- 19.2 per cent, 130.8 +/- 23 vs 105 +/- 20.8 per cent, respectively). These differences were not present at 45 min after epidural injection. Heart rate was not significantly different between groups at either time. The presence of epidural epinephrine reduced the peak plasma concentration of bupivacaine from 0.86 +/- 0.20 to 0.64 +/- 0.33 micrograms.ml-1 and increased the time to achieve this concentration from 16.1 +/- 11.2 to 33.7 +/- 20.1 min.