P. B. Persson

Autoregulation of renal blood flow, glomerular filtration rate and renin release in conscious dogs

The relationship between renal artery pressure (RAP), renal blood flow (RBF), glomerular filtration rate (GFR) and the renal venous-arterial plasma renin activity difference (PRAD) was studied in 22 chronically instrumented, conscious foxhounds with a daily sodium intake of 6.6 mmol/kg. RAP was reduced in steps and maintained constant for 5 min using an inflatable renal artery cuff and a pressure control system.Between 160 and 81 mm Hg we observed a concomitant autoregulation of GFR and RBF with a high precision. The “break off points” for GRF- and RBF-autoregulation were sharp and were significantly different from each other (GFR: 80.5±3.5 mm Hg; RBF: 65.6±1.3 mm Hg;P<0.01). In the subautoregulatory range GFR and RBF decreased in a linerar fashion and ceased at 40 and 19 mm Hg, respectively.Between 160 mm Hg and 95 mm Hg (threshold pressure for renin release) PRAD remained unchanged; below threshold pressure PRAD increased steeply (average slope: 0.34 ng AI·ml−1·h−1· mm Hg−1) indicating that resting renin release may be doubled by a fall of RAP by only 3 mm Hg. At the “break-off point” of RBF-autoregulation (66 mm Hg) renin release was 10-fold higher than the resting level.It is concluded that under physiological conditions (normal sodium diet) GFR and RBF are perfectly autoregulated over a wide pressure range. Renin release remains suppressed until RAP falls below a well defined threshold pressure slightly below the animals resting systemic pressure. RBF is maintained at significantly lower pressures than GFR, indicating that autoregulation of RBF also involves postglomerular vessels. Our data are in agreement with the myogenic hypothesis as a basic mechanism of autoregulation.

Sympathetic modulation of renal hemodynamics, renin release and sodium excretion

SummaryIn anesthetized animals it has been shown previously, that the influence of electrical stimulation of efferent renal nerves on renal function with increasing stimulation frequencies can be graded; renin release is affected at low, sodium excretion at intermediate and vascular resistance at high stimulation frequencies.Experiments in conscious dogs are reviewed, which present evidence for a similar functional dissociation under physiological conditions.Moderate activations of the renal sympathetic nerves, which do not change renal blood flow 1) decrease sodium excretion independent of changes in angiotensin II, 2) interact with the pressure-dependent mechanism of renin release by resetting its threshold pressure and 3) modulate autoregulation by increasing the lower limits of glomerular filtration rate and renal blood flow-autoregulation.These findings may contribute to our understanding of the role of the renal nerves in the pathophysiology of congestive heart failure and hypertension.

Baroreflex sympathetic activation increases threshold pressure for the pressure-dependent renin release in conscious dogs.

Stimulus-response curves relating renal-venous-arterial plasma renin activity difference (P.R.A.-difference) to mean renal artery pressure (R.A.P.) were studied in seven chronically instrumented conscious foxhounds with a daily sodium intake of 6.1 mmol/kg. R.A.P. was reduced in steps and maintained constant for 5 min using an inflatable renal artery cuff and a pressure control system.The stimulus-response curve obtained during control conditions (C) or during common carotid artery occlusion (C.C.O.) could be approximated by two linear sections: a rather flat section or plateau-level of P.R.A.-difference at normal blood pressure or above, and a very steep section between a distinct threshold pressure and 65–70 mm Hg. While the parameters of the curves varied from dog to dog, the curves kept their inique shape in the individual dog for at least 1 week. C.C.O. had no effect on the plateau-level of the P.R.A.-difference (C:0.98±0.14,C.C.O.:0.99±0.14 ng Al·ml−1·h−1) and on the slope of the curve below threshold pressure (C:−0.379±0.041,C.C.O: −0.416±0.082 ng Al·ml−1·h−1·mm Hg−1) but shifted the stimulus-response curve to the right and increased threshold pressure (C:92.7±2.8,C.C.O.:109.7±4.1 mm Hg;P<0.05).Renal blood flow, which was measured simultaneously in three of the dogs, showed good autoregulation down to 70 mm Hg under resting conditions and was not affected by C.C.O. except for a 30% reduction of renal blood flow at the lowest pressure step (70 mm Hg).β-Adrenergic blockade in 4 of the dogs reduced the plateau-level of the P.R.A.-difference from 0.86±0.19 to 0.36±0.05 ng AI·ml−1·h−1 (P<0.05) but had no effect on the increase of threshold pressure elicited by C.C.O.It is concluded that the stimulus-response curve for the pressure-dependent renin release has a remarkable long-term stability in the individual dog. The curve is shifted to the right by a moderate carotid baroreflex increase of renal sympathetic nerve discharge which leaves total renal blood flow largely unchanged. It is suggested that the increase in threshold pressure is independent of β-adrenergic effects.

Effect of sino-aortic denervation in comparison to cardiopulmonary deafferentiation on long-term blood pressure in conscious dogs.

The isolated and combined influence of cardiopulmonary and sinoaortic denervation on long-term blood pressure (MAP), heart rate (HR), plasma renin activity (PRA) and plasmavolume (PV) was studied in 11 conscious, chronically instrumented foxhounds receiving a normal sodium diet. MAP, HR, PV and PRA remained unchanged in the 5 dogs after bilateral thoracic vagal stripping, which eliminates the cardiopulmonary afferents. After sino-aortic denervation in another 5 dogs there was equally little change when compared to the control group. Only total baroreceptor and cardiopulmonary denervation (7 dogs) revealed significantly higher levels of MAP (119.6±4.6 vs. 100.4±1.5,P<0.01), HR (118.2±3.7; vs. 84.1±3.5;P<0.0001), and PRA (3.6±0.9 vs. 0.9±0.2;P<0.05). In conclusion, the function of either arterial baroreceptors or cardiopulmonary receptors is sufficient for normal circulatory control. When both groups of receptor afferents are interrupted, MAP, HR, and PRA rise to significantly higher levels. Thus, both systems interact in a sense of a nonadditive attenuation on “cardiovascular centres”. This may clarify previous disputes concerning neurogenic hypertension, and supplies information for the role of the renin-angiotensin system in blood pressure control.

Resetting of pressure-dependent renin release by intrarenal α1-adrenoceptors in conscious dogs

We investigated the influence of a stimulation of intrarenal α-adrenoceptors on the relationship between renin release and renal artery pressure in 8 conscious, chronically instrumented dogs receiving a normal salt diet. Renin stimulus-response curves were determined by a stepwise reduction of renal artery pressure down to 70 mm Hg (1) under control conditions, (2) during a bilateral common carotid occlusion combined with an intrarenal prazosin infusion, and (3) during an intrarenal methoxamine infusion. Both drug infusions did not alter resting renal blood flow. (1) The control renin stimulus-response curve revealed a flat portion (platcau-level) around and above the resting blood pressure and a very steep portion (slope) below a well-defined threshold pressure 10–15 mm Hg below the resting blood pressure. (2) An intrarenal α-adrenoceptors blockade by prazosin prevented the resetting of the threshold pressure which is regularly observed during bilateral common carotid occlusion. (3) An intrarenal infusion of the α-adrenoceptors agonist methoxamine increased the threshold pressure. We suggest that the neural control of renin release within the autoregulatory range of renal blood flow involves two independent mechanisms: the direct release of renin from juxtaglomerular granular cells by β-adrenoceptors, and the modulation of the threshold pressure of pressure-dependent renin release by intrarenal α-adrenoceptors. The small changes in renal nerve activity necessary to reset the threshold pressure and the close relationship between the threshold pressure and resting blood pressure imply an important function of intrarenal α-adrenoceptors in the regulation of renin release. Our results explain controversial observations regarding the role of intrarenal α-adrenoceptors in the control of renin release.

Autoregulation and non‐homeostatic behaviour of renal blood flow in conscious dogs.

1. Spontaneously occurring haemodynamic variations within 4 h affecting renal blood flow (RBF) were compared with externally induced short changes of renal artery pressure (RAP) in conscious resting dogs. 2. In all animals in which RAP was servo‐controlled (n = 6), perfect autoregulation of RBF was observed. 3. In all 4 h recordings of spontaneous renal blood flow (n = 9), certain combinations of blood pressure and blood flow occurred remarkably frequently as indicated by three‐dimensional frequency distributions. 4. Cluster analysis demonstrated significant differences between these areas of accumulation (P < 0.001). The average number of set points per 4 h session was 3.1 +/‐ 0.3. 5. The shift from one set point to another is probably mediated by multiple control systems impinging on renal haemodynamics as suggested by 1/f fluctuations. 6. In seven dogs, an additional renal venous catheter allowed measurements of the arterial‐venous (A‐V) oxygen partial pressure (PO2) difference as an indicator of the renal metabolic demand. An inverse relationship between A‐V PO2 difference and RBF (Y = X(‐0.034) + 40.9, r = ‐0.9, P < 0.001) was found, indicating that the metabolic demands vary little (if at all) between the different set points. 7. The presented data suggest a modified view of renal homeostasis. There exist distinct combinations between RBF and RAP, which are very stable. Autoregulation merely buffers the fluctuations around these set points.

A physiological role for pressure-dependent renin release in long-term blood pressure control

The relationship between pressure-dependent renin release and long-term blood pressure was studied in 14 conscious dogs on a normal salt diet. Stimulus-response curves were obtained by a controlled reduction of renal artery pressure in 5 or 10 mm Hg steps down to 70 mm Hg. Pressure-dependent renin release was characterized by a threshold pressure, a plateau above threshold pressure, and a steep slope below the threshold pressure. In each dog long-term blood pressure was higher than threshold pressure. Threshold pressure and slope were found to describe more than 90% of long-term blood pressure variability between conscious dogs. The following findings suggest that an on-off switch of pressure-dependent renin release stabilizes long-term blood pressure above the threshold pressure: (1) The intermittent activation of pressure-dependent renin release due to physiological variations in arterial blood pressure induced changes in plasma renin activity by as much as 300%. (2) The individual difference between threshold pressure and long-term blood pressure was highly dependent on the slope. (3) A systemic blockade of the reninangiotensin system by converting-enzyme inhibition resulted in a slope-dependent fall of long-term blood pressure. (4) A spontaneous shift of threshold pressure was accompanied by equivalent changes in arterial blood pressure. Taken together, our results provide evidence for a major role of pressure-dependent renin release in the long-term control of blood pressure in conscious dogs. A chronic resetting of threshold pressure may be an important mechanism in the pathogenesis of hypertension.

On the origin of low-frequency blood pressure variability in the conscious dog.

1. Baroreceptor denervation increases blood pressure variability below 0.1 Hz. This study was undertaken to determine to what extent these fluctuations originate from the central nervous system or from cardiovascular sources. 2. Blood pressure was recorded at a rate of 10 Hz for approximately 3.5 h in conscious, resting dogs. Power density spectra were calculated from all 2(17) points of each recording session and integrated between 0.0002 and 0.1 Hz. 3. Blockade of the afferent limb of the baroreceptor reflex by surgical denervation of sinoaortic and cardiopulmonary afferents (Den; n = 6) significantly increased integrated power more than sixfold compared with a control group (n = 11). 4. Impairment of the efferent limb in non‐deafferented dogs by either alpha 1‐adrenergic blockade with prazosin (Praz; n = 7) or ganglionic blockade with hexamethonium (Hex; n = 6) failed to raise variability. 5. Both prazosin (n = 6) and hexamethonium (n = 3) reduced the increased variability in denervated dogs. 6. In non‐deafferented dogs receiving hexamethonium, elevation of mean blood pressure to the hypertensive level of the Den group, by a continuous infusion of noradrenaline (n = 4), did not change the variability. 7. It is concluded that in the absence of changes in posture, most of the increased blood pressure variability after baroreceptor denervation is derived from the central nervous system. 8. Direct comparison of power spectra of the Den (total variability) and Hex groups (variability derived from the cardiovascular system only) suggests that the central nervous system is also the prevalent source of low‐frequency blood pressure variability in intact animals.

Modulation of erythropoietin formation by changes in blood volume in conscious dogs.

1. A possible influence of the filling of the circulatory system on the plasma concentration of erythropoietin, which is the major regulator of erythrocyte formation, was investigated in conscious dogs. 2. Over an experimental period of 5 h, the animals were subjected to either haemorrhage (hypovolaemia), blood volume expansion (hypervolaemia), or exchange transfusion of blood with dextran (isovolaemic anaemia). 3. A reduction of blood volume by 20% induced by haemorrhage increased plasma erythropoietin levels approximately 1.5‐fold in the absence of significant changes in haematocrit. 4. An expansion of blood volume by 12% induced by an intravenous infusion of dextran did not change plasma erythropoietin levels, although the haematocrit decreased by 0.04. 5. A reduction of the haematocrit by 0.12 in the absence of changes in blood volume induced by an isovolaemic exchange transfusion (dextran vs. blood) increased plasma erythropoietin levels approximately 3‐fold. 6. Total renal oxygen supply did not change in any of the three experimental protocols. 7. These data indicate that in dogs the erythropoietin production rate is modulated by changes in blood volume, and suggest a possible role of erythropoietin in the regulation of blood volume.

Physiology of the Renal Baroreceptor Mechanism of Renin Release and its Role in Congestive Heart Failure

The function of the renal baroreceptor can be quantitatively described by a stimulus-response curve showing a flat section in the high pressure range, a steep slope in the low pressure range, and a well-defined threshold pressure slightly below resting systemic pressure. This stimulus-response curve shows a close functional relation to autoregulation of renal blood flow, glomerular filtration rate and sodium excretion. Threshold pressure and slope are subject to different physiologic control mechanisms: The slope is increased by a low sodium diet, whereas threshold pressure is elevated by an increased renal sympathetic nerve discharge or by circulating catecholamines. Sympathetic influences also reset renal autoregulation. Recent studies have provided evidence for an important role of the renal baroreceptor in the long-term control of arterial blood pressure. The sympathetic modulation of threshold pressure can induce sodium retention in early heart failure, and the sympathetic effects on autoregulation may help to explain clinical reports on a deterioration of renal function during converting-enzyme therapy.