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).-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 -adrenergic effects.This study was supported by the German Research Foundation within the SFB 90, HeidelbergA priliminary part of this investigation has been presented to the meeting of the German Physiological Society, Dortmund, March 1984 [Pflügers Arch (1984) suppl 400:R11,41]     

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

We investigated the influence of a stimulation of intrarenal -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 -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 -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 -adrenoceptors, and the modulation of the threshold pressure of pressure-dependent renin release by intrarenal -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 -adrenoceptors in the regulation of renin release. Our results explain controversial observations regarding the role of intrarenal -adrenoceptors in the control of renin release.This study was supported by the German Research Foundation (FG Niere, Kr. 546/5-1, Projekt 4)     

Dynamic pressure-flow curves in the autoregulating kidney vasculature of conscious dogs

Summary In three healthy conscious dogs blood pressure was measured in the abdominal aorta with an implanted miniature transducer. Flow velocity in the left renal artery was recorded by an electromagnetic flowmeter. An appropriate distance between the transducer sites compensated the time-lag introduced by the flowmeter system and allowed records with a negligable foot to foot phase shift between the flow- and the pressure pulse. Pressure-flow curves (I.-P. curves) were obtained recording flow versus pressure beat by beat on an oscilloscope. Electrical stimulation of the right cervical vagus nerve produced I.-P.-curves, which decayed in less than 3 sec down to a blood pressure of 25 mm Hg (dynamic I.-P.-curve). Static I.-P.-curves were recorded by reducing blood pressure within 1 to 2 min to the same pressure level. The following results were obtained:A unique dynamic I.-P.-curve, which follows the power functionI=a·P ⁿ exists for each level of arterial mean pressure i.e. myogenic vascular tone.An increase of arterial mean pressure (i.e. myogenic vascular tone) decreases the exponentn and increases the coefficienta of the power function.The static I. P.-curve, which runs parallel to the pressure axis above 90 mm Hg is actually composed of a family of different dynamic I.-P.-curves.The kidney resistance vessels are rather distensible. The pressure-dependent increase of myogenic vascular tone, which developes at perfusion pressures above 55 mm Hg, decreases the vessel distensibility.A change of mean perfusion pressure causes the kidney resistance vessels to shift from one to another dynamic I.-P.-curve without altering mean blood flow.This study was supported by the Deutsche Forschungsgemeinschaft (S.F.B. 90; Kardiovaskuläres System, Heidelberg).A preliminary report of a portion of this work was presented at the XXV. International Congress of Physiological Sciences, München, July 1971.     

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.This study was supported by the German Research Foundation within the SFB 320, Heidelberg     

Effect of intrarenal administration of dopamine on renin release in conscious dogs

We investigated the effect of intrarenal administration of dopamine on renin release in conscious dogs. Dopamine in doses ranging from 0.28 to 3.0 micrograms . kg(-1) . min(-1) produced a significant increase in systemic plasma renin activity (PRA) and renin secretion rate without altering systemic blood pressure. Dopamine also induced renal vasodilatation and natriuresis within this dose range. To determine if the dopamine-induced renin release is related to its vasodilatory action, two other vasodilators, papaverine and acetylcholine, were infused into the renal artery, but neither, in doses that produced a rise in renal blood flow similar to that of dopamine, had any effect on PRA. As dopamine can activate alpha- and beta-adrenergic receptors in addition to dopaminergic receptors, experiments were also performed to characterize the type of receptors involved in dopamine-induced renin release. Intrarenal infusion of sulpiride and haloperidol, dopamine antagonists, significantly inhibited dopamine-induced renin release and renal vasodilatation. In contrast, intrarenal infusion of propranolol failed to alter dopamine-induced rise in PRA or renal blood flow. Simultaneous infusion of phentolamine and dopamine, on the other hand, produced a significant potentiation of dopamine-induced renin release and renal vasodilatation. In conclusion, our studies demonstrate that dopamine is capable of inducing renin release and renal vasodilatation in conscious dogs. Moreover, such actions of dopamine are mediated through activation of specific dopamine receptors in the kidney. Finally, we present evidence for the existence of the intrarenal alpha-adrenergic mechanism that is inhibitory to renin release.     

Analysis of beta-adrenoceptors mediating renin release produced by isoproterenol in conscious dogs

Types of beta-adrenoceptors mediating renin release induced by isoproterenol were investigated in conscious dogs. The nonselective beta-adrenoceptor blocking drugs propranolol, D-32, and pindolol significantly inhibited increases in heart rate and plasma renin activity and a fall of blood pressure produced by intravenous infusion of isoproterenol (10 microgram . kg-1 . 20 min-1). d-Propranolol and d-D-32 did not inhibit these three responses to isoproterenol. The selective beta 1-adrenoceptor blocking drug atenolol, at the oral dose of 6 mg/kg, which selectively suppressed isoproterenol-induced tachycardia, significantly inhibited the renin release caused by isoproterenol. By contrast, the renin release induced by isoproterenol was not modified by the selective beta 2-adrenoceptor blocking drug IPS-339 at an oral dose of 3 mg/kg, which fully and selectively antagonized the fall of blood pressure in response to isoproterenol. There was good correlation between suppression of isoproterenol-induced renin release and that of isoproterenol-induced tachycardia after various beta-adrenoceptor blocking drugs. These results lead to the conclusion that in conscious dogs the beta-adrenoceptors mediating release are mainly of the beta 1 type.     

Relationship between perfusion pressure and renin release in the isolated rat kidney

Summary Isolated rat kidneys were perfused with either a modified Krebs-Henseleit solution containing a gelatine preparation (Haemaccel, 35 g/l) or with a suspension of washed bovine red blood cells (RBC). When perfusion pressure (PP) was varied repeatedly in the range between 30 and 210 mm Hg autoregulation of renal plasma flow (RPF) was almost complete in RBC perfused kindneys. Changes of PP by steps of 20 mm Hg at intervals of 5 min resulted in an incomplete autoregulation of RPF and glomerular filtration rate (GFR). Renin release (RR) was inversely related to PP in the range between 50 and 150 mm Hg, while perfusion at a pressure below or above that range had no further effect on RR. The most marked increase in RR was obtained, when PP was reduced from 90 to 70 mm Hg. After reduction of PP, an increase in RR was measurable within 1 min, and a maximum was reached after 5 min. In kidneys perfused with a cell-free medium at a PP of 45 mm Hg for up to 30 min, RR remained elevated for the entire period of pressure reduction. Injection of microspheres into the renal artery resulted in a prompt decrease of RPF, GFR and urinary sodium excretion, but the values returned towards control levels within 15 min; RR increased only transiently after a short initial fall.     

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 animal's 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.This study was supported by the German Research Foundation (FG Niere, Kr. 546/5-1, Projekt 3). A preliminary report of a part of this investigation has been presented to the Vth European Colloquium on Renal Physiology 1985 (Kirchheim et al., Renal Physiol, Basel 9:84, abstract 80, 1986)     

The influence of cardiopulmonary receptors on long-term blood pressure control and plasma renin activity in conscious dogs

The isolated and combined influence of cardiopulmonary and arterial baroreceptor denervation on long-term blood pressure (MAP), heart rate (HR), plasma volume (PV) and plasma renin activity (PRA) was studied in 10 conscious, chronically instrumented foxhounds receiving a normal sodium diet. Cardiopulmonary denervation was achieved by surgically stripping both thoracic vagi. Near complete arterial baroreceptor denervation, leaving most cardiopulmonary fibres intact, was made by left vagal deafferentiation which has been shown to eliminate most aortic baroreceptor afferents, and a carotid sinus denervation. Five groups were studied: (I) control (n = 9), (II) cardiopulmonary denervation (n = 5), (III) aortic baroreceptor denervation (n = 5), (IV) arterial baroreceptor denervation (n = 4) and (V) total denervation (n = 6). No changes in PV were observed. Only group V revealed significantly higher levels of MAP (119.5 +/- 5.4 vs. 100.1 +/- 1.6 mmHg; P less than 0.05), HR (118.1 +/- 4.4 vs. 87.8 +/- 3.7 beats min-1; P less than 0.001) and PRA (3.0 +/- 0.8 vs. 0.9 +/- 0.2 ng AI m-1 h-1; P less than 0.05). It is suggested that the isolated function of either cardiopulmonary or arterial baroreceptors is sufficient to maintain these variables at a normal level. Contrary to the results of other reports the cardiopulmonary receptors do not seem to regulate MAP at a level about which the arterial baroreceptors operate. When both groups of afferents were interrupted MAP, HR and PRA rose to significantly higher levels, implying that cardiopulmonary and arterial baroreceptor afferents interact in a sense of a non-additive attenuation.     

Vasopressin and renin responses to hemorrhage in conscious, cardiac-denervated dogs

We measured plasma arginine vasopressin (AVP) and plasma renin activity (PRA) during continuous hemorrhage in cardiac-denervated and sham-operated conscious dogs. Hemorrhage produced comparable decreases in aortic pressure, cardiac output, stroke volume, pulmonary arterial pressure, and left and right atrial pressures in each group of dogs. After 10 ml blood/kg body wt had been removed, AVP was increased in sham-operated dogs (P less than 0.05) but not in cardiac-denervated dogs. After 20 and 30 ml blood/kg body wt had been removed, AVP was increased in all dogs, but the response was markedly attenuated in cardiac-denervated dogs. Hemorrhage at 10 and 20 ml/kg caused comparable increases in PRA in each group of dogs. However, at 30 ml/kg hemorrhage the increase in PRA was significantly higher in cardiac-denervated dogs than in sham-operated dogs. Our results suggest that cardiac receptors play a dominant role in mediating the release of AVP during hemorrhage in conscious dogs. In contrast, we found no evidence for a dominant role of cardiac receptors in mediating renin secretion during hemorrhage.     

Role of renal kallikrein in control of renin release in conscious rats

Renal kallikrein was reported to activate human inactive renin and to release active renin from rat renal cortical slices. To evaluate the role of renal kallikrein in the control of renin release in vivo, Trasylol and soybean trypsin inhibitor (SBTI) were used to determine whether they can inhibit renin release stimulated by the administration of furosemide and a 2-wk low-sodium diet. Plasma renin activity (PRA) was increased by furosemide and also by the low-sodium diet. Urinary kallikrein excretion was increased by the sodium depletions. Trasylol did not affect basal PRA; however, it inhibited PRA and urinary kallikrein excretion, when stimulated by furosemide and by a low-sodium diet. These results suggest that furosemide and low-sodium diet act on the kidney to release renin via protease production. Because SBTI affected neither PRA nor urinary kallikrein excretion stimulated by these sodium depletions, it is suggested that renal kallikrein may play an important role in the control of renin release stimulated by furosemide and by low-sodium diet.     

Circulating catecholamines and control of plasma renin activity in conscious dogs.

Uninephrectomized dogs were prepared with indwelling catheters in the aorta, inferior vena cava (IVC), and renal artery, and after recovery they were studied in the conscious state. Basal aortic epinephrine and norepinephrine concentrations were 57 +/- 11 and 101 +/- 18 pg/ml, respectively. Elevation of epinephrine concentration to over 2,000 pg/ml by IVC infusion resulted in a sustained 3.5-fold increase in plasma renin activity (PRA), with only a transient decrease in arterial blood pressure. The PRA response to epinephrine was completely blocked by l-propranolol; isoproterenol increased PRA more than did epinephrine. Increasing norepinephrine concentration to 1,600 pg/ml by IVC infusion resulted in only a 1.5-fold increase in PRA. Infusion of epinephrine or norepinephrine directly into the renal artery to achieve similar increments of renal arterial concentration did not increase PRA. Insulin injection or hemorrhage resulted in elevations of arterial epinephrine (but not norepinephrine) concentration greater than the concentrations achieved during IVC infusion in these studies. We conclude that circulating epinephrine in the physiologic range plays a role in the control of PRA by activation of an extrarenal beta-receptor.     

Time-dependent heterogeneity of filtration rate in the autoregulating rat kidney

Experiments were performed to study the regulation of the single-nephron glomerular filtration rate (SNGFR) in superficial and juxtamedullary nephrons, as the left kidney of Sprague Dawley rats was submitted to a reduced arterial pressure of 70 mmHg by means of an aortic clamp. The SNGFR at different cortical levels was measured 0.5, 1, 5, 20 or 45 min after the reduction, in order to ascertain whether the effects of the regulatory mechanisms are modified with time. A Hanssen technique was used, which allows one determination of filtration rates per animal. At a renal arterial pressure (RAP) of 100 mmHg (= control animals) the SNGFR amounted to 20 +/- 1.2 and 23 +/- 0.8 nl X min-1 X g-1 kidney weight in the outer and inner cortical (OC, IC) nephrons. When RAP was further reduced to 70 mmHg, the autoregulation of SNGFR, determined after 0.5 min, was highly efficient for both OC and IC nephrons (19 +/- 2.0, 23 +/- 2.6). A prolonged reduction in RAP caused a gradual decline in SNGFR. The filtration rate measured after 5 min was 15 +/- 1.4 for OC and 20 +/- 1.8 for IC nephrons. The decline was most pronounced for OC nephrons, which led to a fractional redistribution in favour of IC nephrons. Thus, SNGFRIC/SNGFROC was 1.16 +/- 0.065 when RAP was 100 mmHg and 1.41 +/- 0.126 after 5 min with an RAP of 70 mmHg. It is well documented that suprarenal aortic occlusion is a powerful stimulus for the release of renin. This was manifested as an increase in the arterial pressure proximal to the aortic clamp.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of prostacyclin on hepatic vasculature and metabolism of renin in conscious dogs

Prostaglandins have been implicated as important regulators of vascular resistance during high-renin states, and they act as potent stimuli for renin release. This study examines the effects of prostacyclin (PGI2) in conscious sodium-replete and -deplete dogs on the hepatic vasculature and on hepatic function and their role in determining the level of arterial plasma renin activity (PRA). Concurrent measurements of kidney function were made for comparison. Conscious trained dogs with chronic indwelling catheters were given intravenous infusions of PGI2. With a low dose of PGI2 (2 x 10(-8) g . kg-1 . min-1) hepatic blood flow increased while splanchnic vascular resistance fell. With a higher dose (8 x 10(-8) g . kg-1 . min-1) mean arterial pressure fell, and both hepatic and renal blood flow increased while splanchnic and renal resistances fell. The PGI2 infusion was accompanied by an increase in PRA. In both sodium-replete and -deplete animals the increases in PRA were accompanied by proportional increases in the hepatic extraction of renin and increases in the hepatic clearance of renin. Small but significant differences were found in the responses of sodium-replete and -deplete animals to PGI2 infusion. These results demonstrate that PGI2 has a potent influence on both the splanchnic and renal vasculatures and the hepatic clearance of renin and thus the role of the liver in determining hyperreninemia.     

Atrial pressure and postprandial volume regulation in conscious dogs

Conscious, chronically instrumented dogs (n=24; left and right atrial catheter, electromagnetic flow probe around the left renal artery, carotid loop) were used in 97 expts. to study mechanisms mediating postprandial (pp) excretion of sodium and water up to at least 180 min after food intake. The dogs were kept under standardized conditions and maintained on ahigh (14.5 mmol Na/kg b.w./day) or alow (0.5 mmol Na/kg b.w./day) sodium intake diet (HSI, LSI) which was given once daily in the morning.In HSI dogs left atrial pressure (LAP) increased from a fasting control value of 0.2 kPa (2 cm H₂O) to 0.7 kPa (7 cm H₂O) (120–180 min pp), right atrial pressure from 0.0 kPa (0 cm H₂O) to 0.3 kPa (3 cm H₂O). 25% of the sodium intake were excreted up to 180 min pp. There was a highly significant positive correlation between pp sodium excretion (U _Na V) and pp LAP.U _Na V was not related to pp increase in renal blood flow (RBF) and glomerular filtration rate (GFR). Fractional sodium excretion increased from a fasting control value of 0.6% to more than 4% in HSI dogs and from 3.3% to more than 7% in anadrenalectomized HSI dog. DOCA did not diminishU _NA V in HSI dogs.In LSI dogs, RBF and GFR increased pp, LAP did not change pp. No substantial increase inU _Na V was observed.The close correlation between ppU _Na V and pp LAP in HSI dogs supports the hypothesis that intrathoracic vascular receptors are involved in the mediation of volume regulation by stimulation of still unknown natriuretic mechanisms which operate on the tubular level in the presence of high mineralocorticoid activity.     

KATP channels are not essential for pressure-dependent control of renin secretion

 This study aimed to investigate the functional role of ATP-sensitive K⁺ (K_ATP) channels in the control of renin secretion by renal perfusion pressure. We studied the effect of openers and blockers of K_ATP-channels on basal- and low-pressure-induced renin secretion from isolated perfused rat kidneys (IPRK). Cromakalim (0.1–10 μM) stimulated basal renin secretion up to threefold and caused vasorelaxation in the IPRK. Both effects of cromakalim were attenuated by glibenclamide. Cromakalim stimulated renin secretion from isolated juxtaglomerular (JG) cells and from microdissected afferent arterioles, all of which suggests that K _ATP channel openers stimulate renin secretion at the level of JG cells. A decrease in the perfusion pressure from 13.3 to 9.33 kPa (100 mmHg to 70 mmHg) increased renin secretion twofold, and cromakalim further increased renin secretion. At 5.33 kPa (40 mmHg) renin secretion was increased sevenfold and was not further enhanced by cromakalim. The low-pressure-induced stimulation of renin secretion was not changed by glibenclamide. Finally, the dependence on calcium of the cromakalim-induced stimulation of renin was examined. Addition of the calcium antagonist amlodipine to the perfusate stimulated renin secretion, and in this situation cromakalim had no further effect. The stimulation of renin secretion by cromakalim in the IPRK was markedly attenuated by angiotensin II (1 nM). These results suggest that cromakalim could stimulate renin secretion through a pathway that includes a decrease in JG cell calcium. K_ATP channels are not essentially involved in pressure-sensitive renin secretion. Received: 26 March 1997 / Received after revision: 15 November 1997 / Accepted: 1 December 1997