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.     

Inhibition of renin secretion by intrarenal alpha-adrenoceptor blockade

This study was designed to determine whether renal alpha-adrenoceptors can mediate tonic neural stimulation of renin secretion. The effect of alpha-adrenoceptor blockade by phenoxybenzamine (POB) or prazosin on renin secretion rate (RSR) was studied in pentobarbital-anesthetized dogs in which renal perfusion pressure was held constant with an adjustable aortic clamp. POB alone (100 micrograms.kg-1.min-1 iv) did not change arterial plasma renin activity (PRA). However, when beta-adrenoceptors were blocked by intravenous propranolol, intravenous POB infusion (100 micrograms.kg-1.min-1) decreased PRA and RSR to 48 +/- 8 and 21 +/- 9% of previous levels within 30 min. This effect was abolished by acute bilateral renal denervation. Direct intrarenal POB infusion (10 or 3.3 micrograms.kg-1.min-1) decreased RSR, whereas intravenous POB (3.3 micrograms.kg-1.min-1) had no effect on either RSR or PRA in propranolol-pretreated dogs. Prazosin (1 microgram.kg-1.min-1 iv) also significantly decreased PRA. These data indicate that when beta-adrenoceptors are blocked by propranolol, tonic neural stimulation of renin secretion is mediated by renal alpha-adrenoceptors.     

Renin release and pressor response to renal arterial hypotension: effect of dietary sodium.

Changes in plasma renin activity (PRA) and mean arterial pressure (MAP) produced by renal arterial hypotension were studied in conscious, adrenalectomized dogs maintained on low-, normal-, or high-Na diet during constant steroid replacement therapy. In animals maintained on a low-Na diet, reduction of renal perfusion pressure to 50 mmHg for 45 min increased MAP 40 +/- 3 (SE) mmHg, while PRA rose rapidly by 36.5 +/- 6 ng ml-1 h-1. Similar renal hypotension in dogs maintained on a normal-Na diet increased MAP only 21 +/- 3 mmHg while PRA rose 5.5 +/- 0.9 ng ml-1 h-1; dogs on high-Na intake had a 6 +/- 1 mmHg pressure rise without a significant change in PRA. The rise in MAP correlated well with the log deltaPRA. Calculated open-loop gain was -1.2, -0.7, and -0.1 in dogs on low-, normal-, and high-Na diets, respectively. Nonpeptide angiotensin I converting enzyme inhibitor (CEI) reversed the elevated MAP observed during reduction of renal perfusion pressure in dogs on low- and normal-Na diets, but had little effect in dogs on high-Na intake. These observations suggest that the renin-angiotensin system becomes quantitatively more important in the regulation of blood pressure as Na intake is reduced.     

Effects of AVP and DDAVP on plasma renin activity and electrolyte excretion in conscious dogs.

Uninephrectomized adult female dogs with chronic indwelling catheters were maintained on a low sodium diet and studied without anesthesia. Following hydration with 3% dextrose, an intravenous infusion of either arginine vasopressin (AVP) or of 1-desamino-8-D-arginine vasopressin (DDAVP) was begun. The dose was calculated to achieve a near maximal physiological plasma concentration of AVP, or an equimolar concentration of DDAVP. Both AVP and DDAVP increased urinary osmolality from less than 60 to over 800 mosmol/kg H2O within 1 h. AVP infusion increased mean arterial pressure and renal electrolyte excretion and decreased heart rate and plasma renin activity (PRA), while DDAVP was without effect on these parameters. AVP infused into the renal artery at doses which did not alter systemic pressure and heart rate caused kaliuresis and reduced PRA. We conclude that the AVP-induced inhibition of renin secretion and increase in renal electrolyte excretion are not secondary to increased tubular permeability to water, but must represent a more specific action of AVP which is not shared by DDAVP.     

Atrial natriuresis under the condition of a constant renal perfusion pressure

An experimental elevation of left atrial pressure (eLAP ↑) by means of a reversible mitral stenosis is accompanied with an increase in sodium excretion (UNa—) and arterial blood pressure (by about 20 mm Hg, 2.7 kPa), and by a decrease in plasma renin activity. It is well established that an increase in renal perfusion pressure (Pren) can augment UNa—. Therefore the present study was undertaken to examine whether the eLAP ↑-induced natriuresis was caused by the increased Pren. — Four female beagle dogs were kept under controlled environmental conditions. They received asodium rich diet (14.5 mmol/Na/kg/d). The dogs were chronically instrumented: purse string around the mitral annulus, catheter in the left atrium, carotid loop, pneumatic cuff above the renal arteries, pressure transducer below the renal arteries. Pren was kept constant by means of a digital servofeedback control circuit. The dogs served as their own controls (13 experiments without and 15 experiments with a controlled renal perfusion pressure were performed). After eLAP↑(+1.0 kPa), UNa— rose from 4.1±2.6 to 10.3±3.9 μmol Na/min/kg. If Pren was kept constant, the corresponding values were 4.2±2.8 and 9.3±2.9 μmol/min/kg. These data clearly indicate that the atrial natriuresis is not mediated by an augmentation of renal perfusion pressure. Therefore these results support the hypothesis that atrial natriuresis probably is due to an eLAP↑-induced suppression of the renin-angiotensin-system or other natriuretic mechanisms.     

Role of the renin-angiotensin system in potassium control

To determine the importance of the renin-angiotensin system in control of plasma potassium concentration and excretion, potassium control was studied in two groups of dogs in response to a 20-fold increase in sodium intake (from 10 to 200 meq/day). Group I was intact whereas group II lacked feedback control of the renin-angiotensin system, which was eliminated by continuous infusion of 10 ng . kg-1 . min-1 angiotensin II. This rate of infusion reduced endogenous plasma renin activity (PRA) to undetectable levels throughout the study. The sodium forcing did not result in measurable changes in plasma potassium concentration or excretion in group I, in which PRA fell to 40% and plasma aldosterone concentration (PAC) to 60% of the low sodium levels. In group II the same sodium forcing produced a 12% decrease in plasma potassium concentration and a 79% increase in urinary potassium excretion. PAC also fell to 60% of the low sodium level in group II. The results demonstrate the importance of the renin-angiotensin system as a link between the nephron and the zona glomerulosa that is essential in controlling plasma potassium concentration and excretion during changes in sodium balance.     

Plasma renin activity during pentobarbital anesthesia and graded hemorrhage in dogs.

Six dogs were implanted with chronic arterial and venous catheters and were trained to lie quietly on a padded table. The effect of pentobarbital anesthesia and of graded hemorrhage on plasma renin activity (PRA) was then examined in the absence of surgical stress. Pentobarbital anesthesia resulted in a fivefold increase in PRA within 15 min, followed by a slow decline to a level 3 times control at 1.5 h. Mean arterial pressure (MAP) fell transiently but returned to control values. In the unanesthetized dog, graded hemorrhage to 12 ml/kg resulted in a twofold increase in PRA with no change in MAP or heart rate. The same hemorrhage in pentobarbital-anesthetized dogs resulted in a similar increase in PRA, accompanied by a substantial increase in heart rate. It is concluded that 1) pentobarbital anesthesia in the dog results in a rapid and sustained increase in PRA, and 2) in the conscious dog, increased PRA in response to graded hemorrage appears to be independent of an arterial baroreceptor mechanism and of generalized increased sympathetic nervous system activity.     

Mechanism of intrarenal blood flow redistribution after carotid artery occlusion.

Bilateral carotid artery occlusion results in an increase in mean arterial pressure, an increase in renal sympathetic nerve activity, and a redistribution of renal blood flow from inner to outer cortex. To elucidate the mechanism of the renal blood flow redistribution, carotid artery occlusion was performed in anesthetized dogs with the left kidney either having renal perfusion pressure maintained constant (aortic constriction) or having alpha-adrenergic receptor blockade (phenoxybenzamine); the right kidney of the same dog served to document the normal response. When renal perfusion pressure was maintained constant, renal blood flow distribution (microspheres) was unchanged by carotid artery occlusion. In the presence of renal alpha-adrenergic receptor blockade, carotid artery occlusion elicited the usual redistribution of renal blood flow from inner to outer cortex. The redistribution of renal blood flow observed after carotid artery occlusion is mediated by the increase in renal perfusion pressure rather than the increase in renal sympathetic nerve activity.     

Effect of parathyroid hormone on plasma renin activity and sodium excretion.

The interaction between parathyroid hormone (PTH) and the renin-angiotensin system was evaluated in pentobarbital-anesthetized dogs. An intravenous infusion of bovine PTH (1-34) for 1 h was accompanied by a 57% increase (13.7-21.6 ng/ml per h) in plasma renin activity (PRA) which returned toward control levels during the recovery period. Sodium and phosphate excretion also increased. Second the endogenous secretion of PTH was stimulated by infusion of citrate into the blood supply of the thyroparathyroid glands to determine if the stimulatory effect on renin occurred with endogenous secretion of PTH. Phosphate excretion increased, which confirmed PTH secretion. There was a significant rise (57%) in both PRA (6.1-9.8 ng/ml per h) and sodium excretion, the magnitude of the sodium response modulating the increase in PRA. Blood pressure remained constant. In a third set of experiments, thyrocalcitonin was infused intravenously and had no effect on PRA. These data indicate that both exogenous and endogenous PTH can elevate PRA and increase sodium excretion. The sodium effect is probably the result of inhibition of proximal sodium reabsorption by PTH. The mechanism by which PTH elevates PRA is not known.     

Hemodynamic,renal, and hormonal responses to changes in dietary potassium in normotensive and hypertensive man: Long-term antihypertensive effect of potassium supplementation in essential hypertension

Summary The hemodynamic, hormonal, and renal responses to alterations in dietary potassium were studied in normotensive and hypertensive subjects. In a short-term study, nine normotensive and nine hypertensive young men received a normal diet and low potassium, high potassium, and high potassium/low sodium diets for 1 week, each. The long-term effect of potassium supplementation (normal diet plus 96 mmol KCl/d for 8 weeks) was evaluated in 17 patients with essential hypertension. Blood pressure did not change significantly during short-term alterations of potassium intake but decreased during long-term supplementation (from 152.2±3.5/99.6±1.9 mm Hg to 137.4±2.9/89.1±1.4 mm Hg). High dietary potassium induced a significant but transient natriuresis. Plasma potassium concentration was increased during long- but not during short-term high potassium intake. In contrast to plasma renin activity (PRA) and aldosterone, urinary kallikrein was consistently stimulated during long-term potassium supplementation. The plasma concentrations of adrenaline and noradrenaline were significantly higher in hypertensive than in normotensive subjects and were not markedly altered by the dietary changes. It is concluded that long- but not short-term potassium supplementation lowers blood pressure in patients with essential hypertension. The antihypertensive effect may be mediated by potassium-induced natriuresis, by a stimulation of Na-K-ATPase secondary to increased plasma potassium levels, and/or by a modulation of the renin-angiotensin-aldosterone, kallikrein-kinin, and sympathetic nervous systems.Abbreviations MAP mean arterial pressure - Na-K-ATPase sodium-potassium ATPase - PRA plasma renin activity The study was supported in part by the Ministerium für Wissenschaft und Forschung, Nordrhein-Westfalen (FA-92/14)     

Increase in renin release after sionaortic denervation and cervical vagotomy.

The role of the vagi in the control of renin secretion was investigated in dogs maintained on a high-salt diet. Renal perfusion pressure was maintained relatively constant by the manipulation of a suprarenal aortic snare. Mean arterial blood pressure (MAP), plasma renin activity (PRA), and packed cell volume (PCV) increased after sinoaortic denervation and cervical vagotomy. Cooling of cervical vagi to 3-5 degrees C had the same effect as vagotomy. There was no change in MAP, PRA, and PCV in sham-operated animals. Propranolol prevented the increase in PRA following sinoaortic denervation and vagotomy, but not that in MAP or PCV. In splenectomized dogs, PCV still showed increases after sinoaortic denervation and vagotomy. It is suggested that the removal of sinoaortic and/or vagal inhibitory effects on the vasomotor center causes increases in sympathetic discharge to the adrenal medulla and the peripheral vessels, and that this in turn leads to the increase in MAP. The increase in sympathetic discharge to the adrenal medulla and the kidney causes the increases in PRA.     

Plasma K plus and insulin: changes during KCl infusion in normal and nephrectomized dogs.

Potassium chloride was administered by constant, intravenous infusion in splenectomized, but otherwise normal, dogs. The concentration of potassium, [K+], and of insulin, [insulin], in the arterial plasma was measured at frequent intervals. To assess the relative contributions of extrarenal and renal mechanisms toward the maintenance of normal plasma [K+], the results were compared with data obtained previously in splenectomized, nephrectomized dogs. During the infusion, plasma [K+] increased in the dogs with kidneys intact at a mean rate slightly less than that in the nephrectomized dogs. After the infusion was stopped, plasma [K+] declined to about 0.75 meq/liter above control values in both groups of animals. The results indicate the operation of both renal and extrarenal homoeostatic mechanisms. The renal mechanisms contributed measurably during the infusion of KCl, but not immediately after the infusion was stopped. Simultaneous measurements of plasma [K+] and plasma [insulin] indicate that insulin may be involved in the extrarenal homeostatic response.     

Alteration of renal baroreceptor by salt intake in control of plasma renin activity in conscious dogs

We investigated the relationship between renal arterial pressure (RAP) and systemic plasma renin activity (PRA) in five uninephrectomized conscious dogs on normal salt (80 meq Na+/day) and low salt (10 meq Na+/day) diets. The RAP was controlled by an inflatable cuff placed around the origin of the renal artery. In both salt states the PRA was an exponential function of the RAP: log (PRA) = (-0.026 X RAP) + 2 on the normal salt diet (r = 0.96) and log (PRA) = (-0.026 X RAP) + 2.5 on the low salt diet (r = 0.99). At any RAP, the value of the low salt PRA was 3 times that of the normal salt PRA. Accordingly, a reduction in salt intake increases the sensitivity of the renal baroreceptor so that the absolute value of PRA increases at any RAP, but the percentage change in PRA caused by any change in RAP is the same in both normal and low salt states.     

Pharmacological evidence for stimulation of growth hormone secretion by a central noradrenergic system in dogs

The role of brain catecholamines in the regulation of growth hormone secretion was investigated in pentobarbital-anesthetized dogs by using drugs which modify the function of adrenergic neurons and receptors. Intravenous administration of L-dopa produced a prompt, statistically significant increase in plasma growth hormone concentration. This response was not significantly reduced by blockade of peripheral dopa decarboxylase activity with carbidopa. Clonidine, an alpha-agonist which penetrates the brain, increased plasma growth hormone secretion. Norepinephrine, epinephrine, dopamine and isoproterenol, catecholamines which do not penetrate the blood-brain barrier, failed to affect plasma growth hormone concentration when administered intravenously. Apomorphine did not produce a statistically significant increase in plasma growth hormone concentration when administered directly into the the third ventricle, and pimozide failed to abolish the increase in plasma growth hormone produced by L-dopa. The increase in plasma growth hormone concentration produced by intravenous L-dopa and clonidine was prevented by administration of phentolamine or phenoxybenzamine directly into the third ventricle. The response to L-dopa was also abolished by intraventricular procaine. In dogs in which central beta-adrenergic blockade was produced by intraventricular L-propranolol, the growth hormone response to L-dopa was greater than it was in control dogs treated with intraventricular D-propranolol. The data indicate that in pentobarbital anesthetized dogs, the increase in growth hormone secretion produced by L-dopa is mediated by norepinephrine, rather than dopamine, that the site of action of the norepinephrine is central, above the median eminence and inside the 'blood-brain barrier', and that the norepinephrine acts via alpha-adrenergic receptors.     

Influence of renal nerves on renin secretion in the conscious dog

In order to evaluate the influence of renal nerves on renin secretion during changes in blood volume, we studied the mean arterial blood pressure (MAP) and the renal venous plasma renin activity (PRA) in 6 conscious dogs having one intact and one denervated kidney.After a passive head-up tilt PRA increased significantly in the vein of the intact kidney while it remained stable in the denervated one.The intravenous injection of Furosemide (3 mg/kg) induced a rapid elevation of PRA in both renal veins. The kinetics of the variations of renin secretion were similar in the two kidneys, but its magnitude was significantly lower in the denervated side.After a slow hemorrhage of 2, 4 and 6 ml/kg, MAP was unchanged and PRA increased in both renal veins but in a significantly lower degree in the denervated side. When blood loss reached 8 ml/kg, MAP decreased and PRA increased identically in the two renal veins.It was concluded that, in conscious dogs, the renal nerves could participate in the rapid adaptations of renin secretion during small changes in the circulating blood volume.     

Interaction of renal beta 1-adrenoceptors and prostaglandins in reflex renin release

Anesthetized dogs with isolated carotid sinus preparation were used to examine the mechanisms involved in the increase in renin secretion rate produced by carotid baroreceptor reflex renal nerve stimulation (RNS) at constant renal perfusion pressure. Lowering carotid sinus pressure by 41 +/- 5 mmHg for 10 min increased mean arterial pressure and heart rate, caused no or minimal renal hemodynamic changes, decreased urinary sodium excretion, and increased renin secretion rate. Metoprolol, a beta 1-adrenoceptor antagonist, given in the renal artery, did not affect the decrease in urinary sodium excretion but attenuated the increase in renin secretion rate, from 1,764 +/- 525 to 412 +/- 126 ng/min (70 +/- 8%). Indomethacin or meclofenamate, prostaglandin synthesis inhibitors, did not affect the decrease in urinary sodium excretion but attenuated the increase in renin secretion rate, from 1,523 +/- 416 to 866 +/- 413 ng/min (51 +/- 18%). Addition of metoprolol to indomethacin-pretreated dogs attenuated the increase in renin secretion rate from 833 +/- 327 to 94 +/- 60 ng/min (86 +/- 10%). These results indicate that reflex RNS at constant renal perfusion pressure results in an increase in renin secretion rate that is largely mediated by renal beta 1-adrenoceptors and is partly dependent on intact renal prostaglandin synthesis. The beta 1-adrenoceptor-mediated increase in renin secretion rate is independent of and not in series with renal prostaglandins.     

Effect of hypertonic saline infusion on renal vascular resistance in anesthetized dogs.

Changes in renal vascular resistance (RVR) and their mechanisms were investigated following infusion of 7.5% hypertonic saline (4 ml/kg) in anesthetized dogs. In all animals the left kidney was perfused at a constant perfusion flow (59 +/- 6 ml/min) with heparinized blood using a pulsatile roller pump. Renal perfusion pressure (RPP), systemic blood pressure (SBP), central venous pressure (CVP), and heart rate (HR) were measured simultaneously. Electrical stimulation of renal sympathetic nerves was also performed to evaluate the neurally mediated change in renal vasculature before and after infusion of hypertonic saline. In animals with intact vagi, intravenous administration of hypertonic saline resulted in significant increases in both mean blood pressure (MBP) and CVP, and caused significant decreases in HR and RVR. These effects were not affected by bilateral cervical vagotomy. In both intact and vagotomized animals, changes in RVR in response to renal nerve stimulation were attenuated after infusion of hypertonic saline. These results suggest that reduction in RVR after intravenous infusion of hypertonic saline is not a reflex effect mediated by vagal afferents. Instead, vascular response of the renal artery to hypertonic saline may result from a suppression of neurotransmission from renal sympathetic nerve endings to renal vascular smooth muscle.     

Effect of hypoxia on vascular responses to the carotid baroreflex.

The effect of systemic hypoxia on the vascular responses to the carotid baroreflex was studied in anesthetized, vagotomized, artificially ventilated dogs. One hindlimb, kidney, gracilis muscle, and paw were perfused at constant flow, and neurograms were obtained from renal sympathetic fibers. Bilateral carotid occlusions were performed while the animal was breathing a mixture of air and O2 (mean arterial PO2 = 106 mmHg) and again during ventilation with 10% O2 (PO2 = 40 mmHg). With occlusion, the average increase in mean aortic pressure was 36 mmHg greater during hypoxia than during normoxia and the increase in renal perfusion pressure was 87 mmHg greater; the increase in hindlimb perfusion pressure was identical in both situations. Hypoxia did not change the reflex response of the paw to carotid occlusion and increased that of the muscle vessels by only 10%; the increase in renal sympathetic activity averaged 56 plus or minus 10% more with hypoxia than with normoxia. When the carotid chemoreceptors were destroyed, the greater increase in aortic and renal pressure response to carotid occlusion during hypoxia as compared to normoxia was abolished. Thus systemic hypoxia markedly potentiates the reflex renal constriction caused by the baroreflex, and this effect is due to the carotid chemoreceptor afferent input.     

Renal blood flow distribution during E. coli endotoxin shock in dog

The effect of endotoxin on renal blood flow distribution was studied in anesthetized dogs. Renal blood flow was measured as hydrogen clearance by platinum electrodes placed in outer and in inner halves of cortex and by electromagnetic flowmeter. Intravenous injection of E. coli endotoxin, 3–5 mg/kg b. wt., promptly reduced arterial blood pressure (AP) and renal blood flow. After a transient increase for 45 min AP and renal blood flow declined to about 50% of the control 2½-3 h after injection. The reduction in outer cortical blood flow (OCF) was not significantly different from the reduction in inner cortical blood flow (ICF). The hematocrit (Hct) increased from 40.1±3.8% to 54.6±8%, but mean renal vascular resistance did not change. Total plasma protein concentration was not significantly elevated. A marked local flow variability was observed in some periods during the phase of shock with declining AP and total renal blood flow at high Hct. Thus renal blood flow showed phasic changes, but the OCF/ICF ratio was not changed during endotoxin shock. Local blood flow instability was observed periodically at high Hct.     

Arterial baroreceptors have minimal physiological effects on adrenal medullary secretion

The influence of arterial baroreceptors on secretion of catecholamines from the adrenal medulla was evaluated by several methods. Conscious mongrel dogs with surgically denervated hearts were hemorrhaged until an estimated 16% of their blood volume had been removed. On a separate day they were anesthetized and their blood pressure was lowered with intravenous nitroglycerin. Neither of these maneuvers produced appreciable increases in heart rate in these dogs. In contrast, in a group of sham-operated control dogs, hemorrhage induced a mean increase in heart rate of 20 beats/min (P less than 0.05), and nitroglycerin-induced hypotension induced an increase of 50 beats/min (P less than 0.05). In a separate group of conscious dogs with aortic arch denervation but intact cardiac nerves, occlusion of the common carotid arteries for 5 min increased blood pressure and heart rate significantly but elicited only small, insignificant increases in plasma epinephrine and norepinephrine; the peak concentration of epinephrine achieved was considerably less than the amount necessary to cause appreciable effects on blood pressure and heart rate as determined in another experiment by infusing varying amounts of epinephrine into conscious, cardiac-denervated dogs. We conclude that the arterial baroreceptor reflex, within the range of activity likely to occur during most physiological and pathophysiological adjustments in the conscious dog, exerts only minimal effects on the secretion of catecholamines from the adrenal medulla.