Jeffrey L. Osborn

Renal adrenoceptor mediation of antinatriuretic and renin secretion responses to low frequency renal nerve stimulation in the dog.

We evaluated renal adrenoceptor mediation of the renin secretion and antinatriuretic responses to low frequency (1.0 Hz) electrical stimulation of the renal nerves in the dog using renal a-adrenoceptor blockade with phentolamine {α-i/α-i), prazosin (α,), yohimbine (α2), and rauwolscine (α2), and β-adrenoceptor blockade with d,β-propranolol Oβ1//β2) and atenolol (β,). In all animals studied, renal blood flow and glomerular filtration rate remained constant throughout the experiment. In 11 dogs, low frequency renal nerve stimulation decreased urinary sodium excretion (119 ± 13 to 86 ± 18 μEq/min) and increased renin secretion (79 ± 22 to 348 ± 73 μg/ min). Renal arterial infusion of phentolamine (2–10 μg/kg per min) prevented the antinatriuresis but did not change the response of renin secretion (96 ± 46 to 412 ± 93 μg/min). In six dogs, renal arterial infusion of prazosin (0.7 μg/kg per min) similarly blocked the antinatriuretic but not the renin secretion responses to low frequency renal nerve stimulation. Renal arterial infusion of either yohimbine or rauwolscine did not affect the antinatriuretic or renin secretion responses to low frequency renal nerve stimulation. Intrarenal /S]-adrenoceptor blockade with low dose atenolol (0.5 μg/kg per min, n = 9) had no effect on the antinatriuretic responses to low frequency renal nerve stimulation (—47 ± 12 vs. —37 ± 8 μEq/min) but significantly decreased the increment in renin secretion during low frequency renal nerve stimulation (636 ± 249 vs. 305 ± 157 μg/ min; P < 0.05). Renal arterial infusion of d,β-propranolol (0.5 μgAg per min, n = 4) or a high dose of atenolol (5.0 μg/kg per min, n = 8) abolished the renin secretion but not the antinatnuretic responses to low frequency renal nerve stimulation. These results demonstrate that: antinatriuresis during 1.0 Hz renal nerve stimulation (where renal blood flow and glomerular filtration rate are unchanged) is mediated by renal oα-adrenoceptors and not by α2- or β-adrenoceptors, that renin secretion elicited by low frequency renal nerve stimulation is mediated by renal βi-adrenoceptors and not by a-adrenoceptors, and that the renin secretion response to low frequency renal nerve stimulation is evoked by direct stimulation of juxtaglomerular granular cell β-adrenoceptors and not indirectly by stimulation of the macula densa receptor through decreased urinary sodium excretion.

Effect of Renal Nerve Stimulation on Renal Blood Flow Autoregulation and Antinatriuresis During Reductions in Renal Perfusion Pressure

Abstract Renal nerve stimulation increases renal vascular resistance and decreases glomerular filtration rate and urinary sodium excretion. The purpose of this study was to determine whether neurally mediated changes in renal vascular resistance, glomerular filtration rate, and urinary sodium excretion at control renal perfusion pressure modified the autoregulation of renal blood flow and glomerular filtration rate and the antinatriuresis observed during reductions in renal perfusion pressure in pentobarbital-anesthetized dogs. Renal blood flow, glomerular filtration rate, and urinary sodium excretion were determined during stepwise reductions in renal perfusion pressure from 137 to 55 mm Hg (suprarenal aortic constriction) before and during electrical stimulation of the renal nerves at 0.5, 1.0, 2.0, and 4.0 Hz. In the absence of renal nerve stimulation, renal blood flow and glomerular filtration rate remained constant until renal perfusion pressure was reduced to 70 and 85 mm Hg, respectively. Urinary sodium excretion decreased linearly as renal perfusion pressure decreased. Renal nerve stimulation at 0.5, 1.0, 2.0, and 4.0 Hz increased renal vascular resistance and decreased glomerular filtration rate and urinary sodium excretion. These frequencies of renal nerve stimulation, however, did not alter the decreases in renal vascular resistance and glomerular filtration rate or the antinatriuretic response to stepwise reductions in renal perfusion pressure to 55 mm Hg. These data demonstrate that increased renal vascular resistance at either the afferent or efferent arteriole does not change the responses of these vessels to reductions in renal perfusion pressure. Renal nerve stimulation at frequencies which decrease urinary sodium excretion at control renal perfusion pressure also does not enhance the antinatriuretic response to reductions in renal perfusion pressure.

Influence of vasopressin and angiotensin on baroreflexes in the dog.

Cardiovascular responses to step-changes of carotid sinus pressure were evaluated at normal and elevated levels of plasma argjnine vasopressin in anesthetized neurohypophysec- tomized dogs (n = 12). Arginine vasopressin influenced autonomic function in two ways: first, maximum carotid reflex gain increased; second, cardiac output was decreased. The enhancement of reflex strength was observed only in response to decreases of intrasinus pressure below the equilibrium point (pressures of between 60 and 105 mm Hg). Aortic pressure rose twice as high for a given decrease of intrasinus pressure, elevations of total peripheral resistance responses were triple those observed at normal plasma arginine vasopressin. hi this way, arginine vasopressin more than doubled the ability of the carotid reflexes to return a drop in arterial pressure to normal. Arginine vasopressin enhancement of reflex gain was not observed with elevations of intrasinus pressures above the equilibrium point. Elevation of aortic pressure expected from the vasoconstrictor actions of infused arginine vasopressin were buffered by associated reductions in cardiac output. Vagally mediated bradycardia was consistently observed with elevated arginine vasopressin, but the reflex response of heart rate to step-changes of intrasinus pressure was unchanged. Time control studies in five neurohypophysectomuzed dogs indicated no significant change in carotid reflex response over the 3- to 4-hour protocol. Comparison of reflex responses in anephric dogs (n = 8) at low and elevated levels of angiotensin II indicated that this vasoactive peptide did not significantly alter reflex responsiveness. We conclude that arginine vasopressin enhances the ability of the carotid reflexes to normalize decreases of arterial pressure, but buffers a rise in pressure from its own vasoactive properties by initiating a fall of cardiac output.

Sympathetic Efferent Nerve Activity in Conscious and Isoflurane-anesthetized Dogs

The hypotension accompanying isoflurane suggests that the anesthetic produces an attenuation of sympathetic tone. Previous studies examining the effects of isoflurane on sympathetic efferent nerve activity have required concomitant use of a basal anesthetic or decerebration, both of which independently alter sympathetic activity. This study was performed to examine the effects of isoflurane on sympathetic efferent nerve activity in the absence of basal anesthetic or decerebration. Five mongrel dogs were anesthetized with 4% isoflurane by mask. Platinum electrodes chronically were implanted around a renal nerve adjacent to the renal artery in order to measure renal sympathetic efferent nerve activity in the conscious and anesthetized animal. After 5–24 h for recovery, renal nerve activity and arterial pressure (via an implanted femoral artery cannula) were measured in the conscious, resting animal (control); during induction (4% isoflurane) and intubation; in the anesthetized animal (1.5% and 2.5% isoflurane); and during recovery and extubation.Isoflurane produced a significant dose-dependent depression of arterial blood pressure but did not significantly change heart rate from control. Renal sympathetic efferent nerve activity at 1.5% isoflurane was not significantly different from that in conscious animals, but nerve activity at 2.5% isoflurane was depressed significantly from both control and 1.5% isoflurane. Both intubation and extubation were accompanied by an increase in sympathetic nerve activity. Isoflurane appeared to directly depress sympathetic activity at both levels of anesthesia, but the direct depression of activity at 1.5% isoflurane seemed to be countered by reflex increases in sympathetic tone due to the hypotension accompanying the anesthesia. At 2.5% isoflurane, the central depression of reflex activity by isoflurane combined with direct depression of sympathetic efferent activity resulted in the attenuation of renal nerve activity.

Forebrain osmotic regulation of the sympathetic nervous system.

1 Accumulating evidence in both humans and animals indicates that acute increases in plasma osmolality elevate sympathetic nerve activity (SNA). In addition, plasma hyperosmolality (or hypernatraemia) can produce sustained increases in SNA and arterial blood pressure (ABP) through stimulation of forebrain osmoreceptors. 2 Although an abundance of information exists regarding the osmoregulatory circuits for thirst and secretion of antidiuretic hormone, much less is known about those pathways and synaptic mechanisms linking osmotic perturbations and SNA. To date, the available evidence suggests that osmosensitive sites within the forebrain lamina terminalis, such as the organum vasculosum of the lamina terminalis, are key elements that link plasma hypertonicity to elevated SNA. 3 The major efferent target of osmosensitive regions in the forebrain lamina terminalis is the hypothalamic paraventricular nucleus (PVH). Evidence from a number of studies indicates that the PVH contributes to both acute and chronic osmotically driven increases in SNA. In turn, PVH neurons increase SNA through a direct vasopressinergic spinal pathway and/or a glutamatergic pathway to bulbospinal sympathetic neurons of the rostral ventrolateral medulla. 4 Future studies are needed to: (i) define the contribution of various osmosensitive regions of the forebrain lamina terminalis to acute and chronic osmotically driven increases in SNA; (ii) identify the cellular mechanisms and neural circuitry linking plasma osmolality and SNA; and (iii) define whether such mechanisms contribute to elevated SNA in salt‐sensitive hypertension.

Renal Neurogenic Mediation of Intracerebroventricular Angiotensin II Hypertension in Rats Raised on High Sodium Chloride Diet

Chronic elevation of sodium intake may affect the sensitivity of the central nervous system to intracerebroventricular (I.C.V.) angiotensin II (Ang II) infusion. Experiments were conducted to determine the influence of raising Sprague-Dawley rats from 2 to 3 weeks of age on low (5.0 mmol/L per kg food), normal (50 mmol/L per kg food), or high (250 mmol/L per kg food) NaCl diets on renal and cardiovascular responses to low-dose I.C.V. Ang II infusion. At 12 weeks of age, Sprague-Dawley rats were instrumented for chronic study, including brain lateral ventricular cannulation. Artificial cerebrospinal fluid was infused (0.25 microL/min I.C.V.) during control and recovery, whereas Ang II (20 ng/min) was infused for 5 days. During the experiment, respective sodium intakes were infused intravenously over 24 hours. In rats fed high sodium, control mean arterial pressure was 115+/-2 mm Hg and increased to 132+/-4 mm Hg by day 5 of I.C.V. Ang II infusion. This increase in arterial pressure was associated with significant (P<.05) decreases in sodium excretion, leading to the retention of 5.4+/-0.6 mmol/L total sodium over the 5 days of Ang II infusion. In rats raised on low and normal sodium intakes from weaning and in 10-week-old rats exposed to a high sodium diet for only 2 weeks, arterial pressure was not increased and sodium was not retained during I.C.V. Ang II infusion at 20 ng/min. In rats raised on the high sodium diet, bilateral renal denervation abolished the arterial hypertension and reduced the sodium retention over 5 days of I.C.V. Ang II infusion. Thus, chronic elevation of sodium intake increases the hypertensive response to low-dose I.C.V. Ang II infusion, which is dependent on intact renal nerves. We conclude that elevated postnatal NaCl intake enhances the pressor sensitivity of the brain to Ang II.

Renal nerves and the development of Dahl salt-sensitive hypertension.

Several experimental forms of hypertension require intact renal innervation for the development or maintenance (or both) of the elevated arterial pressure. We determined the relationships between urinary sodium and water excretion and arterial pressure in Dahl salt-sensitive rats (DS) with innervated (n = 6) and denervated (n = 7) kidneys after switching from a low to a high sodium diet. Arterial pressure significantly increased in both groups within 48 hours after they began to eat an 8% sodium chloride diet. This hypertension increased to 188 +/- 9 and 190 +/- 7 mm Hg, respectively, in rats with innervated and denervated kidneys after 12 days. Mean arterial pressures were not significantly different between groups on any day. The rise in arterial pressure of DS placed on a high sodium intake was associated with an elevation of urine flow rate and urinary sodium excretions in rats with either innervated or denervated kidneys. Urine flow rates and urinary sodium excretions were greater in denervated than in innervated rats on Days 4 through 7 after beginning the high sodium diet. This diuresis and natriuresis in rats with denervated kidneys were associated with greater water and sodium intakes on Days 4 to 7 of the high sodium diet when compared with rats with innervated kidneys. These results demonstrate that, following exposure to a high sodium intake, DS have increased arterial pressure within 24 hours. The development of this arterial hypertension is not dependent on intact renal innervation. In conscious DS, the renal innervation does participate in the regulation of urinary sodium excretion by promoting renal sodium and water reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Motor activity and transit in the autonomically denervated jejunum

The role of extrinsic (autonomic) innervation in postprandial contractile activity of the small intestine is unknown. Using a canine model, we investigated the effects of complete extrinsic denervation on the parameters of fasting and postprandial jejunal contractions and their relationship to intestinal transit. Individual contractions were recorded using strain gauge transducers. Spatial and temporal parameters of contractions were analyzed by computer methods. Bolus injection of 14C-polyethylene glycol was used to calculate intestinal transit rates. Statistical comparisons of control and denervated animals were made by nonparametric tests. Extrinsic denervation did not abolish fasting or fed motor activity, but the following effects were observed: (1) the frequency of migrating motor complexes (MMCs) increased; (2) the onset of fed motor activity was delayed, and the duration of fed activity was shortened; (3) frequency, mean amplitude, and mean area of postprandial contractions were decreased; (4) fewer contractions propagated distally, and mean propagation distance was shortened; and (5) intestinal transit was slower for solids, but not for liquids. In the small intestine, extrinsic nerves modulate motor activity, which is under primary control of the intrinsic (enteric) nervous system.

The renal handling of 2,4,5-trichlorophenoxy-acetic acid (2,4,5-T) in the dog

Abstract The herbicide 2,4,5-T is actively transported by renal cortical slices of dogs and rats, suggesting that the compound should be rapidly eliminated from the body via the kidneys. The prolonged plasma half-life of 2,4,5-T in the dog (77 hr) indicates that factors other than secretion into the urine are important determinants of elimination in the dog. This study was designed to determine the renal handling of 2,4,5-T in anaesthetized dogs, and an attempt was made to increase excretion of the herbicide with sodium acetate. Injection of 2,4,5-T decreased clearance of p -aminohippurate in a dose-dependent manner, suggesting that the compound was actively secreted. The clearance of the herbicide, however, was exceedingly low, being less than 1% of inulin clearance. The clearance of 2,4,5-T was increased by sodium acetate and by acetazolamide. Additional studies with mannitol, sodium bicarbonate and ammonium chloride demonstrated that clearance of 2,4,5-T was related to urinary pH, but only when the pH exceeded 6, and was not affected by changes in urine volume. Addition of plasma inhibited the transport of 2,4,5-T by renal cortex slices in vitro , suggesting that the low clearance in vivo was due to very tight binding of the herbicide to plasma protein.

Control of renin release. Effects of d-propranolol and renal denervation on furosemide-induced renin release in the dog.

We determined the effects of </-propranolol and renal denervation on furosemide-induced renin release in the anesthetized dog. rf-Propranolol possesses only membrane-stabilizing properties, whereas the /-isomer produces beta adrenergic blockade. To separate the vascular and macula densa mechanisms of the juxtaglomerular apparatus effectively, nonfiltering kidneys were produced by combining 2.5 hours of renal ischemia with ureteral ligation. In some dogs, renal denervation was accomplished by relocating the nonfiltering kidney into the neck during the 2.5-hour ischemic interval. Administration of d-propranolol in a priming dose of 1 mg/kg, iv, followed by an intravenous infusion of 1 mg/kg per hour decreased renin release in both the filtering and nonfiltering kidney. Subsequent furosemide injection (5 mg/kg, iv) failed to increase renin release in the nonfiltering kidney. Similarly, after the infusion of lidocaine into the renal artery of the nonfiltering kidney (1 mg/kg per hour), furosemide did not alter renin release. In the denervated nonfiltering kidney, furosemide in a dose of 5 mg/kg, iv, increased renin release and decreased renal resistance. Treatment with dor rf,/-propranolol decreased renin release in five out of six denervated nonfiltering kidneys. Following propranolol, furosemide failed to increase renin release. These results demonstrate that the ability of </,/-propranolol to decrease renin release may be due partially to the membranestabilizing activity of the rf-isomer. Stimulation of renin release by furosemide occurs at both the vascular and macula densa sites which may act independently in the control of renin release. The data demonstrate that, whereas renal sympathetic innervation may modulate renin release under a variety of circumstances, this innervation is not an absolute requirement for renin release at the juxtaglomerular apparatus.