Norepinephrine Secretion Rate Research Articles

Effects of bradykinin on renal nerve stimulation-induced antidiuresis and norepinephrine overflow in anesthetized dogs.

We examined effects of bradykinin on antidiuresis and norepinephrine overflow induced by renal nerve stimulation (RNS) in anesthetized dogs, with or without blockade of the B2 receptor by Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) or the endogenous nitric oxide generation by N(G)nitro-L-arginine (NOARG), a nitric oxide synthase inhibitor. RNS (0.5-2.0 Hz) produced significant decreases in urine flow, urinary and fractional excretions of sodium, and increases in norepinephrine secretion rate (NESR), without affecting systemic and renal hemodynamics. Intrarenal arterial infusion of bradykinin (5 ng/kg per minute) significantly suppressed the RNS-induced antidiuresis and increase in NESR. Hoe 140 (100 ng/kg per minute) did not affect the RNS-induced renal actions, but in the presence of Hoe 140, bradykinin-induced suppressive actions on reductions in urine formation and increases in NESR in response to RNS were abolished. RNS during intrarenal arterial infusion of NOARG (40 microg/kg per minute) led to potent reductions in urine formation and decreased renal blood flow and glomerular filtration rate. Simultaneously, NESR was markedly increased. During NOARG infusion, bradykinin-induced decreases in renal actions elicited by RNS were markedly attenuated. These findings suggest that bradykinin suppresses the RNS-induced norepinephrine overflow and renal actions via nitric oxide production mediated by activation of B2 receptor. Renal noradrenergic neurotransmission may be inhibited by bradykinin at the prejunctional level, when its local production in the kidney is enhanced.

Interaction between norepinephrine release and intrarenal angiotensin II formation during renal nerve stimulation in dogs.

We examined possible interactions between intrarenal angiotensin II (ANG II) formation and norepinephrine (NE) release during renal sympathetic nerve stimulation (RNS) in anesthetized dogs. During 10 min of continuous RNS (1.5-2 Hz), the ANG II formation rates (ANG II-FR) and NE secretion rates (NE-SR) were determined at 1 and 10 min. Under control conditions, almost the same extent of increase in the NE-SR was observed at 1 and 10 min of RNS, whereas a significant increase in ANG II-FR was observed at 10 min but not at 1 min. During intrarenal arterial infusion of enalaprilat or losartan, the increase in NE-SR and reduction in renal blood flow at 10 min of RNS were suppressed, whereas the NE release and vasoconstriction responses at 1 min remained unaffected. The RNS-induced increases in ANG II-FR were completely abolished during infusion of enalaprilat. These results suggest that NE release on continuous RNS is enhanced by concomitantly formed ANG II, and this interaction depends on the time-related changes in intrarenal ANG II formation during RNS in the canine kidney.

Effects of FK409, a nitric oxide donor, on renal responses to renal nerve stimulation in anesthetized dogs

We examined the effects of (±)-( E)-4-ethyl-2-[( E)-hydroxyimino]-5-nitro-3-hexenamide (FK409), a nitric oxide (NO) donor, on renal actions and norepinephrine overflow induced by renal nerve stimulation in anesthetized dogs, with or without N G-nitro- l-arginine (NOARG), a NO synthase inhibitor. Renal nerve stimulation at a low frequency (0.5–2.0 Hz) produced significant decreases in urine flow and urinary excretion of Na + and increases in norepinephrine secretion rate. Renal nerve stimulation at a high frequency (2.5–5.0 Hz) which diminishes renal hemodynamics, elicited more marked decreases in urine formation and increases in norepinephrine secretion rate. Intrarenal arterial infusion of FK409 (0.25 μg/kg/min) failed to alter renal actions and increases in norepinephrine secretion rate in response to both low- and high frequency renal nerve stimulation. When NOARG (40 μg/kg/min) was administrated intrarenally, low-frequency renal nerve stimulation caused a potent antidiuresis and renal vasoconstriction. The renal nerve stimulation-induced increase in norepinephrine secretion rate was markedly enhanced by NOARG infusion. Simultaneous infusion of FK409 markedly attenuated the NOARG-induced enhancement of renal actions and increases in norepinephrine secretion rate, in response to low-frequency renal nerve stimulation. These results suggest that exogenous NO suppresses the renal nerve stimulation-induced norepinephrine overflow and renal actions in NO-depleted conditions. We also propose that endogenous NO functions tonically as an inhibitory modulator of renal noradrenergic neurotransmission.

Involvement of nitric oxide in endothelin ETB receptor-mediated inhibitory actions on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

We examined the effect of sarafotoxin S6c (S6c), a selective endothelin ETB-receptor agonist, on renal actions and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) in anesthetized dogs, with or without blockade of endogenous nitric oxide (NO) generation by NG-nitro-L-arginine (NOARG), a NO synthase inhibitor. RNS (0.5-2.0 Hz) produced significant decreases in urine flow, urinary and fractional excretion of sodium, and increased NE secretion rate, without affecting systemic and renal hemodynamics. When S6c (1 ng/kg/min) was infused intrarenally, there was a slight and transient increase in renal blood flow at 1-2 min after the start of the infusion, without any change in systemic hemodynamics and this response was followed by a gradual reduction. There was a significant increase in the basal level of urine flow with no effects on urinary and fractional excretion of sodium. In addition, S6c administration elicited an increase in urinary excretion of NO metabolites. NO2- and NO3-. During S6c infusion, RNS-induced antidiuretic action and increases in NE secretion rate were significantly attenuated. RNS during intrarenal arterial infusion of NOARG (40 micrograms/kg/min) led to potent reductions in urine formation and decreased renal blood flow and glomerular filtration rate. Simultaneously. NE secretion rate was markedly increased. In the presence of NOARG, S6c-induced suppressive actions on reductions in urine formation and increase in NE secretion rate in response to RNS were markedly attenuated. The peptide did not increase urinary excretion of NO metabolites. These findings suggest that ET functions as an inhibitory modulator of renal noradrenergic neurotransmission through ETB-receptor mechanisms, events that may be caused by NO production induced by the peptide.

Cilnidipine Attenuates Renal Nerve Stimulation-Induced Renal Vasoconstriction and Antinatriuresis in Anesthetized Dogs.

We examined the effects of cilnidipine, which is an L- and N-type Ca2+ channel blocker, on adrenergically regulated renal functions in anesthetized dogs. Renal nerve stimulation (RNS) at high frequency (3-7 Hz) decreased renal blood flow (RBF) without changes in systemic blood pressure. The RBF response was inhibited by intrarenal arterial (i.r.a.) infusion of cilnidipine at 0.1-0.3 microgram/kg/min. Low-frequency RNS (0.5-1 Hz) reduced absolute and fractional urinary sodium excretion. These responses were attenuated during i.r.a. infusion of cilnidipine at 0.3 microgram/kg/min. An increase in norepinephrine secretion rate induced by low-frequency RNS was also attenuated during cilnidipine infusion. These results suggest that cilnidipine can suppress norepinephrine release from the renal nerve endings and thereby interfere with the neural control of renal functions.

Inhibitory Effects of Endothelin-3 on Antidiuresis and Norepinephrine Overflow Induced by Stimulation of Renal Nerves in Anesthetized Dogs

The effects of endothelin-3 (ET-3) on changes in renal hemodynamics, urine formation, and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) were examined in anesthetized dogs. RNS at a low frequency (0.5-2.0 Hz) produced significant decreases in urine flow (UF), urinary excretion of sodium (UNaV), and fractional excretion of sodium (FENa), and increased the NE secretion rate (NESR) without affecting systemic or renal hemodynamics. RNS at a high frequency (2.5-5.0 Hz), which diminishes renal hemodynamics by causing renal vasoconstriction, affected urine formation and NESR more potently than did low-frequency RNS. When ET-3 (2.0 ng/kg/min) was infused into the renal artery, there was a slight and transient increase in renal blood flow (RBF); this response was followed by a gradual reduction. ET-3 infusion tended to increase the basal levels of UF without affecting UNaV, indicating the excretion of hypotonic urine with administration of this peptide. During ET-3 infusion, low-frequency RNS-induced antidiuretic action was significantly attenuated. Simultaneously, increase in NESR elicited by low-frequency RNS was markedly suppressed. Qualitatively similar results were observed in the case of high-frequency RNS. In addition, high-frequency RNS-induced decreases in the glomerular filtration rate (GFR) and the filtration fraction (FF) were suppressed by ET-3 infusion. These findings suggest that ET-3 suppresses renal responses to stimulated renal noradrenergic neurotransmission by inhibiting the release of NE. These findings, together with our previous findings, suggest that ET-3 (and/or ET-1) functions as an inhibitory modulator of the renal noradrenergic nervous system through the prejunctional ETB-receptor mechanism.

Effect of sodium nitroprusside on norepinephrine overflow and antidiuresis induced by stimulation of renal nerves in anesthetized dogs.

To investigate the role of nitric oxide (NO) in the regulation of renal sympathetic nerve activity and renal function, we examined the effect of sodium nitroprusside (SNP), a NO donor, on renal actions induced by renal nerve stimulation (RNS) in anesthetized dogs, with or without blockade of an endogenous NO generation by NG-nitro-L-arginine (NOARG), a NO synthase inhibitor. Low-frequency RNS (0.5-2.0 Hz) enhanced the rate of norepinephrine secretion rate (NESR) from the kidney and decreased urine flow (UF), urinary excretion of sodium (U(Na)V), and fractional excretion of sodium (FENa, without affecting systemic and renal hemodynamics. The intrarenal arterial infusion of SNP, in a dose (1 mu g/kg/min) that does not affect renal hemodynamics and urine formation at the basal level, significantly attenuated the RNS-induced decreases in UF, UNa V and FENa. The intrarenal administration of NOARG (40 mu g/kg/min) elicited renal vasoconstriction and reduced urine formation. RNS during NOARG administration reduced renal blood flow (RBF) and glomerular filtration rate (GFR) and augmented RNS-induced reduction in urine formation. Simultaneously, NESR was markedly enhanced. The renal actions observed with NOARG administration during control and RNS periods were almost completely abolished by treatment with SNP. Therefore, we suggest that NO plays an important role in the regulation of renal function. Endogenous NO probably functions as an inhibitory modulator of renal noradrenergic neurotransmission at the prejunctional level.

P-1059 - Effects of sarafotoxin S6c on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

We previously reported that endothelin (ET) may function as an inhibitory modulator of renal noradrenergic neurotransmission (Suzuki et al., J. Cardiovasc. Pharmacol. 19: 905–910, 1992). In our study, we examined the effect of sarafotoxin S6c (S6c), a selective ETB receptor agonist, on changes in renal function and norepinephrine overflow induced by renal nerve stimulation (RNS) in anesthetized dogs. RNS at a low frequency (0.5–2.0 Hz) caused significant decreases in urine flow, urinary excretion of sodium and fractional excretion of sodium and increased norepinephrine secretion rate, without affecting systemic and renal hemodynamics. RNS at a high frequency (2.5–5.0 Hz), which diminishes renal hemodynamics, produced more potent decreases in urine formation and increase in norepinephrine secretion rate than seen with low frequency RNS. When S6c (1 ng/kg/min) was infused intrarenally, there was a slight and transient increase in renal blood flow, and then this response was followed by a gradual reduction. S6c administration produced increase in the basal level of urine flow with no apparent effects on urinary excretion of sodium and fractional excretion of sodium. During S6c infusion, low frequency RNS-induced antidiuretic action and increase in norepinephrine secretion rate were markedly attenuated. Qualitatively, similar results were observed in the case of high frequency RNS. In addition, high frequency RNS-induced decreases in glomerular filtration rate and filtration fraction were significantly suppressed by S6c infusion. Taken together with our previous findings, it seems likely that ET plays an important role as an inhibitory modulator of renal noradrenergic neurotransmission, through ETB receptor mechanisms.

Effects of Endothelin-1 on Antidiuresis and Norepinephrine Overflow Induced by Stimulation of Renal Nerves in Anesthetized Dogs

The effects of endothelin-1 (ET-1) on renal function and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) were examined in anesthetized dogs, and comparisons were made with effects of Bay K 8644, a calcium channel agonist. RNS at a low frequency (0.5-2.0 Hz) produced significant decreases in urine flow and urinary excretion of sodium and increased NE secretion rates without influencing renal hemodynamics. RNS, at a high frequency of 2.5-5.0 Hz which diminishes renal hemodynamics, affected urine formation and NE secretion rate more potently than did low-frequency RNS. Intrarenal arterial infusion of ET-1 (1.0 ng/kg/min) decreased the baseline level of renal blood flow by 25% and that of urinary excretion of sodium by 54-69% but did not alter basal levels of NE secretion rate. During ET-1 infusion, low-frequency RNS-induced antidiuresis was observed to an extent similar to that seen without ET-1 infusion, whereas increase in NE secretion rate elicited by RNS was significantly inhibited by ET-1 infusion (45-65% of the values without ET-1 infusion). In addition, in the case of high-frequency RNS, ET-1 did not affect antidiuretic responses but did inhibit the increase in NE secretion rate by approximately 55%. In contrast, alterations in renal excretory responses and NE secretion rate elicited by RNS were not influenced by Bay K 8644 infusion (1.0 micrograms/kg/min), a dose that decreased renal blood flow to the same degree as did 1.0 ng/kg/min of ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal renin secretion rate and norepinephrine secretion rate in response to centrally administered angiotensin-II: role of the medial basal forebrain.

The influence that centrally administered angiotensin-II (ANG-II) and saralasin (SAR) has on renal norepinephrine secretion rate (NESR) and renal renin secretion rate (RSR) were studied. Rats were given thermal lesions of the medial basal forebrain (MBF) or sham surgery. Twenty-four hours later the right kidney was vascularly isolated (but neurally intact) and perfused with an artificial plasma at either a constant pressure (100 mm Hg) or constant flow (600 microliters/min). Renal perfusate was collected before (pre-injection) and at 10 min intervals after central administration of peptides for determination of NESR and RSR. In both perfusion models, intracerebroventricular (ICV) ANG-II increased renal NESR. In MBF lesioned rats pre-injection renal NESR is reduced and the response to ICV ANG-II is blocked. In both perfusion models ICV ANG-II decreases renal RSR. Concomitant administration of SAR blocks the effect of ANG-II on both NESR and RSR. MBF lesioned rats had significantly elevated pre-injection levels of RSR and there is no change in RSR following ICV ANG-II. These experiments indicate that centrally administered ANG-II increases renal NESR concomitant with a decrease in renal RSR and that MBF lesions block those changes.

The Role of Endogenous Angiotensin II in Antidiuresis and Norepinephrine Overflow Induced by Stimulation of Renal Nerves in Anesthetized Dogs

We examined the possible involvement of endogenous angiotensin II (ANG II) in norepinephrine (NE) overflow and antidiuresis induced by renal nerve stimulation (RNS). RNS at a frequency of 0.5-2.0 Hz, which did not influence renal hemodynamics, produced significant reductions in urine flow and urinary excretion of sodium, and elevations in NE secretion rate (NESR) and renin secretion rate (RSR). Intrarenal arterial (i.r.a.) infusion of phentolamine (10 micrograms/kg/min) abolished the RNS-induced antidiuresis. In dogs receiving captopril (15 micrograms/kg/min i.v.), RNS-induced antidiuresis and increase in NESR were significantly attenuated. The i.r.a. administration of propranolol at 5 micrograms/kg/min, a dose that inhibited completely the RNS-induced increase in RSR, did not influence the alterations in NESR and urine formation in response to RNS. During ANG II infusion (1 ng/kg/min i.r.a.), RNS produced a reduction in urine formation and an increase in NESR, at a magnitude similar to that seen without ANG II infusion. These results suggest that RNS at a low frequency increased the NESR and RSR without affecting renal hemodynamics and that the antidiuretic effect was probably produced via the activation of postsynaptic alpha-adrenoceptors, but not via the ANG II receptor, located on the renal tubules. The release of NE appears to be modulated by ANG II through the activation of a facilitatory prejunctional mechanism, which is maximally stimulated by endogenously and locally generated basal levels of ANG II.

Effects of adenosine on adrenergically induced renal vasoconstriction in dogs

The role of exogenous and endogenous adenosine in the neural control of renal blood flow was studied in anesthetized dogs. The plasma norepinephrine (NE) concentration was measured by high-performance liquid chromatography and the renal NE secretion rate was calculated. Renal nerve stimulation (1–3 Hz) reduced renal blood flow and increased NE secretion rate. The intrarenal arterial injection of NE (0.3–1.0 μg) also reduced renal blood flow. Infusion of adenosine (10–100 μg/min) into the renal artery attenuated the increase in NE secretion rate induced by renal nerve stimulation, but the nerve stimulation-induced decrease in renal blood flow was unaffected. On the other hand, adenosine potentiated the NE-induced renal blood flow response. Similar results were obtained with an adenosine potentiator, dipyridamole (1–10 μg/min). An adenosine receptor blocker, theophylline (0.3–1.0 mg/min), potentiated the NE secretion rate response induced by nerve stimulation, without any change in the renal blood flow response. The NE-induced renal blood flow response was attenuated by theophylline. These results suggest that adenosine inhibits neural NE release and enhances vasoconstriction in the dog kidney during sympathetic stimulation under in vivo conditions. These post- and presynaptic mechanisms may thus be activated by endogenous adenosine.

Splanchnic Nerve Stimulation Modulates Steroid Secretion in Hypophysectomized Dogs

To test whether or not splanchnic neural input to the adrenal gland affects secretion of steroids from the adrenal cortex, the thoracic splanchnic nerve was electrically stimulated in pentobarbital-anesthetized dogs after hypophysectomy and replacement with physiological concentrations of ACTH. An adrenal vein cannula was placed to permit measurement of cortisol, corticosterone, 11-deoxycortisol, epinephrine and norepinephrine secretion rates and adrenal blood flow. Plasma ACTH was measured and the presentation rate of ACTH was calculated as the product of plasma ACTH concentration and adrenal plasma flow. Dogs were infused initially with ACTH for 60 min at 2 ng/min followed by infusion for 60 min at 10 ng/min. Within each infusion period, the distal end of the nerve was stimulated (20 V; 0.5-ms pulse duration) at 4 and at 20 Hz for 10 min each. Nerve stimulation resulted in a frequency-dependent increase in mean arterial pressure, in epinephrine and norepinephrine secretion and in adrenal blood flow. Arterial ACTH remained constant during nerve stimulation; however, increased adrenal blood flow resulted in increased presentation rate of ACTH to the adrenal. Cortisol secretion increased in response to nerve stimulation at 4 and 20 Hz during infusion of 2 and 10 ng/min ACTH and occurred prior to changes in presentation rate of ACTH. Corticosterone secretion also increased after stimulation at both frequencies, but the response was observed only during infusion of 10 ng/min ACTH. In contrast, 11-deoxycortisol decreased after nerve stimulation at 4 Hz but showed no response after stimulation at 20 Hz during infusion of 2 and 10 ng/min ACTH.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory Effect of Cilazaprilat on Norepinephrine Release Induced by Renal Nerve Stimulation in Anesthetized Dogs

In pentobarbital-anesthetized dogs, the increase in the renal norepinephrine secretion rate elicited by renal nerve stimulation (1 Hz) during infusion of angiotensin I (15 ng/kg/min) was partially but significantly inhibited (by 21-37%) after dosing with cilazaprilat (0.1 mg/kg), an angiotensin converting enzyme inhibitor, accompanied by a decrease in the renal venous plasma norepinephrine concentration. These results may suggest that cilazaprilat exerts at least a part of its hypotensive effect through decreasing the facilitator/ action of endogenous angiotensin II on adrenergic transmission.

Role of prostaglandin in norepinephrine and renin release in canine kidney.

We investigated renin and norepinephrine (NE) release during electrical renal nerve stimulation (RNS) in relation to prostaglandin (PG) E2 concomitantly produced by the kidney in anesthetized dogs. During 10 min of continuous RNS (2.5-4 Hz), the increases in renin, NE, and PGE2 secretion rates were determined at 1 and 10 min after the start of stimulation. Under control conditions, almost the same extent of increase in the NE secretion rate was observed at 1 and 10 min of RNS, whereas the increase in renin secretion rate at 1 min of RNS was followed by a further increase at 10 min of RNS. On the other hand, an upward but not significant trend of increase in PGE2 secretion at 1 min of RNS was followed by a substantial level at 10 min of RNS. After administration of indomethacin, the increase in NE secretion rates at both 1 and 10 min of RNS were not altered, but the increase in renin secretion rate at 10 min of RNS was suppressed by approximately 50%, without any reduction of the increase in the renin secretion rate at 1 min of RNS. Consequently, the time-related change in the renin secretion rate during RNS was abolished. These results suggest that renin response to continuous RNS is enhanced by concomitantly generated PGs but not by NE, and furthermore, that endogenously generated PGs do not inhibit the release of NE from canine renal nerve endings.

Sympatho-adrenal medullary functions in response to intracerebroventricularly injected corticotropin-releasing factor in anesthetized rats

Effects of intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) on adrenal sympathetic efferent nerve activity, adrenal catecholamine secretion rate and cardiovascular function (i.e. blood pressure, heart rate and renal nerve activity) were investigated in halothane-anesthetized rats. Administration (i.c.v.) of CRF resulted in a dose-dependent increase (to 140% of control, for a 6.4 nmol dose) in adrenal sympathetic nerve activity which began several minutes after injection and reached maximum values approximately 30–60 min later. This increase was significant, when tested against vehicle injected controls, for doses of 6.4 nmol and 640 pmol; however, a 64 pmol dosage did not produce significant effects. Acute hypophysectomy did not influence the response of adrenal nerve activity to i.c.v. injection of CRF. Intravenous administration of CRF (6.4 nmol) did not produce any significant increases in ongoing activity of the adrenal nerve. Following i.c.v. administration of CRF (640 pmol), epinephrine and norepinephrine secretion, as measured from adrenal venous blood samples, showed a similar response pattern to that of the adrenal nerve. Significant increases (maximum increases, from 13.2 to 31.5 ng/kg/min and from 4.1 to 8.6 ng/kg/min for epinephrine and norepinephrine secretion rates, respectively) were observed over the 90 min blood sampling period. The present study demonstrates by direct recording of adrenal sympathetic nerve activity and measurement of adrenal catecholamine secretion rate, that i.c.v. administered CRF can increase adrenal sympathetic efferent nerve activity resulting in increases in catecholamine secretion. In addition, renal nerve activity also showed dose-dependent increases after CRF i.c.v. administration (to 160% of control, for a 6.4 nmol dose) as did heart rate (increases of 35 beats/min for a 6.4 nmol dose). However, blood pressure did not change with the same dose of CRF administered intracerebroventricularly, possibly as a result of direct effects of halothane upon peripheral blood vessels.

Sympathetic Adrenal Denervation Decreases Adrenal Blood Flow without Altering the Cortisol Response to Hemorrhage*

To test whether or not adrenal sympathetic innervation is required for the adrenocortical response to small hemorrhage, awake dogs were studied after unilateral adrenal sympathetic denervation. Bilateral adrenal vein cannulas were placed chronically to permit measurement of cortisol, epinephrine, and norepinephrine secretion rates and adrenal blood flow simultaneously from the intact and the denervated adrenal. Plasma ACTH concentration was measured and the presentation rate of ACTH was calculated as the product of plasma ACTH concentration and adrenal plasma flow. Unilateral isolation of the sympathetic chain from the spinal cord at thoracic levels 9-12 (T9-12) had no effect on adrenal blood flow, on the presentation rate of ACTH, or on cortisol secretion after 10 mg/kg hemorrhage. However, thoracic levels 9-12 denervation prevented the secretory response of catecholamines to hemorrhage without lowering basal catecholamine secretion. Unilateral splanchnicotomy, the sectioning of the thoracic and upper lumbar splanchnic nerves, reduced adrenal blood flow and the presentation rate of ACTH, suppressed basal catecholamine secretion, and prevented the catecholamine response to hemorrhage. However, there was no reduction in the secretory response of cortisol to 10% or 20% hemorrhage. These findings suggest that in the absence of sympathetic innervation to the adrenal, increases in adrenal sensitivity to ACTH occur to offset decreased ACTH presentation rate resulting in a normal cortisol response to hemorrhage. However, adrenal sensitivity to exogenous ACTH was not increased in non-hemorrhaged dogs after unilateral splanchnicotomy. Thus, hemorrhage must activate a non-ACTH mechanism that is independent of sympathetic adrenal innervation to augment adrenal sensitivity to ACTH. Sympathetic innervation to the adrenal has profound effects on catecholamine secretion and on adrenal blood flow but is not required for the secretory response of cortisol to small hemorrhage.

Elevated plasma norepinephrine concentrations in decompensated cirrhosis. Association with increased secretion rates, normal clearance rates, and suppressibility by central blood volume expansion.

Plasma norepinephrine concentrations are elevated in patients with decompensated cirrhosis, and correlate inversely with urinary sodium and water excretion. Increased plasma norepinephrine concentrations may result from a decreased metabolic clearance rate or an increased secretion rate, possibly in response to a decreased "effective arterial blood volume." If the latter hypothesis is correct, plasma norepinephrine might be expected to be suppressed when central blood volume is expanded by head-out water immersion. In the present study, plasma norepinephrine secretion and clearance rates were determined by infusion of tritiated norepinephrine. Norepinephrine secretion rates were elevated in eight cirrhotic patients as compared to control subjects (1.50 +/- 0.25 vs. 0.26 +/- 0.08 micrograms/m2 per min, P less than 0.001), whereas clearance rates were similar (3.13 +/- 0.48 vs. 2.60 +/- 0.28 liters/min, NS). Baseline plasma norepinephrine concentrations were markedly elevated in the cirrhotic patients (830 +/- 136 vs. 185 +/- 12 pg/ml, P less than 0.001). Head-out water immersion significantly suppressed plasma concentrations of both norepinephrine (704 +/- 72 to 475 +/- 70 pg/ml, P less than 0.005) and epinephrine (121 +/- 33 to 57 +/- 10 pg/ml, P less than 0.05) in all seven patients studied. We conclude that the high circulating catecholamine concentrations in cirrhosis are secondary to increased secretion, rather than to decreased metabolic clearance, and are suppressible by central blood volume expansion.

Norepinephrine secretion and production in diabetic autonomic neuropathy.

Orthostatic hypotension (OH) in patients with diabetic autonomic neuropathy may result from sympathetic neuronal dysfunction and inadequate norepinephrine (NE) release as patients shift from the supine to an upright posture. The biochemical basis for this physiological abnormality is not understood. We measured basal supine NE secretion and production in 10 diabetic patients with OH, 9 diabetic patients without OH, and in 13 age-matched normal subjects. Apparent NE secretion, the rate at which NE enters the bloodstream, was 1.22 +/- 0.24 (SEM) nmol/m2 X min in the diabetic patients with OH, significantly lower than in the diabetic patients without OH and normal subjects in whom apparent NE secretion rates were 2.27 +/- 0.48 and 1.86 +/- 0.12 nmol/m2 X min, respectively. NE production, estimated from integrated NE metabolite excretion, was 10.2 +/- 0.85 nmol/mg creatinine in the diabetic patients with OH, which was significantly lower (P less than 0.01) than that in the diabetic patients without OH and normal subjects in whom NE production was 14.8 +/- 1.8 and 16.9 +/- 1.2 nmol/mg creatinine, respectively. These data demonstrate that supine basal apparent NE secretion and NE production are decreased in patients with OH secondary to diabetic autonomic neuropathy.

Responses of adrenal sympathetic nerve activity and catecholamine secretion to cutaneous stimulation in anesthetized rats

Reflex effects of cutaneous mechanical stimulation on adrenal sympathetic efferent nerve activity and secretion rates of the adrenal medullary hormones (epinephrine and norepinephrine) were studied in anesthetized rats. Noxious pinching stimulation of the lower chest or hindpaw skin for 3 min produced proportional reflex increases in both the nerve activity and secretion rates of epinephrine and norepinephrine from the adrenal medulla in animals with an intact central nervous system. However, lower chest stimulation elicited a longer lasting response than hindpaw stimulation. 7–17 min vs 1 min after cessation of the stimulation, respectively. After spinal transection at the C1–2 level, only lower chest stimulation was capable of producing a reflex response, lasting 1 min after cessation of the stimulation. Contrary to the responses elicited by pinching, non-noxious brushing stimulation of the lower chest of hindlimb skin for 3 min in animals with an intact central nervous system produced proportional reflex decreases in nerve activity and epinephrine and norepinephrine secretion rates during the stimulation period only. Some slight increases in both nerve activity and secretion rates, lasting several minutes, followed cessation of the stimulation. However, in spinalized animals, non-noxious lower chest or hindlimb stimulation produced opposite effects, increasing both the nerve activity and secretion rates of epinephrine and norepinephrine. In spinalized animals lower chest brushing stimulation elicited a much stronger response than hindlimb brushing stimulation. It was concluded that: (1) the secretion of adrenal medullary hormones can he controlled reflexly by mechanical cutaneous stimulation through the central nervous system via adrenal sympathetic efferent nerves; (2) the excitatory effect of the cutaneo-adrenal medullary reflexes was independent of noxious or non-noxious stimulation at the spinal level, whereas in rats with an intact central nervous system the effect was either excitatory or inhibitory in response to noxious or non-noxious stimulation, respectively; (3) there is a marked segmental organization of this reflex at the spinal level which is modified into a generalized response through supraspinal central structures.