Central kappa opioids blunt the renal excretory responses to volume expansion by a renal nerve-dependent mechanism.

Central administration of kappa opioids produce significant alteration in the renal excretion of sodium and water under basal conditions. To determine whether enhanced central kappa opioid activity alters the renal handling of sodium and water to an integrated physiological stimuli, we compared the renal excretory responses produced by acute i.v. isotonic saline volume expansion in conscious Sprague-Dawley rats pretreated with i.c.v. isotonic saline vehicle or the selective kappa opioid agonist, U-50488H. In vehicle-treated animals, isotonic saline volume expansion produce an increase in urine flow rate and urinary sodium excretion and a decrease in efferent renal sympathetic nerve activity. In comparison with these control responses, isotonic saline volume expansion produced a similar magnitude change in urine flow rate in rats pretreated i.c.v. with U-50488H. In contrast, the natriuretic response produced by the isotonic saline load was markedly blunted in these central kappa opioid-treated animals. Moreover, the sympathoinhibitory response characteristically produced by the isotonic saline volume expansion was completely prevented in animals receiving i.c.v. U-50488H. To elucidate further the role of the renal nerves in mediating this central kappa opioid-induced renal excretory response, these studies were repeated in chronic bilaterally renal denervated rats. The results of these studies demonstrated that bilateral renal denervation restored the capacity of i.c.v. U-50488H-pretreated rats to maximally excrete the sodium load. Together, these studies demonstrate that, in conscious Sprague-Dawley rats, increased central kappa opioid activity significantly blunts the natriuretic response to isotonic saline volume expansion by a renal nerve-dependent mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of endogenous central opioid mechanisms in maintenance of body sodium balance.

The role of endogenous central opioids in the regulation of renal function was studied in Sprague-Dawley rats. In metabolism studies, changes in sodium balance were examined during normal dietary sodium intake (days 1-7; Na+ of 174 meq/kg) and sodium restriction (days 8-14; Na+ of 4.0 meq/kg). The influence of endogenous central opioids was investigated by repeating the protocol in the same rats during intracerebroventricular infusion of the opioid antagonist naltrexone methylbromide (NMBR). Intracerebroventricular NMBR did not alter sodium balance in rats fed normal sodium chow. In contrast, on low-sodium days 8 and 9, rats exhibited a more negative sodium balance during intracerebroventricular NMBR (day 8; -1,191 +/- 37 mu eq) compared with respective predrug control levels (day 8; -641 +/- 39 mu eq). Subcutaneous NMBR did not alter renal adaptation to sodium restriction. Thus central opioids are not involved in the maintenance of sodium balance during normal sodium intake. However, when dietary sodium is restricted, central opioid pathways are activated as a mechanism to maximally retain sodium.

Central kappa opioid receptor-evoked changes in renal function in conscious rats: participation of renal nerves.

The present investigations examined the cardiovascular and renal responses produced by central nervous system stimulation of kappa opioid receptors by the selective kappa opioid receptor agonist, U-50488H, in conscious Sprague-Dawley rats. Administration of U-50488H (1 microgram total) into the lateral cerebroventricle produced a profound diuretic and antinatriuretic response. In addition, concurrent with the decrease in urinary sodium excretion, i.c.v. U-50488H elicited an increase in renal sympathetic nerve activity. The increases in urine flow rate and renal sympathetic nerve activity and the decrease in urinary sodium excretion produced by U-50488H were completely prevented in rats that had undergone pretreatment with the selective kappa opioid receptor antagonist, nor-binaltorphimine. In contrast, in animals that had undergone irreversible mu opioid receptor blockade with the selective mu opioid receptor antagonist, beta-funaltrexamine, central U-50488H administration elicited similar diuretic and antinatriuretic responses as observed in intact naive animals. In further studies, the antinatriuretic response produced by i.c.v. U-50488H was completely abolished in rats that had undergone chronic bilateral renal denervation, a technique used to remove the influence of the renal sympathetic nerves. Glomerular filtration rates and effective renal plasma flows were not altered by i.c.v. administration of U-50488H in intact or renal denervated animals. Together, these studies provide evidence for the role of central kappa opioid receptor mechanisms in the regulation of urinary sodium and water excretion. Moreover, these studies indicate that the changes in renal sodium handling produced by central kappa opioid agonists result from an action of these compounds to modulate sympathetic neural outflow to the kidneys.

Central mu opioid receptor-mediated changes in renal function in conscious rats.

Studies were performed in conscious Sprague-Dawley rats to determine whether the renal sympathetic nerves contribute to the renal excretory responses produced by central mu opioid agonist administration. Intracerebroventricular, but not i.v. injection of the selective mu opioid agonist dermorphin (0.1 nmol/kg), produced an increase in urine flow rate and a sustained decrease in urine sodium excretion. These renal excretory responses were completely prevented by pretreatment with the selective mu opioid antagonist, beta-funaltrexamine (20 micrograms, i.c.v.). Central dermorphin administration did not alter glomerular filtration rate or effective renal plasma flow. In contrast, efferent renal sympathetic nerve activity increased over the same time frame as the reduction in urinary sodium excretion. To investigate whether the dermorphin-induced antinatriuretic response was mediated via the increase in renal sympathetic nerve activity, experiments were repeated in Sprague-Dawley rats that had undergone chronic bilateral renal denervation. In renal denervated rats, i.c.v. dermorphin produced similar diuretic and antinatriuretic responses as were seen in rats with an intact renal innervation. Together, these studies indicate that the changes in urine flow rate and urinary sodium excretion produced by i.c.v. dermorphin were not mediated via central induced changes in renal hemodynamics or sympathetic outflow to the kidneys. Because an antinatriuretic response occurred in renal denervated animals, this suggests that central mu opioid receptor agonists may exert an influence on tubular reabsorption of sodium via mu opioid receptor-mediated mechanisms independent of intact renal innervation.

Increased glucose uptake by intestinal mucosa and muscularis in hypermetabolic sepsis.

The purpose of the present study was to determine the following: 1) whether the sepsis-induced increase in glucose uptake was a generalized response along the entire length of the gastrointestinal tract; 2) the relative contribution of the mucosa and muscularis to the enhanced uptake; and 3) whether reducing intestinal blood flow would attenuate the elevated rate of glucose uptake. Hypermetabolic sepsis increased in vivo glucose uptake in all sections of the gastrointestinal tract (57-93%) except the stomach. The rates of glucose uptake per gram of tissue by the mucosa and muscularis were not different. However, because the mucosa accounted for the majority of the whole intestine mass, this layer was responsible for 76-78% of the glucose uptake by the entire small intestine. Intestinal blood flow, determined with the use of radiolabeled microspheres, increased by 127% in sepsis. In both groups, approximately 70% of the total intestinal blood flow was distributed to the mucosa. Somatostatin was infused to produce splanchnic vasoconstriction and decreased the sepsis-induced increment in intestinal flow to the mucosa and muscularis (38 and 54%), whereas the enhanced rate of glucose uptake was not altered. Somatostatin also produced a severe insulinopenia. These results indicate that hypermetabolic sepsis increases glucose uptake to a similar extent along the length of the small and large intestine and that the majority of this increase is due to an enhanced uptake by the mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of changing extracellular potassium concentration on synaptic transmission in isolated spinal cords.

Hemisected spinal cords of infant mice were exposed in vitro to varying concentrations of K+ in the bathing fluid. Interstitial potassium concentration ([K+]o) as well as dorsal and ventral root (DR and VR) potentials evoked by DR stimulation were recorded. [K+]o in spinal tissue was made to change from its control level of 3.5 mM by superfusing the preparation with modified artificial cerebrospinal fluid (ACSF). [K+]o in tissue followed bath [K+] in the range from 2.0 to 13 mM, but diverged from bath concentration at levels at or below 1.0 mM. Relatively high tissue [K+]o during exposure to low bath [K+] was attributed to leakage of K+ ions from cells. Between 2.0 and 5.0 mM [K+]o a shallow but consistent positive correlation was found between [K+]o and dorsal root reflex (DRR) amplitude, while segmental reflex (VRR) amplitude changed little. Outside the range of 2.0-5.5 mM DR and VR responses were severely depressed in both elevated and lowered [K+]o. In spite of depressed reflex responses, transient stimulus-evoked elevations of [K+]o were strikingly increased when the resting [K+]o fell below 2.0 mM, suggesting enhancement of voltage-dependent K+-current.