Apparent absence of direct renal effect of imidazoline receptor agonists.

Imidazoline receptor agonists such as moxonidine and rilmenidine increase sodium excretion whether administered within the central nervous system, intravenously, or directly into the renal artery. To determine if this natriuresis was mediated by a direct renal effect and was independent of the renal sympathetic nerves, we used two different preparations in the pentobarbital-anesthetized rat. In the first series of studies, rats were unilaterally nephrectomized 7 to 10 days before the experiment. On the day of the experiment, the remaining kidney was denervated (surgical and 10% phenol/ 95% ethyl alcohol) or sham treated. The effect of an intravenous infusion of rilmenidine was determined. Rilmenidine (10 nmol/kg/minute) decreased blood pressure and increased urine flow rate and sodium excretion in the sham- but not the denervation-treated rats. The response to furosemide (5.05 nmol/kg/minute) remained intact following denervation. We then used a two-kidney rat model that allowed for separate urine collection from each ureter. We used low infusion rates of moxonidine directly into the left renal artery. An increase in urine flow rate from the left but not the right kidney would suggest a direct renal action. Low infusion rates of moxonidine (10, 30 nmol/kg/minute) increased urine flow rate similarly from both ureters. A low infusion rate of furosemide (9.1 nmol/kg/minute) into the left renal artery increased urine flow rate only from the left ureter. The failure of moxonidine to increase urine flow rate selectively only in the left kidney indicated the agonist acts at an extrarenal site to increase urine flow rate from both kidneys equally. The complete attenuation of the response to rilmenidine indicates the importance of the renal nerves and suggests that the extrarenal site is most probably the central nervous system. Collectively, these studies do not support a direct renal action of imidazoline agonists in producing natriuresis.

Intrahepatic adenosine triggers a hepatorenal reflex to regulate renal sodium and water excretion.

The mechanism for water and sodium retention in liver cirrhosis is related to the disturbance in hepatic portal circulation. We hypothesize that the increases in intraportal adenosine, which occur when the portal blood flow decreases, may trigger the hepatorenal reflex to inhibit renal water and sodium excretion. In anesthetized rats, intravenous vs. intraportal adenosine-induced effect on renal water and sodium excretion was compared in normal animals and animals with hepatic or renal denervation, and in the presence of an adenosine receptor antagonist. Compared to saline infusion, intraportal adenosine (0.02 mg kg(-1) min(-1) for 1 h) infusion decreased urine flow by 51.3% (11.7 +/- 2.3 vs. 5.7 +/- 0.5 microl min(-1)) for the first 30 min and by 49% (22.8 +/- 5.4 vs. 11.6 +/- 1.5 microl min(-1)) for the second 30-min duration. Urinary sodium excretion was also decreased. Intraportal administration of an adenosine receptor antagonist (8-phenyltheophylline (8-PT), 3 mg kg(-1) bolus injection followed by 0.05 mg kg(-1) min(-1) continuous infusion), as well as liver or kidney denervation, abolished adenosine-induced inhibition. In contrast, intravenous adenosine infusion had no influence on either urine flow or sodium excretion. The data indicated that selectively increased intraportal adenosine inhibited renal water and sodium excretion. The water and sodium retention commonly seen in the hepatorenal syndrome may be related to intraportal adenosine accumulation due to the decrease in intraportal portal flow.

Regulation of aquaporin-2 expression by the alpha(2)-adrenoceptor agonist clonidine in the rat.

Aquaporin-2 (AQP-2), the major water channel responsible for water balance, has been shown to be regulated by the binding of vasopressin to V(2) vasopressin receptors in the medullary collecting duct. alpha(2)-Adrenoceptor agonists such as clonidine have been associated with an increase in free water clearance that was secondary to an inhibition of the ability of vasopressin to increase cAMP levels in the collecting ducts. This investigation focused on the possibility that this increase in free water clearance following administration of an alpha(2)-adrenoceptor agonist was associated with a reduction in medullary AQP-2 expression. In the anesthetized rat, clonidine increased urine flow rate (32+/-5 versus 137+/-16 microl/min, p<.05) and free water clearance (-58+/-6 versus 3+/-8 microl/min, p<.05) compared with the group receiving the saline vehicle infusion. The increase in free water clearance with clonidine administration was associated with a reduction in whole kidney AQP-2 mRNA levels (282+/-25 versus 216+/-11 A units, p<.05). This decrease in water reabsorption was associated with a redistribution of AQP-2 away from the luminal membrane of the medullary collecting duct to the cytosol. These effects were not secondary to changes in serum vasopressin levels, as these were similar in the vehicle control and clonidine groups (59+/-5 pg/ml versus 64+/-7 pg/ml, p = NS). The rapid redistribution of AQP-2 and the reduction in AQP-2 mRNA following clonidine administration are consistent with the hypothesis that the alpha(2) adrenoceptor regulates water excretion at least in part by effects on AQP-2.

Peripheral and central imidazoline receptor-mediated natriuresis in the rat.

On the basis of both radioligand and functional studies, the existence of a novel receptor that was unique from the alpha 2-adrenoceptor has become evident. Our initial studies contrasted the function of I1 imidazoline receptor agonists with that of purported alpha 2-adrenoceptor agonists in the kidney. The mechanism by which urine flow increased (osmolar vs free water clearance) as well as the effects of idazoxan, rauwolscine, a V2 vasopressin receptor antagonist, indomethacin pretreatment, and one-kidney one clip hypertension in rats were different following moxonidine when compared to an alpha 2-adrenoceptor agonist. This indicated two separate receptor systems. Subsequent studies determined that i.c.v. administration of moxonidine would also increase the urine flow rate by increasing osmolar clearance. This response to i.c.v. moxonidine differed from the response of an alpha 2-adrenoceptor agonist administered i.c.v.. Moreover, this effect of i.c.v. moxonidine was unique from that observed following the intrarenal infusion of moxonidine (Fig. 2). Denervation, intravenous prazosin, and i.c.v. idazoxan selectively blocked the effects of i.c.v. moxonidine. Intravenous idazoxan selectively blocked the response to intrarenal infusion of moxonidine. On the basis of the response to i.c.v. moxonidine in SH rats, the site(s) and/or receptor(s) responsible for blood pressure lowering were altered and those for increasing sodium excretion appear to be inactive. The significance of the findings in long-term regulation of blood pressure remain to be determined.

In vivo analysis of amantadine renal clearance in the uninephrectomized rat: functional significance of in vitro bicarbonate-dependent amantadine renal tubule transport.

Amantadine transport into renal proximal and distal tubules is bicarbonate dependent. In the present study, we addressed the effects of bicarbonate on renal clearance and urinary excretion of amantadine. Renal clearance of kynurenic acid was also studied to determine whether bicarbonate effects are specific for organic base transport by the kidney. After a moderate diuresis was established, animals received i.v. [(3)H]amantadine or [(3)H]kynurenic acid followed by an acute dose of sodium bicarbonate or physiological saline. Urine and blood samples were analyzed for [(3)H]amantadine or [(3)H]kynurenic acid, blood gases, and pH. Amantadine and kynurenic acid were excreted by the kidneys, and both compounds underwent renal tubular secretion. Amantadine metabolism occurred, and one metabolite was detected in the urine. In the bicarbonate-treated rats, the total amount of amantadine excreted in the urine was decreased, whereas the amount of metabolite recovered was similar in both groups. Bicarbonate treatment caused a sustained increase in blood bicarbonate levels, a mild increase in blood pH, and a decrease in amantadine renal clearance and in the amantadine/creatinine clearance ratio. Only a transient decrease in the renal clearance of kynurenic acid and the kynurenic acid/creatinine clearance ratio was observed. This study demonstrates that short-term changes in bicarbonate concentration may have significant effects on renal organic cation elimination. Coupled with our previous in vitro demonstration of bicarbonate-dependent organic cation transport, the present study suggests that bicarbonate inhibition of renal tubule organic cation secretion may explain the previous observation that bicarbonate dosing decreases amantadine excretion by the kidney.

Imidazoline receptor mediated natriuresis: central and/or peripheral effect?

The ability of imidazoline agonists, such as moxonidine and rilmenidine, to lower blood pressure has been attributed to a central effect resulting in a decrease in peripheral sympathetic nerve activity. A similar decrease in sympathetic nerve activity to the kidney has been proposed to explain the increase in sodium excretion. The observed increase in sodium excretion following an intrarenal infusion of moxonidine or rilmenidine suggested the existence of a direct renal action. We therefore tested the hypothesis that direct renal infusions were acting at a central rather than a peripheral site. Thus, interventions which would decrease the natriuretic effects of central administered moxonidine would also block the effects of intrarenal administered moxonidine. Studies were performed in anesthetized Sprague-Dawley rats (280-320 g) which had undergone unilateral nephrectomy 7 to 10 days prior to the experiment. The interventions utilized resulted in minimal effects on blood pressure and creatinine clearance. Intracerebroventricular (icv) or intrarenal (ir) administration of moxonidine produced a significant increase in urine flow rate and sodium excretion. Intravenous (iv) prazosin was used to block the ability of the sympathetic nerves to alter sodium excretion secondary to alpha1-adrenoceptor stimulation. Prazosin prevented the natriuresis following icv moxonidine but only partially antagonized the effects of ir moxonidine. To determine if central imidazoline receptors mediated the effects of moxonidine, animals were pretreated with icv idazoxan. Following icv idazoxan, the effects of icv moxonidine were blocked, whereas the response to intrarenal moxonidine was only partially blocked. Peripheral (iv) administration of idazoxan blocked the actions of intrarenal moxonidine but left the response to icv moxonidine intact. Finally, chemical sympathectomy with reserpine did not alter the response to intrarenal moxonidine suggesting that this effect was independent of the sympathetic nervous system. In conclusion, these studies indicate the ability of central and peripheral moxonidine to increase urine flow rate through sodium excretion at two unique sites of action, one central and the other one peripheral, most conceivably within the kidney.

Renal alpha 2a/d-adrenoceptor subtype function: Wistar as compared to spontaneously hypertensive rats.

1. The alpha 2a/d-adrenoceptor subtype in the rat kidney modulates solute excretion (osmolar clearance). Since the kidney plays a role in chronic regulation of blood pressure, altered renal function may be implicated in the development of hypertension. A second alteration-that of the alpha 2a/d-adrenoceptor subtype gene-has also been correlated with hypertension in rats and man. 2. We hypothesized that as a consequence of the altered alpha 2a/d-adrenoceptor subtype gene previously shown in spontaneously hypertensive (SH) rats, the increase in osmolar clearance following stimulation of the renal alpha 2a/d-subtype would be attenuated in SH rats as compared to normotensive Wistar rats. In contrast, based on the theory that such functional unresponsiveness of the alpha 2a/d-subtype would be genetically determined, we further hypothesized that in one kidney-one clip (1K-1C) rats, the response to stimulation of the renal alpha 2a/d-subtype would be intact as compared to the normotensive Wistar 1K-sham rats. 3. Male rats were unilaterally nephrectomized under ether anaesthesia. In the 1K-1C rats, a silver clip (diameter 0.254 mm) was also placed around the left renal artery. On the experimental day, rats were administered pentobarbitone (50.0 mg kg-1, i.p.). The carotid artery and jugular vein were cannulated for blood pressure monitoring and saline infusion. The ureter was catheterized for urine collection. A 31 gauge needle was advanced into the renal artery for infusion of the alpha 2a/d-selective agonist, guanfacine (vehicle, 1.0, 3.0 and 10.0 nmol kg-1 min-1 in Wistar and SH rats; vehicle and 10.0 nmol kg-1 min-1 in Wistar 1K-sham and 1K-1C rats). 4. In Wistar rats, guanfacine dose-dependently increased urine flow and sodium excretion. An increase in osmolar clearance but not free water clearance was also observed. However, in SH rats guanfacine failed to alter urine flow, sodium excretion, osmolar and free water clearance. In contrast, in both Wistar 1K-sham and 1K-1C rats, guanfacine increased urine flow rate. Again, this response was due solely to an increase in osmolar clearance. At these doses, guanfacine did not alter blood pressure or creatinine clearance during the experiment. 5. In summary, the ability of the alpha 2a/d-adrenoceptor subtype to mediate an increase in osmolar clearance was absent in a genetic model of hypertension, the SH rats. This effect was intact in an acquired model of hypertension (1K-1C rats). This suggested a defective modulation of solute excretion in SH rats which was probably due to alteration of the alpha 2a/d-subtype gene and not secondary to the elevated blood pressure. The altered alpha 2a/d-subtype gene and function may therefore play a causal role in the pathogenesis of hypertension.

Alpha-2a/d adrenoceptor subtype stimulation by guanfacine increases osmolar clearance.

We have previously demonstrated that the osmolar and free water responses to an intrarenal infusion of clonidine could be dissociated pharmacologically into naltrexone-sensitive and prazosin-sensitive responses, respectively. These results supported the notion that two distinct alpha-2 adrenoceptor sites were mediating the effects of clonidine. The ability of prazosin to selectively block the increase in free water clearance suggested the involvement of the alpha-2b subtype. Based on the identification by others of only the alpha-2a/d and alpha-2b subtypes in the rat kidney, the osmolar response was, by deduction only, speculated but not proven to involve the alpha-2a/d subtype. To provide evidence that the alpha-2a/d subtype mediated osmolar clearance, we investigated the effects of intrarenal infusion of the selective alpha-2a/d adrenoceptor agonist guanfacine. Studies were conducted in anesthetized Sprague-Dawley rats that were unilaterally nephrectomized 7 to 10 days before the experiment. The infusion of guanfacine (3.0 nmol/kg/min) into the remaining renal artery increased urine flow without altering blood pressure or creatinine clearance. The increase in urine flow was associated with an increase in osmolar clearance but no increase in free water clearance. The effects of the alpha-2a/d adrenoceptor selective antagonist, RX-821002, on the renal actions of guanfacine were determined. RX-821002 (3.0 mg/kg) attenuated the ability of guanfacine to increase urine flow rate and osmolar clearance. Similarly to the increase in osmolar clearance observed with clonidine, the guanfacine-induced increase in osmolar clearance was attenuated by naltrexone (3.0 mg/kg) and unaltered by prazosin (0.15 mg/kg) pretreatment (i.e., naltrexone-sensitive and prazosin-insensitive). These results were consistent with the alpha-2a/d adrenoceptor subtype in the rat kidney which mediated an increase in osmolar clearance. A physiological function of this alpha-2a/d adrenoceptor subtype may therefore involve regulation of solute/sodium excretion.

Renal denervation altered the hemodynamic and renal effects following intracerebroventricular administration of the I1-imidazoline receptor agonist, rilmenidine, in pentobarbital anaesthetized rats.

Previous studies have reported on the effects of intracerebroventricular (icv) administration of the I1-imidazoline receptor agonist moxonidine. In the present study, the relationship between increasing doses of the I1-agonist rilmenidine (administered icv) with blood pressure and renal function has been determined. Moreover, the importance of the renal nerves in this response have also been assessed. In pentobarbitone anesthetized rats, icv rilmenidine (30, 100, 300 nmol in 5 microliters) produced a dose related decrease in blood pressure and heart rate. Urine flow was not altered at the lower doses although at the highest dose (300 nmol) the increase approached significance (p = 0.06). Sodium excretion and osmolar clearance were not altered. Free water clearance was increased at 100 and 300 nmol rilmenidine (p < 0.05). Consistent with the above dose response studies, in sham denervated rats icv rilmenidine (300 nmol) decreased blood pressure and increased free water clearance. In rats having undergone renal denervation, baseline levels of urine flow rate, sodium excretion and osmolar clearance were increased. In these denervated rats, icv rilmenidine (300 nmol) failed to decrease blood pressure. Urine flow rate was increased with a decrease in sodium excretion and osmolar clearance. Free water clearance was increased. These results indicate the importance of the renal nerves in mediating the acute decrease in blood pressure following icv administration of the I1-imidazoline receptor agonist rilmenidine. The increase in free water clearance seen following icv rilmenidine appears to be mediated independent of the renal nerves. The changes associated with sodium excretion on the contrary are dependent on intact renal nerves.

Clonidine-induced increase in osmolar clearance and free water clearance via activation of two distinct alpha 2-adrenoceptor sites.

1. Clonidine, an alpha 2-adrenoceptor agonist, will increase urine flow rate in the anaesthetized rat by increasing both free water and osmolar clearance. In the present study, we investigated whether these effects of clonidine were mediated at two sites which could be distinguished pharmacologically in uninephrectomized male Sprague-Dawley rats. 2. Clonidine (1.0 nmol kg-1 min-1) infused into the renal artery increased osmolar and free water clearance. Following pretreatment with prazosin (0.15 mg kg-1, i.v.), an antagonist with reported selectivity for the alpha 2b-adrenoceptor subtype, the increase in free water but not osmolar clearance was decreased. Pretreatment with the opioid receptor antagonist, naltrexone (3.0 mg kg-1, i.v.) attenuated the increase in osmolar but not free water clearance. This disparate antagonism of clonidine by prazosin and naltrexone was consistent with two distinct sites. 3. We submit the hypothesis that the alpha 2a- and alpha 2b-adrenoceptor subtypes mediated the clonidine-induced osmolar and free water clearance. The blockade in free water clearance by prazosin indicated a possible role of the alpha 2b-adrenoceptor subtype whereas the alpha 2a-adrenoceptor subtype was considered as the site mediating the clonidine-induced increase in osmolar clearance. UK-14,304 (1.0 nmol kg-1 min-1), a mixed alpha 2-adrenoceptor/imidazoline receptor agonist with selectivity for the alpha 2a-subtype increased only osmolar clearance. This increase was blocked by naltrexone but not prazosin pretreatment. The imidazoline receptor was not involved, as naltrexone failed to alter the moxonidine (3.0 nmol kg-1-min-1) induced increase in osmolar clearance. These data suggested to us that the alpha 2a-/alpha 26-subtype hypothesis should be investigated more closely in future studies. 4. These findings indicate that the increase in osmolar and free water clearance following clonidine can be distinguished pharmacologically indicating that two sites were involved. Furthermore, we propose the hypothesis that the alpha 2a-adrenoceptor subtype mediated osmolar clearance whereas the alpha 2b-subtype mediated free water clearance. The prazosin-sensitive increase in free water clearance following clonidine suggested a possible role for the alpha 2b-subtype. The naltrexone-sensitive increase in osmolar clearance following clonidine and UK-14,304 (but not moxonidine) suggested a possible role of the alpha 2a-subtype. Clearly, this postulate requires further study.

Natriuresis following central and peripheral administration of agmatine in the rat.

Agonists specific for the I1 imidazoline receptor increase sodium excretion following intrarenal (ir) infusion or intracerebroventricular (icv) injection in the rat. Although agmatine has been suggested to be a putative endogenous agonist for these receptors, the ability of this compound to alter sodium excretion has not been determined. The effects of agmatine, whether administered ir or icv, on blood pressure and solute and water excretion were studied in Sprague-Dawley rats. Agmatine was administered by icv injection (0, 10, 100, 300 or 1,000 nmol in 5 microliters) or by direct ir infusion (0, 3, 10, 30 or 100 nmol/kg/min at 3.4 microliters/min) in pentobarbitone-anesthetized rats. Agmatine administered by icv injection or ir infusion did not alter blood pressure or heart rate. Only an ir infusion of agmatine produced an increase in creatinine clearance, which occurred at the lowest (3 nmol/kg/min) and highest dose (100 nmol/kg/min). Concomitantly, the ir infusion of agmatine produced a dose-related increase in urine flow rate, but both routes of administration were associated with an increase in sodium excretion and osmolar clearance. Similar to previous reports with I1 imidazoline receptor-selective compounds, agmatine increased urine flow rate secondary to an increase in osmolar clearance at doses that failed to alter blood pressure. These results were consistent with agmatine functioning as a physiological agonist resulting in alterations in sodium excretion.

Antagonism by idazoxan at low dose but not high dose, of the natriuretic action of moxonidine.

1. Recent studies concerning the imidazoline receptor have utilized idazoxan as a specific imidazoline receptor antagonist. The aim of the present study was to describe the in vivo effects of various doses of idazoxan on renal function, in the presence and absence of moxonidine, an I1 imidazoline receptor agonist. 2. In anaesthetized, unilaterally nephrectomized (7 to 10 days) Sprague Dawley rats, an intrarenal infusion of moxonidine (3 nmol kg-1 min-1) increased urine flow rate, sodium excretion and osmolar clearance without altering free water clearance. Pretreatment with intravenous idazoxan at 0.1 and 0.3 mg kg-1 produced a dose-related decrease in the renal actions of moxonidine. However, a higher dose of idazoxan (1 mg kg-1) was not as effective as the 0.3 mg kg-1 dose in blocking the effects of moxonidine. 3. In a separate series of experiments, the direct renal actions of idazoxan alone were investigated. Idazoxan at 0.3 mg kg-1 failed to alter urine flow rate and sodium excretion. However, idazoxan at 1 mg kg-1 produced a significant increase in urine flow rate and sodium excretion in association with an increase in osmolar clearance. 4. These results do not prove but are consistent with low doses of idazoxan antagonizing the sites stimulated by moxonidine (renal imidazoline receptors). However, at higher doses, idazoxan may function as a partial agonist and/or interact with other receptors to increase urine flow rate, independent of imidazoline receptor blockade. These studies underscore the importance of the dose of idazoxan administered when this antagonist is used as a tool to investigate imidazoline receptors.

Inhibition of the natriuretic action of the imidazoline receptor agonist moxonidine by indometacin in the rat.

Indometacin pretreatment potentiates the natriuretic action of the mixed alpha 2-adrenoceptor/imidazoline receptor agonist clonidine. In the present study we determined the effects of indometacin pretreatment on natriuretic actions of the selective I1 imidazoline receptor agonist. In anaesthetized rats, an intrarenal infusion of moxonidine (0, 0.3, 1, and 3 nmol/kg/min) increased urine flow rate and sodium excretion without altering blood pressure or creatinine clearance. Indometacin pretreatment abolished the subsequent natriuretic response to an intrarenal infusion of moxonidine (1 nmol/kg/min) without altering blood pressure or creatinine clearance. Administration of prostaglandin E2, at an infusion rate (1 microgram/kg/min) which alone failed to alter urine flow rate, sodium excretion, blood pressure, or creatinine clearance, partially, but not completely, restored the natriuretic response to moxonidine. The ability of indometacin pretreatment to potentiate natriuretic actions of an alpha 2-adrenoceptor agonist and to attenuate those of an imidazoline agonist indicates that these two receptors in the kidney are unique and may serve distinct functions in the regulation of sodium and water excretion.

The role of the peripheral sympathetic nervous system in the natriuresis following central administration of an I1 imidazoline agonist, moxonidine.

1. Central administration of the I1-imidazoline receptor agonist moxonidine increases sodium excretion without alteration of blood pressure. In the present study we determined whether this natriuretic action was mediated through a decrease in activity of the sympathetic nervous system, as has been reported for the antihypertensive action of this compound. Interruption of the sympathetic nervous system was achieved with prazosin (alpha 1-adrenoceptor antagonist) and renal denervation. 2. In pentobarbitone-anaesthetized Sprague-Dawley rats, intracerebroventricular (i.c.v.) injection of moxonidine alone increased urine volume and sodium excretion. Prazosin (0.15 mg kg-1, i.v.) alone decreased urine flow rate and sodium excretion as compared to the vehicle controls. In the presence of prazosin, i.c.v. injection of moxonidine failed to increase sodium excretion or urine volume as compared to animals which received the prazosin alone. 3. The administration of moxonide (i.c.v.) to sham renal-denervated animals caused an increase in urine flow rate, urine sodium excretion, osmolar clearance and free water clearance. The increase in sodium excretion and osmolar clearance were completely attenuated in renal denervated rats, however, urine flow rate was still increased and this was secondary to the increase in free water clearance which remained intact. 4. These results indicate the importance of an intact sympathetic nervous system in the renal response to i.c.v. moxonidine. Moreover, the differential antagonism of these interventions on solute and water excretion indicate that they may be mediated at two separate sites and/or receptors following i.c.v. moxonidine.

Efaroxan acts peripherally to block the antisecretory and gastroprotective effects of moxonidine in rats.

I1-imidazoline receptor activation by moxonidine has potent antigastric secretory and gastroprotective effects in rats. We therefore tested whether an imidazoline receptor antagonist, efaroxan, would influence gastric secretion and block the antisecretory and antiulcer effects of moxonidine. When given intracerebroventricularly (i.c.v.), moxonidine inhibited basal acid output in conscious rats to a maximum of 38%. Moxonidine given i.p. also significantly increased gastric adherent mucus levels in rats subjected to cold-restraint stress. Efaroxan alone given i.c.v., did not influence gastric secretion nor did it affect moxonidine's ability to decrease gastric secretion. Similarly, peripherally administered efaroxan did not block the antisecretory effect of moxonidine given i.c.v. However, when both compounds were given i.p., efaroxan pretreatment at all but the lowest doses significantly blocked the antigastric secretory effect of moxonidine. Efaroxan alone (i.p.) did not influence stress-induced gastric mucosal injury or adherent mucus levels. However, pretreatment of rats with efaroxan i.p. significantly blocked the mucus-preserving effect of i.p. moxonidine. These results demonstrate that central (i.c.v.) or peripheral (i.p.) administration of the I1-imidazoline receptor agonist moxonidine is associated with gastroprotection. The ability of i.p. efaroxan to block the effects of i.p. moxonidine but not i.c.v. moxonidine indicates that imidazoline receptors located centrally and peripherally may represent two unique sites associated with gastroprotection.

Agmatine, an endogenous imidazoline receptor agonist, increases gastric secretion and worsens experimental gastric mucosal injury in rats.

The present experiments tested the actions of a putative endogenous imidazoline receptor agonist, agmatine, on gastric secretion and on experimental gastric mucosal injury in rats. Agmatine, given i.p. (0.5-20.0 mg/kg) or i.c.v. (0.5-2.5 micrograms), augmented basal gastric acid secretion in conscious rats to a maximum of 40% when given i.p. and 44% when given i.c.v. Agmatine also potentiated total secretory volume as well as gastric acid and pepsin output in pylorus-ligated rats. When administered before exposure to stress, agmatine significantly decreased gastric glandular mucus levels and exacerbated stress-induced gastric mucosal injury. These results are in contrast to our data showing that an exogenous agonist of I1-imidazoline receptors, moxonidine, is a potent antisecretory and gastroprotective agent. A precise physiological role for agmatine in blood pressure regulation and in gastrointestinal function awaits clarification. However, it is possible that agmatine functions as an "inverse agonist" at central imidazoline receptors, resulting in hypertension, augmented gastric secretion and exacerbated gastric mucosal injury.