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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.

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.

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.

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.

1. Previous reports of the effects of alpha 2-adrenoceptor stimulation on gastric secretion are inconsistent because it was not clear whether the compounds were activating alpha 2-adrenoceptors and/or newly described imidazoline receptors. In the present experiments, the effects of moxonidine, an I1-imidazoline receptor agonist and antihypertensive agent, on gastric secretion and on experimental gastric mucosal injury were examined. 2. Moxonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) potently inhibited basal (non-stimulated) gastric acid secretion in conscious rats with an ED50 of 0.04 mg kg-1. Two hours following administration of the highest dose of moxonidine (1.0 mg kg-1), gastric acid output was completely suppressed. Moxonidine also significantly increased intragastric pH, at the two highest doses. 3. The alpha 2-adrenoceptor agonist, clonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) decreased basal acid secretion at the lowest dose (37%) and at the highest dose (46%), while the intermediate dose did not affect gastric acid output. 4. In an ethanol-induced model of gastric mucosal injury, moxonidine decreased the length of lesions at the lowest and highest doses (0.01 and 1.0 mg kg-1) as well as the number of the lesions, at the highest dose (1.0 mg kg-1). 5. In pylorus-ligated rats, moxonidine significantly decreased acid secretion (all doses), total secretory volume (1.0 mg kg-1) as well as pepsin output (1.0 mg kg-1). 6. In comparison to clonidine, moxonidine appears to be a more potent anti-secretory and gastric-protective compound. These data indicate a potential role for imidazoline receptor agonists in the management of gastroduodenal diseases associated with hypertension. The relative contribution of the central and peripheral effects of moxonidine to these gastrointestinal actions remains to be determined.

In the present study, we investigated the renal actions of two compounds reported to interact with the imidazoline receptor: rilmenidine (I1-receptor selective, centrally acting antihypertensive) and agmatine (an endogenous clonidine-displacing substance). Rilmenidine (saline vehicle, 3 or 30 nmol/kg/min) or agmatine (saline vehicle, 3 or 30 nmol/kg/min) was infused directly into the renal artery of anesthetized (pentobarbitone) Sprague-Dawley rats (280-300 g) that had undergone a unilateral nephrectomy 7 to 10 days before the experiment. Rilmenidine produced an increase in urine flow rate at doses that failed to significantly alter blood pressure, creatinine clearance, or heart rate. The increase in urine flow rate was secondary to an increase in osmolar clearance, primarily composed of sodium. Free water clearance was not altered at these infusion rates. Agmatine also increased urine flow rate at doses that failed to alter blood pressure, creatinine clearance, and heart rate. The increase in urine flow rate was secondary to an increase in osmolar clearance, again primarily composed of sodium. The natriuretic action of rilmenidine and agmatine, at doses that do not lower blood pressure acutely, could be beneficial in the antihypertensive actions of these centrally acting agents.

1. Previously we have shown that an intrarenal infusion of moxonidine, an I1-imidazoline receptor agonist, resulted in a natriuresis which was inhibited by intravenous idazoxan, a selective imidazoline receptor antagonist. Therefore we examined the effects of renal function of intracerebroventricular (i.c.v.) administration of moxonidine with or without i.c.v. idazoxan. 2. Seven days after unilateral nephrectomy, Sprague-Dawley rats had i.c.v. cannulae implanted. Three days later the rats were anaesthetized (pentobarbitone), followed by cannulation of the jugular vein (fluid and drug administration), carotid artery (blood pressure) and the ureter (urine collection). 3. After a 45 min stabilization period, the effect of moxonidine was investigated by the i.c.v. administration of either isotonic saline or moxonidine (0.1, 0.3 or 1 nmol in isotonic saline) administered in 5 microliters over 1 min. All doses of moxonidine resulted in an increase in urine flow with a concomitant increase in sodium excretion without affecting blood pressure. The highest dose of moxonidine (1 nmol) also increased free water clearance. 4. In a second series of experiments, the effects of idazoxan on the natriuretic response to i.c.v. moxonidine were determined. Moxonidine (0.3 nmol) again increased sodium and water excretion as compared to the i.c.v. saline control animals. Pretreatment with i.c.v. idazoxan (0.3 nmol), at a dose which alone failed to alter sodium and water excretion, completely attenuated the renal response to moxonidine. These results are consistent with central I1-imidazoline receptors mediating a moxonidine-induced increase in sodium and water excretion at doses that do not alter blood pressure.

1. I1 non-adrenoceptor, imidazoline receptor agonists, such as moxonidine, increase urine flow rate and sodium excretion following infusion into the renal artery. The functions of these agonists in genetic and acquired models of hypertension have not been determined. 2. We therefore studied the renal effects of two known non-adrenoceptor, imidazoline receptor agonists, rilmenidine and moxonidine, in 1K-1C hypertensive and 1K-sham normotensive rats. Rilmenidine (0, 3, 10, 30 nmol kg-1 min-1) or moxonidine (0, 1, 3, 10 nmol kg-1 min-1) was infused directly into the renal artery (30 gauge needle) of 1K-sham normotensive and 1K-1C hypertensive rats. 3. In 1K-sham normotensive rats, rilmenidine and moxonidine produced dose related increases in urine flow rate, sodium excretion and osmolar clearance. Both rilmenidine and moxonidine failed to increase urine flow rate, sodium excretion and osmolar clearance in 1K-1C hypertensive rats to the same extent as in 1K-sham animals. At comparable doses, rilmenidine had no effect, while moxonidine (3 and 10 nmol kg-1 min-1) did result in a small increase in urine volume and osmolar clearance which was less than that observed in the 1K sham control animals. 4. These studies indicate that the renal effects of non-adrenoceptor, imidazoline receptor stimulation are diminished in 1K-1C hypertensive rats compared with 1K-sham normotensive rats. Whether this decrease in activity of the natriuretic non-adrenoceptor, imidazoline receptors contributes to the increase in blood pressure in the 1K-1C acquired model of hypertension remains to be determined.

1. Moxonidine has been found to have an approximately 600 fold greater affinity for I1 imidazoline preferring sites as compared to alpha 2-adrenoceptors in the rat kidney. The effects of an intrarenal infusion of moxonidine in an anaesthetized rat preparation were investigated and contrasted with the effects previously reported for alpha 2-adrenoceptor stimulation. 2. An intrarenal infusion of moxonidine (1, 3 and 10 nmol kg-1 min-1) produced an increase in urine flow rate and sodium excretion. Moxonidine increased urine volume through an increase in osmolar clearance rather than an increase in free water clearance as previously reported for alpha 2-adrenoceptor stimulation. 3. The effects of moxonidine also appeared to be unique from the effects of alpha 2-adrenoceptor stimulation. An imidazoline preferring site specific blocking dose of idazoxan (0.3 mg kg-1), but not an alpha 2-adrenoceptor specific blocking dose of rauwolscine (0.3 mg kg-1) attenuated the renal effects of moxonidine (3 nmol kg-1 min-1). Moreover, unlike alpha 2-adrenoceptor agonists, the effects of moxonidine were not altered by prior treatment with a V2 vasopressin receptor antagonist. 4. These results indicate differences between stimulation of alpha 2-adrenoceptors and I1 imidazoline preferring sites in the rat kidney and suggest a direct physiological function of renal imidazoline preferring sites.

Chronic (3-day) treatment with prazosin causes an increase in renal alpha 2-adrenergic receptor density and the relocation of renal tubular alpha 2-adrenergic receptors from extrajunctional to postjunctional sites. We investigated whether chronic prazosin treatment (2 mg/kg, i.p.) caused a functional alteration of other renal alpha 2-adrenergic receptors, using the isolated perfused rat kidney. Prazosin significantly reduced blood pressure and increased heart rate during the 3-day treatment. Renal nerve stimulation (2-8 Hz, 10 V, 1 msec) caused a frequency-dependent increase in renovascular resistance, which was potently blocked by prazosin in vitro in both control and prazosin-treated rat kidneys. The vasoconstrictor response to the alpha 2-adrenergic receptor-selective agonist BHT 933 (3-300 microM) was significantly higher in kidneys from prazosin-treated rats. Yohimbine (3-300 nM) potentiated the response to renal nerve stimulation in both treatment groups. The increase in vascular resistance following renal nerve stimulation was lower in kidneys from prazosin-treated rats, but the response to the alpha 1-adrenergic receptor agonist methoxamine (0.3-1 microM) was unchanged. Further studies revealed that renal nerve stimulation-evoked norepinephrine release from prazosin-treated rat kidneys was significantly lower than release from untreated controls. This response could be normalized to control levels by a combination of cocaine (10 microM) and yohimbine (100 nM). Thus, chronic prazosin treatment caused enhanced alpha 2-adrenergic receptor-mediated vasoconstriction and facilitated renal prejunctional inhibitory mechanisms. We conclude that with chronic alpha 1 adrenergic receptor blockade there is increased alpha 2-adrenergic receptor function in at least two and possibly three sites in the kidney; these include postjunctional tubular, prejunctional vascular, and possibly extra-junctional vascular sites.

1. The effect of chronic prazosin pretreatment (3 days) on the ability to excrete a modest saline load (i.v. saline, 0.097 ml min-1) was studied in the anaesthetized rat. Three days before the experiment, the drinking water was replaced with 0.5% dextrose (control), 0.015 mg ml-1 prazosin in 0.5% dextrose (low dose) or 0.15 mg ml-1 prazosin in 0.5% dextrose (high dose). 2. The selectivity of the prazosin for alpha 1-adrenoceptors was evaluated in pithed rats. The pressor response to phenylephrine was partially attenuated by the low dose of prazosin and completely attenuated by the high dose of prazosin. The pressor response to clonidine was slightly decreased by the 3 day prazosin pretreatment indicating a selectivity for alpha 1-adrenoceptors. 3. In rats pretreated with the low dose of prazosin, there was a significant decrease in sodium and water, but not potassium excretion as compared to the control group. Captopril failed to alter these effects of the low dose of prazosin. Blood pressure and creatinine clearance were the same in both groups. In rats pretreated with the high dose of prazosin, there was a further decrease in sodium and water but not potassium excretion. However, this dose of prazosin also significantly decreased blood pressure and increased creatinine clearance. A decrease in renal perfusion pressure with an aortic clamp to the same level as that observed with the high prazosin dose also decreased sodium and water but not potassium excretion. The decrease in sodium and water excretion was not as great as that observed with the high dose of prazosin. 4. The results indicate that chronic a,-adrenoceptor blockade with prazosin attenuates the ability to excrete a saline load in a dose-related manner. Whether this inability to excrete a saline load is analogous to the sodium and water retention observed with the clinical use of prazosin remains to be determined.

Rats were placed on either a low sodium intake (low sodium diet 0.025% dry weight, tap water for drinking) or a high sodium intake (normal sodium diet 0.45% dry weight, 0.9% saline for drinking) for 10 days. The pressor-response curve to angiotensin II in rats previously on a high sodium intake was shifted to the left of that found in rats previously on a low sodium intake. Suppression of endogenous angiotensin II formation with captopril (0.3 mg kg-1) or acute volume repletion (3% body wt per 30 min) resulted in a significant parallel shift of the pressor-response curve for angiotensin II to the left in the low salt group. In the high salt group captopril produced a similar but smaller parallel shift of the dose-response curve to the left. Similar manipulation of endogenous angiotensin II concentrations with high and low salt intake plus captopril treatment or acute volume repletion, produced no alterations in the pressor response for noradrenaline. The attenuated in vivo response to angiotensin II in the low salt intake group may be explained in part by the suppressed vascular sensitivity to angiotensin II in this group, as measured in the isolated perfused kidney of the rat. In kidneys from rats previously on a low sodium intake, an enhanced maximal vasoconstrictor response to noradrenaline was observed as compared to kidneys from high sodium intake rats. These results indicate that, whereas alterations in endogenous angiotensin II concentrations within physiological limits affects the response to exogenous angiotensin, there is little if any effect on the pressor response to noradrenaline.

Renal nerve stimulation-induced antinatriuresis normally is mediated through post-synaptic alpha 1-adrenergic receptors; however, prazosin-induced alpha 1-adrenergic receptor blockade is associated clinically with sodium retention and not natriuresis. To study whether alpha 2-adrenergic receptors mediate renal nerve stimulation-induced antinatriuresis after chronic prazosin treatment, Sprague-Dawley rats were pretreated for 3 days with prazosin (3 mg/kg/day i.p. plus 0.15 mg/ml drinking water) or vehicle (untreated). In isolated perfused (Krebs-Henseleit; Ficoll, 3.5 g/dl, + albumin, 1.0 g/dl at 36 degrees C) kidneys from untreated rats, subpressor levels of renal nerve stimulation (approximately 1 Hz, 10 V, 1 msec) decreased (p less than 0.05) sodium (from 4.50 +/- 0.42 to 1.71 +/- .23 muEq/min) and urinary excretion rate (from 87.2 +/- 4.1 to 57.9 +/- 3.9 microliter/min). Adding prazosin (30 nM) to the perfusate completely (approximately 90%) reversed this effect (p less than 0.05), while alpha 2-adrenergic receptor blockade with yohimbine (300 nM) had no effect. In perfused kidneys from prazosin-treated rats, renal nerve stimulation decreased (p less than 0.05) sodium (from 3.24 +/- .40 to 1.32 +/- .27 muEq/min) and urinary excretion rate (from 78.7 +/- 5.0 to 54.1 +/- 5.3 microliter/min). However, adding prazosin (100 nM) to the perfusate produced only a slight, insignificant reversal of these effects; prazosin plus yohimbine were required to completely reverse the effects. These results suggest that renal nerve stimulation-induced sodium reabsorption was activated by alpha 1-adrenergic receptors in untreated rats and in part by alpha 2-adrenergic receptors in rats pretreated for 3 days with prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Research on alpha 2-adrenoceptors has been explosive since the first functional or pharmacologic classification of these agents in 1977. While several properties of renal alpha 2-adrenoceptors have been characterized, their possible role in the pathophysiology of hypertension remains elusive. Under normal circumstances, alpha 1-adrenoceptors appear to be located postjunctionally and alpha 2-adrenoceptors are extrajunctional. However, following chronic alpha 1-adrenoceptor blockade with prazosin, the renal alpha 2-adrenoceptor density increases and they may assume the otherwise exclusive alpha 1-adrenoceptor postjunctional domain. This assumed role of alpha 2-adrenoceptors may explain the absence of natriuresis with the clinical use of prazosin and, if a similar change occurs in vascular tissue, the temporary nature of the first-dose phenomenon (orthostatic hypotension) that occurs with the use of this drug. Finally, our description of the "postsynaptic" location of the ubiquitous plasma membrane alpha 2-adrenoceptors in the original functional or pharmacologic basis of classification of alpha-adrenoceptors should now be updated. Under normal conditions, the predominant alpha 2-adrenoceptors on effector organ plasma membranes appear to be extrajunctional and do not ordinarily mediate the effects of sympathetic neuronally released norepinephrine. Postjunctional alpha 1-adrenoceptors remain postjunctional and ordinarily mediate effects of nerve-stimulated norepinephrine release.

Previous studies in our laboratory demonstrated that alpha 2-adrenoceptor activation reversed arachidonic acid induced diuresis in the rat. However, the site of action was not elucidated. Since prostaglandin E2 is the predominant prostaglandin metabolite of arachidonic acid, we studied the effect of renal alpha 2-adrenoceptor stimulation on prostaglandin E2 (PGE2) induced cAMP formation. The study was done in intact single nephron segments and glomeruli. All incubations were done in the presence of 1-methyl-3-isobutylxanthine (phosphodiesterase inhibitor) and propranolol at 37 degrees C for two minutes. PGE2 increased cellular cAMP levels in the thin descending limb of Henle (tDL), cortical collecting tubule (CCT) and glomerulus. Alpha 2-adrenoceptors were activated with varying concentrations of epinephrine (E). In the tDL, alpha 2-adrenoceptor activation with E (5 X 10(-6)M to 5 X 10(-5)M) suppressed (p less than 0.05) PGE2 stimulated cAMP production by 35%. This suppression by E was inhibited by 5 X 10(-6)M yohimbine but not by 5 X 10(-6)M prazosin confirming alpha 2-adrenoceptor mediation of the effects of E. Conversely, in the CCT and glomerulus, E had no effect on PGE2-stimulated increases in cellular cAMP levels. Thus, the capacity of alpha 2-adrenoceptors to inhibit PGE2-stimulated adenylate cyclase is anatomic site-specific. This effect of alpha 2-adrenoceptors on cAMP in the tDL may explain, at least in part, the effect of alpha 2-adrenoceptors on arachidonic acid induced diuresis in the rat.

Renal alpha 2-adrenoceptor stimulation by epinephrine infusion reverses cyclic adenosine monophosphate-mediated effects of vasopressin on sodium and water excretion. We used this response to determine whether renal nerve stimulation can activate renal alpha 2-adrenoceptors in the non-recirculating isolated perfused rat kidney (Krebs-Henseleit solution; 3.5 g/100 ml Ficoll; 1 g/100 ml albumin; 36 degrees C; propranolol 100 nM). In the presence of alpha 1-adrenoceptor blockade with prazosin (30 nM) alpha 2-adrenoceptor stimulation with epinephrine reversed the cyclic adenosine monophosphate-mediated effects of vasopressin on sodium (P less than 0.05) and water (P less than 0.05) excretion. Subthreshold (for vasoconstriction) renal nerve stimulation (10 V; 1 msec; 0.65 +/- 0.10 Hz) failed to alter the effect of vasopressin. Similarly, higher levels of renal nerve stimulation [plus prazosin (100 nM) or phenoxybenzamine (1.0 mg/kg per hr) to block alpha 1-adrenoceptors] did not activate renal alpha 2-adrenoceptors which are associated with the antagonism of the effects of vasopressin. The same level of subthreshold renal nerve stimulation (0.85 +/- 0.14 Hz) in the absence of vasopressin, and without alpha 1- or alpha 2-adrenoceptor blockade, decreased (P less than 0.05) sodium and water excretion. The reversal of this effect by alpha 1-adrenoceptor blockade (prazosin 30 nM) but not alpha 2-adrenoceptor blockade (yohimbine 300 nM) indicates that this effect of renal nerve stimulation is mediated through alpha 1-adrenoceptors. Thus, subthreshold renal nerve stimulation in the rat kidney induces sodium and water retention through activation of alpha 1-adrenoceptors, as shown by others in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)