1 Moxonidine has been found to have an approximately 600 fold greater affinity for I, imidazoline preferring sites as compared to ox2-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 a2-adrenoceptor stimulation. 2 An intrarenal infusion of moxonidine (1, 3 and 10 nmol kg-min') 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 z2-adrenoceptor stimulation. 3 The effects of moxonidine also appeared to be unique from the effects of x2-adrenoceptor stimulation. An imidazoline preferring site specific blocking dose of idazoxan (0.3 mg kg-'), but not an M2-adrenoceptor specific blocking dose of rauwolscine (0.3 mg kg 1) attenuated the renal effects of moxonidine (3 nmol kg'-min -). Moreover, unlike 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 M2-adrenoceptors and I, imidazoline preferring sites in the rat kidney and suggest a direct physiological function of renal imidazoline preferring sites.

alpha 2-Adrenoceptors were first described pharmacologically ten years ago. Within three years their capacity to inhibit adenylate cyclase had been demonstrated in many tissues. They were demonstrated biochemically in the kidneys in 1981 even before any renal physiological effects of their activation were known. They predominate numerically over alpha 1-adrenoceptors in renal membranes and their density is increased in genetic forms of rat hypertension. alpha 1-Adrenoceptors normally mediate the vasoconstriction and sodium- and water-retaining effects of sympathetic neuronally released norepinephrine. Norepinephrine or epinephrine must be infused to activate alpha 2-adrenoceptors, suggesting that renal alpha 2-adrenoceptors are extrajunctional, whereas alpha 1-adrenoceptors are postjunctional. When alpha 1-adrenoceptors are chronically blocked, renal alpha 2-adrenoceptor density increases and they assume a location at postjunctional sites, the otherwise exclusive domain of alpha 1-adrenoceptors. Results from microdissection studies have established that alpha 2-adrenoceptors are present on most segments of the nephron and that their activation can suppress adenosine 3,'5'-cyclic monophosphate (cAMP) accumulation induced by most renal hormones. However, failure of alpha 2-adrenoceptor activation to suppress cAMP accumulation in some tubular segments induced by certain hormones suggests compartmentalization of adenylate cyclase regulation that is hormone-function specific. In view of the potent inhibitory effects of alpha 2-adrenoceptor stimulation on hormone activated cAMP accumulation in several discrete areas of the nephron, we suggest that alpha 2-adrenoceptors fulfill important regulatory role(s) in renal function. To date, alpha 2-adrenoceptor activation has been shown to reverse vasopressin-induced sodium and water retention, and arachidonic acid- and furosemide-induced cAMP, sodium, and water excretion in the isolated perfused kidney. Thus the effects are qualitatively and quantitatively dependent in these studies on the hormone being infused and are therefore hormone-function specific. Physiological effects of alpha 2-adrenoceptor activation of thyrocalcitonin and on parathyroid hormone-induced effects have not been studied. alpha 2-Adrenoceptor activation can inhibit renin release in some model systems and can activate a sodium-hydrogen antiporter system in proximal tubules. The physiological roles of these actions are unknown.

The regulation of renal sodium and water excretion through a hepatorenal reflex activated by the changes in hemodynamics of the portal circulation has been suggested. We hypothesize that the changes in intrahepatic blood flow and flow-related intrahepatic adenosine are involved in the control of renal water and sodium excretion by triggering a hepatorenal reflex. Anesthetized rats were instrumented to monitor the systemic, hepatic, and renal circulation. A vascular shunt connecting the portal vein and central vena cava was established to allow for control of the portal venous blood flow (PVBF). Urine was collected from the bladder. The effects of decreased PVBF on renal water and sodium excretion were compared in normal and hepatic denervated rats. T he liver is involved in the regulation of renal excretion of sodium and water. [1][2][3][4][5] In this regard, the existence of a hepatorenal reflex to regulate urine production has been suggested. Lang et al. observed in a rat model that infusion of glutamine into the liver induced a hepatic and renal nerve-dependent reduction in renal glomerular filtration rate (GFR), renal plasma flow, and urine production. Other studies have also suggested that the activation of hepatic afferent nerves could result in the activation of renal sympathetic nerves to regulate renal function in health and diseases. [6][7][8][9][10] The changes in the hemodynamics of hepatic portal circulation have been considered as the major event in triggering the hepatorenal reflex. Theoretically, both increased portal veous blood pressure (PVP) and decreased portal venous blood flow (PVBF) could be the initial event that triggers the hepatorenal reflex. [3][4][5][6] Previous studies have been interpreted to indicate that PVP is the major event responsible for the triggering of the observed activation of the hepatorenal reflex. However, the maneuvers used in those studies to increase PVP unavoidably decreased or even stopped intrahepatic PVBF, leaving the issue unresolved. Moreover, an increased PVP as the trigger of the hepatorenal reflex would represent a positive-feedback mechanism, in which fluid retention would lead to an elevated PVP in healthy livers that would then result in more fluid retention. Little is known about the contribution of decreased intrahepatic PVBF in the regulation of renal water and sodium excretion.Thus, we tested the hypothesis that intrahepatic PVBF is involved in the regulation of renal water and sodium excretion. The experiments were performed in two different animal models: intrahepatic PVBF was reduced either by the portacaval shunt or by ligation of the superior mesenteric artery (SMA). The results revealed that renal water and sodium excretion were significantly decreased after reducing intrahepatic PVBF. The mechanism may relate to the flow-dependent accumulation of adenosine within the liver, triggering a hepatorenal reflex. Materials and Methods Surgical PreparationMale Sprague-Dawley rats weighing 260 to 300 g were maintained in the animal house under contro...

We studied the short-term effect of oral doses of quinine and quinidine on the renal clearance of amantadine in healthy young (age range, 27 to 39 years) and older (age range, 60 to 72 years) adults of both genders in a three-limbed randomized crossover study. Renal clearance of amantadine (13.2 +/- 5.8 L/hr) was significantly inhibited by quinine (9.7 +/- 4.8 L/hr) and quinidine (8.9 +/- 4.0 L/hr) only in male subjects and was not associated with age. The chiral selectivity for the renal clearance of quinidine over quinine was confirmed and extended with the suggestion of both age- and gender-associated changes on the renal clearance ratio for these two diastereomeric drugs. These data support the continued use of amantadine for studies on the renal elimination of organic cationic drugs.

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)