Renal Alpha 2-adrenoceptors Research Articles

Alpha-adrenoceptors in Dahl hypertensive and normotensive rats: effect of sodium.

Sodium ions play an important role in vitro and in vivo in the regulation of alpha 2-adrenoceptors. The in vitro effect of sodium on cerebral and renal alpha-adrenoceptors was investigated in Dahl salt-sensitive and salt-resistant rats. Cerebral alpha 2-adrenoceptor densities were higher in Dahl salt-resistant rats. In contrast, the renal alpha 2-adrenoceptor density was higher in Dahl salt-sensitive than in Dahl salt-resistant rats. No difference in cerebral and renal alpha 1-adrenoceptor densities was observed between the two types of rat. Noradrenaline contents in the cerebral and renal cortex were also similar in these two rat substrains. An influx of sodium ions markedly increased cerebral and renal high-affinity alpha 2-adrenoceptor densities in Dahl salt-sensitive but not in Dahl salt-resistant rats. Under these conditions alpha 1-adrenoceptor densities remained unchanged. The absence of sodium regulation in Dahl salt-resistant rats may be linked either to a particular receptor conformation or to an abnormal structure of the alpha 2-adrenoceptor system. We conclude from the present study that there are marked differences in density and in the role of sodium regulation of cerebral and renal alpha 2-adrenoceptors from salt-sensitive and salt-resistant Dahl rats. These differences may play a primary role in the resistance or in the sensitivity of salt-induced hypertension.

Ontogeny of alpha-adrenoceptor responses in renal vascular bed of sheep.

The renal hemodynamic response to renal arterial infusions of guanabenz (alpha 2-adrenoceptor agonist) and phenylephrine (alpha 1-adrenoceptor agonist) were compared in conscious and chronically instrumented fetal (132-140 days gestation; term 145 days), newborn (6-15 days postnatal), and nonpregnant adult sheep. Phenylephrine produced similar dose-related decreases in renal blood flow velocity in all three groups at low concentrations (less than 1.8 X 10(-7) M) of drug in renal blood, whereas at the highest concentration adults demonstrated the most vasoconstriction and newborns the least (P less than 0.05 ANOVA). Responses to phenylephrine infusion during renal alpha 1-adrenoceptor blockade with prazosin were completely inhibited. Guanabenz produced greater renal vasoconstriction in adult sheep (P less than 0.05 ANOVA) at all concentrations (0.6 X 10(-6) to 8 X 10(-6) M) when compared with fetal and newborn sheep. Guanabenz-mediated vasoconstriction was not affected by alpha 1-adrenoceptor blockade with prazosin but was completely inhibited by the addition of an alpha 2-adrenoceptor antagonist idazoxan. Results of the present study demonstrate that renal vasoconstriction is mediated by both alpha 1- and alpha 2-adrenoceptors in fetal, newborn, and adult sheep. Moreover, these results suggest that renal alpha 1- and alpha 2-adrenoceptor-mediated vasoconstrictor responses mature at different rates.

Effects of epinephrine on the renal vascular bed of fetal, newborn, and adult sheep.

The renal hemodynamic response to renal artery infusions of epinephrine were compared in conscious and chronically instrumented fetal (125-139 days gestation; term 145 days), newborn (5-13 days postnatal), and nonpregnant adult sheep. Epinephrine produced similar dose related decreases in renal blood flow velocity in all three groups. The mean estimated concentration of epinephrine in renal blood producing a 50% decrease in renal blood flow velocity, ED50, was 0.008 microgram/ml. Epinephrine infusions during renal alpha-adrenoceptor blockade with phentolamine produced increases in renal blood flow velocity that were of greater magnitude in fetal compared to newborn and adult sheep. The maximal increase in renal blood flow velocity observed were 57 +/- 11%, 22 +/- 3%, and 18 +/- 3% in fetal, newborn, and adult sheep, respectively (p less than 0.001). This vasodilation produced by epinephrine during alpha-adrenoceptor blockade was completely inhibited by ICI 118,551, a beta 2-adrenoceptor antagonist. Inhibition of renal vascular beta-adrenoceptors with propranolol in fetal sheep did not enhance alpha-adrenoceptor-mediated renal vasoconstriction with epinephrine infusions. Results of the present study demonstrate similar renal vasoconstrictor responses to renal artery infusion of epinephrine in fetal, newborn, and adult sheep. In contrast, the renal vasodilator responses observed with epinephrine infusions during renal alpha-adrenoceptor blockade were greater in fetal compared to newborn and adult sheep. However, epinephrine-mediated renal vasoconstriction was not enhanced by blockade of beta-adrenoceptors in fetal sheep.

Effects of alpha-adrenoceptor blockers on renal function and blood pressure adjustment in human hypertension.

In this paper the different aspects of the role played by alpha-adrenoceptors in the control of renin secretion from the juxtaglomerular apparatus and renal sodium and water reabsorption, and the effects of alpha-adrenoceptor antagonists on systemic haemodynamics, will be investigated. Animal experiments suggest that the renal alpha-adrenoceptors exert a restraining action on renin secretion while increasing tubular reabsorption of sodium and water. A recent study in man has confirmed the alpha-adrenoceptor-mediated inhibition of renin secretion. Previously available ganglion blocking and antiadrenergic agents, while causing a significant supine blood pressure reduction, can cause at the same time clinically relevant side effects such as orthostatic hypotension, sedation, drowsiness etc. The advent of selective alpha 1-adrenoceptor blockers, such as prazosin and urapidil, allow a significant blood pressure reduction without significant interference on haemodynamic adjustments and only induce a limited incidence of side effects.

Renal alpha 2-adrenoceptors and the adenylate cyclase-cAMP system: biochemical and physiological interactions.

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.

Characterisation of the alpha-adrenoceptors of the rat renal vascular bed.

Postjunctional renal alpha-adrenoceptors were studied (1) in vivo, on the renal vasculature of the anaesthesized rat and compared with those in the femoral vasculature, and (2) in vitro, on the renal vascular bed of isolated perfused rat kidney. In vivo, renal and iliac blood flows were measured with an electromagnetic flow meter. The i.v. injection of (-)-phenylephrine (1-16 micrograms/kg) and B-HT 920 (0.6-600 micrograms/kg) induced an increase in both renal and iliac vascular resistance, inhibited respectively with prazosin (300 micrograms/kg) or yohimbine (300 micrograms/kg). In the kidney, maximum response to B-HT 920 was equivalent to 64% of that to (-)-phenylephrine; on the iliac vasculature, vasoconstrictor responses to both drugs were identical, but only corresponded to 50% of the maximum renal response to (-)-phenylephrine. This indicates the predominance of alpha 1- over alpha 2-adrenoceptors in the renal vascular bed. In vitro, on the isolated perfused rat kidney, vasoconstriction was induced by the preferential alpha 1-adrenoceptor agonists [(-)-phenylephrine, cirazoline and methoxamine] and the preferential alpha 2-adrenoceptor agonists (alpha-methylnoradrenaline, dopamine and clonidine) at concentrations at which they lose their selectivity for the alpha 2-adrenoceptors; all responses were antagonised by prazosin but not by yohimbine. B-HT 920, the selective alpha 2-adrenoceptor agonist, only induced renal vasoconstriction in vitro under concomitant infusion of rabbit plasma.

Elevation of plasma renin activity by alpha-adrenoceptor agonists in conscious dogs.

Experiments were performed in conscious trained dogs to determine whether renal alpha-adrenergic receptors mediate stimulation or inhibition of renin release. All dogs were uninephrectomized and surgically prepared with chronically indwelling catheters in the aorta, vena cava, and remaining renal artery at least 8 days before experiment. Direct renal artery (ia) infusion of the alpha-adrenoceptor agonist phenylephrine, 0.25 or 0.50 microgram X kg-1 X min-1 for 30 min, increased plasma renin activity (PRA) to 145 +/- 13 and 212 +/- 28% of control, respectively, within 5 min of drug infusion (P less than 0.01) in conscious sodium-replete dogs. In contrast, intravenous phenylephrine infusion decreased PRA by 50% (P less than 0.001). The increase in PRA observed during ia phenylephrine infusion was prevented by renal alpha-adrenoceptor blockade with phenoxybenzamine but not by beta-adrenoceptor blockade with propranolol. Methoxamine, another alpha-adrenoceptor agonist, also increased PRA when infused ia in both sodium-replete dogs and in dogs maintained on a low-sodium diet. In dogs with renal arterial electromagnetic flowprobes, ia phenylephrine infusion increased PRA without decreasing total renal blood flow. In summary, stimulation of renal alpha-adrenoceptors increases PRA in conscious dogs. This stimulation can occur in the absence of significant changes in total renal blood flow.

Renal nerve stimulation causes alpha 1-adrenoceptor-mediated sodium retention but not alpha 2-adrenoceptor antagonism of vasopressin.

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)

Effect of sympathetic stimulation and intrarenal alpha‐blockade on the secretion of renin by the human kidney

This study was initiated to explore the possible involvement of renal alpha-adrenoceptors in the regulation of active and inactive renin. In fifteen hypertensive patients who proved not to have vascular abnormalities on diagnostic renal arteriography, blood samples were collected simultaneously from the renal artery and vein before and during an intrarenal infusion of either saline (n = 5), or the alpha-1 blocker doxazosin (n = 5) or the non-selective alpha-1 blocker doxazosin (n = 5) or the non-selective alpha-blocker phentolamine (n = 5). Subsequently, responses of renal blood flow and renin secretion were assessed following 3 min of handgrip exercise. In none of the experiments secretion of inactive renin could be detected. Release of active renin increased from 580 (SEM 170) to 650 (SEM 220) microU min-1 (100 g)-1 during infusion of doxazosin (P less than 0.05) and from 760 (SEM 100) to 1000 (SEM 340) microU min-1 (100 g)-1 during infusion of phentolamine (P less than 0.01). Saline infusion had no effect on secretion of active renin. While handgrip exercise had no significant effect on active renin secretion in the saline and in the doxazosin group, it enhanced secretion from 1000 (SEM 340) to 1280 (SEM 390) microU min-1 (100 g)-1 in the phentolamine group (P less than 0.01). The results indicate that mainly alpha-2 adrenoceptors exert an inhibitory effect on release of active renin, although alpha-1 receptors participate to some degree. There is no evidence that the kidney secretes inactive renin.

Alpha2-adrenoceptors and cellular cAMP levels in single nephron segments from the rat.

A functional role for the numerically predominant renal alpha2-adrenoceptors, which in other tissues inhibit adenylate cyclase, remains undefined. We therefore examined the effect of alpha2-adrenoceptor stimulation with (-)-epinephrine (E) on cell cAMP content in the isolated proximal convoluted tubule (PCT), medullary and cortical thick ascending limb of Henle, and collecting tubule (MTAL, CTAL, MCT, and CCT, respectively). Parathyroid hormone (1-34 PTH), in PCT or CTAL, or arginine vasopressin (AVP), in MTAL, CTAL, MCT, or CCT, was used to activate adenylate cyclase in intact cells from these microdissected nephron segments in the presence of 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor) and propranolol. Alpha2-Adrenoceptors were activated using varying concentrations of E (37 degrees C, 2 min). Alpha2-Adrenoceptor activation with E (5 X 10(-7) to 5 X 10(-6) M) suppressed cellular cAMP stimulation by PTH by 35% in PCT and stimulation by AVP in CCT by 50%. This suppression by E in PCT and CCT was inhibited by 5 X 10(-6) M yohimbine or 5 X 10(-7) M phentolamine but not by 5 X 10(-6) M prazosin. E also suppressed cAMP stimulated by AVP in MCT, but it did not suppress the PTH-or AVP-stimulated increase in cellular cAMP in CTAL and MTAL. These studies show that there are alpha2-adrenoceptors in the rat nephron. Activation of these alpha 2-adrenoceptors can inhibit cAMP formation stimulated by PTH in PCT and by AVP in the CCT and MCT but not in the CTAL and MTAL. A pathophysiological role of altered regulation of these receptors is yet to be described.

Influence of renal perfusion pressure on alpha- and beta-adrenergic stimulation of renin release

Experiments were performed in pentobarbital-anesthetized dogs to 1) determine if neural stimulation of renin release can be mediated by renal alpha-adrenoceptors at renal nerve stimulation (RNS) frequencies that have little or no effect on total renal blood flow (less than or equal to 1.2 Hz) and 2) ascertain whether alpha-adrenergic control of renin release is affected by renal perfusion pressure (RPP). The renal nerves were electrically stimulated both in the absence of RPP control and with RPP controlled near 85 mmHg. Decreased RPP lowered the threshold for neurogenic stimulation of renin release from less than or equal to 1.2 to 0.3 Hz. beta-Adrenoceptor blockade with propranolol blunted the renin secretion rate (RSR) response to graded RNS (0.3-5.0 Hz), but the extent of inhibition during low-frequency RNS was dependent on RPP. Propranolol prevented increased RSR at 0.6-1.2 Hz RNS when RPP was 111-120 mmHg but not when RPP was 85 mmHg. Combined alpha- and beta-blockade with prazosin and propranolol totally prevented increased RSR during 0.6-1.2 Hz RNS at reduced RPP. In summary, both alpha- and beta-adrenoceptors mediate neural stimulation of renin release at RNS frequencies that do not decrease total renal blood flow when RPP is 85 mmHg.

Radioligand Binding and Functional Assays Demonstrate Postsynaptic Alpha2Receptors on Proximal Tubules of Rat and Rabbit Kidney

We have explored the localization of renal alpha 2-adrenoceptors by radioligand binding techniques and studies of 22Na+ influx into isolated renal tubular cells. Initially, we validated the use of the alpha 2-adrenergic antagonist [3H]rauwolscine as a high-affinity (Kd = 2.5 +/- 0.65 nM) probe that binds to a single class (Hill slope = 0.94 +/- 0.06) of alpha 2-adrenoceptors in rat renal cortical membranes (Bmax = 340 +/- 50 fmol/mg). [3H]Rauwolscine and [3H]yohimbine identified an identical number of sites, but [3H]rauwolscine bound with a several-fold higher affinity. Treatment of rats with 6-hydroxydopamine depleted renal norepinephrine greater than 80% but failed to alter the number or affinity of renal cortical alpha 2-receptors, thus suggesting that these alpha 2-receptors are not located on presynaptic sites. Further evidence for the postsynaptic localization of these receptors was obtained by in vitro autoradiographic studies, which showed that [3H]rauwolscine sites were preferentially located on proximal tubular cells, and by functional assays with isolated rabbit proximal tubular cells. In the latter studies, Na+-H+ antiport activity was stimulated up to 2-fold by the selective alpha 2-adrenergic agonist guanabenz, and this stimulation was blocked by yohimbine but not by the alpha 1-blocker prazosin. Although amiloride was able to block this response to guanabenz, radioligand binding studies demonstrated that amiloride can compete for [3H]rauwolscine sites at the concentrations used to block Na+-H+ antiport activity. These data suggest that alpha 2-adrenoceptors are present on proximal tubular cells in rats and rabbits and that these receptors appear to stimulate Na+-H+ antiport activity.(ABSTRACT TRUNCATED AT 250 WORDS)

On the existence of renal vasodilator nerves.

The renal vasoconstrictor responses to graded frequencies of direct electrical renal nerve stimulation and renal arterial norepinephrine injections were evaluated before and during renal alpha-1 adrenoceptor blockade in anesthetized dogs. Renal alpha-1 adrenoceptor blockade was achieved by infusing increasing doses (1, 10, 20, 40 micrograms/kg/min) of prazosin, a selective postsynaptic alpha-1 adrenoceptor antagonist, into the renal artery. The renal vasoconstrictor response to norepinephrine (1.5 micrograms) was completely abolished by 10 micrograms/kg/min prazosin. However, the renal vasoconstrictor response to a frequency of renal nerve stimulation which produced less renal vasoconstriction than norepinephrine (1.5 micrograms) in the absence of prazosin was not abolished by either 10, 20, or 40 micrograms/kg/min prazosin. During prazosin administration, neither renal nerve stimulation nor norepinephrine produced renal vasodilatation. Therefore, at prazosin doses two- and fourfold greater than that demonstrated to produce complete renal alpha-1 adrenoceptor blockade, no renal vasodilator responses to graded renal nerve stimulation were observed. These studies provide no evidence in support of a neural renal vasodilator mechanism in the dog.

The subtype of alpha-adrenoceptor involved in the neural control of renal tubular sodium reabsorption in the rabbit.

A study was undertaken in pentobarbitone anaesthetized rabbits, undergoing a saline diuresis, to determine the subtype of alpha-adrenoceptor mediating renal tubular sodium reabsorption. Stimulation of the renal nerves at low rates, to cause an 11% fall in renal blood flow, did not change glomerular filtration rate but significantly reduced urine flow rate, and absolute and fractional sodium excretions by approximately 40%. These responses were reproducible in different groups of animals and with time. Renal nerve stimulation during an intra-renal arterial infusion of prazosin, to block alpha 1-adrenoceptors, had no effect on the renal haemodynamic response but completely abolished the reductions in urine flow rate, and absolute and fractional sodium excretion. During intra-renal arterial infusion of yohimbine, to block renal alpha 2-adrenoceptors, stimulation of the renal nerves to cause similar renal haemodynamic changes resulted in significantly larger reductions in urine flow rate, and absolute and fractional sodium excretion of about 52-58%. These results indicate that in the rabbit alpha 1-adrenoceptors are present on the renal tubules, which mediate the increase in sodium reabsorption caused by renal nerve stimulation. They further suggest the presence of presynaptic alpha 2-adrenoceptors on those nerves innervating the renal tubules.

Cerebral and renal alpha-adrenoceptors in Sabra hypertensive (SBH) and normotensive (SBN) rats: effects of high-sodium diet.

The aim of the present study was to investigate the effect of high (8%) versus normal (0.2%) sodium diet on cerebral and renal alpha-adrenoceptors of Sabra hypertensive (SBH) and normotensive (SBN) rats. Cerebral alpha 2-adrenoceptor densities were higher in SBN than in SBH rats. In contrast, renal alpha 2-adrenoceptor density was higher in SBH than in SBN rats. No difference in alpha 1-adrenoceptor densities was observed between the two strains. After 2 and 5 weeks of high-sodium diet, alpha 2-adrenoceptor densities were increased in renal cortex of SBH and SBN rats. In contrast, cerebral alpha 2-adrenoceptor densities were markedly decreased in SBN but not in SBH rats. alpha 1-Adrenoceptor densities were unchanged by high salt intake. Blood pressure increased only after 5 weeks of high-sodium diet, markedly in SBH and to a lesser extent in SBN rats. The variation in alpha 2-adrenoceptor densities thus preceded the blood pressure elevation. The dietary sodium-induced increase in renal alpha 2-adrenoceptor densities observed both in SBH and SBN rats does not appear to be a genetic marker of hypertension. In contrast, the marked decrease in cerebral alpha 2-adrenoceptors in SBN rats may represent an adaptative change in sympathetic activity responsible for the resistance to the development of salt-induced hypertension.

Effects of a non-vasoconstrictor dose of phenylephrine on prostaglandin E2 and renin release in anaesthetized dogs.

Phenylephrine (1 microgram/min) was infused into the renal artery of pentobarbitone anaesthetized dogs. Systemic blood pressure and renal blood flow were monitored. Arterial and renal venous blood samples were collected before and 10 min after the start of the infusion. Plasma prostaglandin E2 concentration and plasma renin activity were measured by radioimmunoassay. This dose of phenylephrine did not affect systemic blood pressure and renal blood flow. However, both prostaglandin E2 and renin secretion rates were increased by the infusion of phenylephrine. These results suggest that renal alpha-adrenoceptors participate in prostaglandin and renin release independent of the changes in systemic blood pressure and renal blood flow.

Changes in renal alpha 2-adrenoceptor in experimental hypertension in rats.

alpha 2-Adrenoceptors were studied in renal membrane fractions from spontaneously hypertensive (SHR), two-kidney, one clip hypertensive (2K, 1C HT) and DOCA-salt hypertensive (DOCA-salt HT) rats, using radioligand binding method. alpha 2-Adrenoceptor concentration in the kidney measured by [3H]yohimbine binding was significantly increased in SHR at 4 weeks old (41.5 +/- 2.8 fmol/mg protein, mean +/- SEM, p less than 0.01), 12 weeks old (54.9 +/- 2.5 fmol/mg protein, p less than 0.01) and 35 weeks old (59.8 +/- 3.4 fmol/mg protein, p less than 0.01) as compared with age-matched Wistar-Kyoto rats (WKY, 31.5 +/- 2.5, 40.9 +/- 1.8, 47.8 +/- 2.0 fmol/mg protein, respectively). There were no significant differences in binding affinity and 5'-nucleotidase activity (plasma membrane marker enzyme) between SHR and WKY at any age. In 2K, 1C HT rats, alpha 2-adrenoceptor concentration in the clipped kidney was higher than that of control rats, but alpha 2-adrenoceptor concentration in the unclipped kidney was unchanged. Binding affinity and 5'-nucleotidase activity showed no significant changes in renal hypertensive rats. In DOCA-salt HT rats, no significant change was found in concentration and affinity of renal alpha 2-adrenoceptor. The observed increase in renal alpha 2-adrenoceptor concentration in SHR may contribute to the pathogenesis and maintenance of hypertension through increased sodium and water reabsorption in the kidney.

Role of renal alpha-adrenoceptors mediating renin secretion.

The increase in renin secretion resulting from low-frequency renal nerve stimulation (0.5 Hz) occurs in the absence of changes in urinary sodium excretion or renal blood flow and is apparently derived from a direct effect of renal sympathetic nerves on juxtaglomerular granular cells. We sought to determine the role of renal alpha-adrenoceptors in this neurally evoked renin secretion. The neurally evoked renin secretion was unaffected by renal alpha-adrenoceptor blockade with phentolamine or prazosin; however, two dose levels of phenoxybenzamine equally inhibited the renin secretion. The renal vasoconstrictor response to graded renal nerve stimulation was similarly diminished by phentolamine, prazosin, and the higher phenoxybenzamine dose, whereas the lower phenoxybenzamine dose was significantly less effective. Renal alpha-adrenoceptor stimulation with methoxamine infusion at doses that were just subthreshold for altering renal blood flow and urinary sodium excretion or at doses that just reduced urinary sodium excretion also did not change renin secretion. Higher doses of methoxamine that decreased both renal blood flow and sodium excretion increased renin secretion. Based on the inability of phentolamine and prazosin to prevent neurally mediated renin secretion and on the dose-response relationship between methoxamine and changes in renin secretion, renal blood flow, and urinary sodium excretion, we conclude that renal alpha-adrenoceptors do not mediate renin secretion elicited by direct neural activation of the juxtaglomerular granular cells. The data suggest that phenoxybenzamine inhibits neurally mediated renin secretion by a mechanism other than renal alpha-adrenoceptor blockade.

Inhibition of renin secretion by intrarenal alpha-adrenoceptor blockade.

This study was designed to determine whether renal alpha-adrenoceptors can mediate tonic neural stimulation of renin secretion. The effect of alpha-adrenoceptor blockade by phenoxybenzamine (POB) or prazosin on renin secretion rate (RSR) was studied in pentobarbital-anesthetized dogs in which renal perfusion pressure was held constant with an adjustable aortic clamp. POB alone (100 micrograms.kg-1.min-1 iv) did not change arterial plasma renin activity (PRA). However, when beta-adrenoceptors were blocked by intravenous propranolol, intravenous POB infusion (100 micrograms.kg-1.min-1) decreased PRA and RSR to 48 +/- 8 and 21 +/- 9% of previous levels within 30 min. This effect was abolished by acute bilateral renal denervation. Direct intrarenal POB infusion (10 or 3.3 micrograms.kg-1.min-1) decreased RSR, whereas intravenous POB (3.3 micrograms.kg-1.min-1) had no effect on either RSR or PRA in propranolol-pretreated dogs. Prazosin (1 microgram.kg-1.min-1 iv) also significantly decreased PRA. These data indicate that when beta-adrenoceptors are blocked by propranolol, tonic neural stimulation of renin secretion is mediated by renal alpha-adrenoceptors.