Renal Alpha 2-adrenergic Receptor Research Articles

Sexual dimorphism of renal alpha2-adrenergic receptor regulation in Dahl rats.

Male Dahl salt-sensitive hypertensive (S) rats develop hypertension faster than females. We measured renal alpha2-adrenergic receptor density of inbred Dahl salt-sensitive (SS/JR) and salt-resistant (SR/JR) rats, using [3H]-rauwolscine saturation binding studies. Male and female SS/JR rats were gonadectomized or sham-operated at 6 weeks of age and fed a high salt diet for 4 weeks. Additional intact SS/JR and SR/JR rats of both sexes were fed the high salt diet for a longer period of time (7 weeks instead of 4 weeks). Both blood pressure and renal alpha2-adrenergic receptor density were significantly higher in male than female SS/JR rats on high salt diet for 4 weeks. Gonadectomy did not change blood pressure nor did it change renal alpha2-adrenergic receptor density measured at the 4th week of high salt feeding in either male or female SS/JR rats. When the SS/JR rats were fed high salt diet for a longer period (for 7 weeks), blood pressure of female SS/JR reached the level of males, but the density of renal alpha2-adrenergic receptors was still significantly lower than that of males. Both renal alpha2-adrenergic receptor density and blood pressure were higher in male than female SR/JR. We conclude that higher blood pressure in male Dahl SS/JR and SR/JR rats is associated with higher renal alpha2-adrenergic receptor density compared with their female counterparts.

Sex influence on renal alpha 2-adrenergic receptor density in the spontaneously hypertensive rat.

Male spontaneously hypertensive rats (SHR) have higher blood pressure than females. We compared renal alpha 2-adrenergic receptor density among intact SHR and Wistar-Kyoto (WKY) rats of both sexes, male and female SHR gonadectomized at 4 weeks of age, and gonadectomized SHR supplemented with testosterone. Additional groups of SHR were treated with enalapril (30 mg/kg per day), an angiotensin-converting enzyme inhibitor, from 5 to 14 weeks of age. Renal alpha 2-adrenergic receptor density was higher in males than females in both SHR and WKY rats. Female SHR and WKY rats had identical low renal alpha 2-adrenergic receptor density. Castration of male SHR reduced the male-female differences in blood pressure and renal alpha 2-adrenergic receptor density by 60%. Treatment with testosterone raised blood pressure and renal alpha 2-adrenergic receptor density to the intact male levels in both gonadectomized males and females. Treatment with enalapril decreased blood pressure but not renal alpha 2-adrenergic receptor density in both male and female SHR. We conclude that (1) both renal alpha 2-adrenergic receptor density and blood pressure are influenced by sex in SHR and WKY, (2) renal alpha 2-adrenergic receptor density like blood pressure is regulated by androgens, and (3) increased renal alpha 2-adrenergic receptor density is not a consequence of high blood pressure in male SHR.

Upregulation of renal alpha 2-adrenergic receptors is not indicative of salt-related increases in blood pressure in spontaneously hypertensive rats.

The aim of the present study was to determine if elevations in salt intake were coupled to increases in renal alpha 2-adrenergic receptors in SHR that differ in their blood pressure response to high salt diets. Salt-resistant spontaneously hypertensive rats (SHR-R), which do not increase their blood pressure in response to high salt intake, and salt-sensitive spontaneously hypertensive rats (SHR-S), which do exhibit significant elevations in blood pressure on high salt diets (3.15% NaCl), were used. Radioligand binding studies using [3H]rauwolscine were performed on 6- and 11-week-old SHR-S and Wistar-Kyoto (WKY) rats to determine the effects of age, strain, and salt intake on alpha 2-adrenergic receptor number and affinity. One week of high salt intake significantly increased blood pressure 22% in 6-week-old SHR-S and increased the blood pressure of 11-week-old SHR-S 12% without altering WKY rat controls. This treatment did not significantly increase renal alpha 2-adrenergic receptors in either SHR-S or WKY rats. SHR-S had significantly higher numbers of renal alpha 2-adrenergic receptors than WKY rats on the high salt diets. One week of high (3.15%) or low (0.05%) salt intake did not significantly alter renal alpha 2-adrenergic receptor number in 11-week-old SHR-S or WKY rats; however, blood pressure was significantly elevated in the SHR-S (175.0 +/- 3.5 versus 196.0 +/- 3.0 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Neural-Renal Interactions in the Hypertension Induced by Papillary Necrosis: Role of Dietary Salt Intake

The effects of high salt intake (1.0% NaCl in the drinking water) on rats made hypertensive by 2-bromoethylamine hydrobromide (BEA) treatment (200 mg/kg, i.p.) were examined. BEA-induced medullary necrosis resulted in a mild hypertension (146 +/- 5 mm Hg) that was exacerbated by 4 weeks of high salt intake (163 +/- 6 mmHg). BEA-treated rats had significant salt-induced increases in urinary norepinephrine excretion and hypothalamic and brainstem norepinephrine content, that were not present in BEA-treated rats drinking tap water or control rats drinking saline. BEA treatment in combination with increased salt intake produced a decrease (p less than 0.05) in renal dopamine content and adrenal norepinephrine stores relative to BEA treatment alone. BEA treatment also significantly decreased renal norepinephrine stores and dopamine binding sites irrespective of salt intake. Renal alpha 2-adrenergic receptors and central nervous system stores of dopamine and serotonin were unaffected by BEA treatment. Renal function was well preserved as indicated by normal creatinine, glucose and protein excretion; however, significant (p less than 0.05) disruption of the urinary concentrating mechanism was present. These studies suggest that BEA-induced hypertension has a neural component that is exacerbated by high salt intake. The primary defect in BEA hypertension appears to be the lack of circulating antihypertensive lipids that attenuate the ability of salt loads to simulate sympathetic nervous system activity.

Two renal alpha 2-adrenergic receptor sites revealed by p-aminoclonidine binding

[3H]p-aminoclonidine [3H]PAC, a specific alpha 2-adrenergic agonist, was used to characterize alpha 2-adrenoceptor binding in rat renal membranes. Rosenthal plots demonstrated two binding sites with Kds of approximately 1.7 and 14.2 nM and Bmaxs (maximum binding) of 47.3 and 218.8 fmol/mg protein for the high- and low-affinity sites, respectively. These characteristics were confirmed by estimate of Kd parameters based on association and dissociation experiments. Pseudo-Hill coefficients generated from drug inhibition experiments were all less than unity, suggesting differential binding at two alpha 2-adrenoceptor binding sites. Specific alpha 2-adrenergic agonists exhibited greater binding affinity to both sites than did nonspecific drugs, and all drugs displayed greater affinity for the high- than the low-affinity binding site. Both guanyl nucleotides and sodium chloride inhibited [3H]PAC binding more at the high-affinity than at the low-affinity site. Renal denervation resulted in significant upregulation of receptor density only at the high-affinity sites with no change in receptor affinity at either site, suggesting that a majority of the alpha 2-adrenoceptors in the kidney are postsynaptic. Thus all lines of evidence in this study indicate that two alpha 2-adrenoceptor binding sites exist in the rat kidney.

Renal catecholamines and alpha 2-adrenergic receptors in salt-related and genetic hypertension.

Increased dietary salt intake alters renal function which often leads to deleterious cardiovascular consequences. Studies were carried out to characterize the effects of high-salt diets on renal catecholamines and alpha 2-adrenergic receptors. These parameters were evaluated in both genetic and acquired forms of hypertension and also in normotensive rats on high-salt diets. Renal catecholamine content was determined by high-performance liquid chromatography with electrochemical detection. Renal alpha 2-adrenergic receptor-binding studies were performed on whole kidney homogenates using 3H-p-aminoclonidine to label both high- (0.5 nM) and low-affinity (5.0 nM) renal alpha 2-adrenergic receptors. Increased salt intake elevated blood pressure, decreased renal norepinephrine stores and resulted in renal alpha 2-adrenergic receptor up-regulation in deoxycorticosterone acetate salt hypertensive rats, Dahl-S rats and COX-SHR. The decreased renal stores of norepinephrine (NE) appeared to reflect increased renal NE utilization. In contrast, SHR (Charles River) had elevated NE stores and alpha 2-adrenergic receptors while on normal salt diets. Short-term (10-14 days) exposure to high-salt diets had modest effects in normotensive rats or COX-SHR, although it was sufficient to increase low affinity renal alpha 2-adrenergic receptor number. Renal dopamine metabolism was also altered by high-salt diets. These studies demonstrated a relationship between renal NE content and renal alpha 2-adrenergic receptors. The implications of this relationship and other salt-related changes in renal catecholamine metabolism were discussed as they pertained to hypertension and renal function.

Role of renal alpha 2-adrenergic receptors in spontaneously hypertensive rats.

To identify a physiological role for renal alpha 2 adrenergic receptors, renal vascular and tubular responses to administration of graded frequencies of renal nerve stimulation or graded doses of adrenergic agonists were determined in anesthetized spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rats. Renal vasoconstrictor responses to renal nerve stimulation and alpha 1-adrenergic receptor agonists (norepinephrine, phenylephrine) were inhibited by an alpha 1-adrenergic receptor antagonist (prazosin) but not by an alpha 2-adrenergic receptor antagonist (rauwolscine). A semilog plot of renal vasoconstrictor responses a fraction of control renal blood flow versus agonist dose (in nanograms) was linear with the slope, k, taken as the fractional decrease in renal blood flow per nanogram. The alpha 2-adrenergic receptor agonists (clonidine, guanabenz) produced minimal renal vasoconstrictor responses (fractional decrease in renal blood flow per nanogram: norepinephrine, 0.011; phenylephrine, 0.003; clonidine, 0.00087; guanabenz, 0.000037). The small renal vasoconstrictor responses to clonidine and guanabenz were more inhibited by rauwolscine than by prazosin. Low frequency renal nerve stimulation produced antidiuresis and antinatriuresis without decreasing glomerular filtration rate or renal blood flow. The antidiuretic and antinatriuretic responses were inhibited by prazosin but unaffected by rauwolscine. The magnitude of the renal vascular and tubular responses and their adrenergic receptor mediation were not different between spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal alpha 2-adrenergic receptors multiply and mediate sodium retention after prazosin treatment.

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)

Renal alpha-adrenergic receptor abnormality in the spontaneously hypertensive rat.

Activation of renal alpha-adrenergic receptors induces vasoconstriction, proximal tubular reabsorption of sodium, and inhibition of renal release. Excesses of these effects are present in varying degrees in animal models of, and in patients with, "essential" hypertension. Since essential hypertension is genetically determined, we sought abnormalities of renal alpha-adrenergic receptors in the Okamoto-Aoki strain of spontaneously hypertensive rats (sr-SHR) and their stroke-prone variant (sp-SHR). Total alpha-adrenergic receptor concentrations were determined by Scatchard analysis of [3H]dihydroergocryptine binding to a renal membrane fraction and were found to be increased (p less than 0.02) in male sr-SHR at 4, 16, and 32 weeks of age and in female sr-SHR at 16 weeks of age as compared to age- and sex-matched Wistar-Kyoto controls. They were also increased in 9-week-old sp-SHR renal membranes (p less than 0.005). Further studies revealed that this increase in renal alpha-adrenergic receptors was due entirely to an increase in alpha 2-receptors as measured by [3H]yohimbine binding rather than to an increase in alpha 1-receptors as quantitated by [3H]prazosin binding. No difference in binding affinities of the various radioligands could be demonstrated between any of the hypertensive and normotensive groups of rats. Plasma norepinephrine levels were elevated (p less than 0.01) in the 4-, 9- and 16-week-old SHR, but not in the 32-week-old hypertensive rats. Thus, high renal alpha 2-adrenergic receptor number is coupled with a significant increase in plasma norepinephrine concentrations during the development of hypertension in SHR. By mediating an enhanced receptor-coupled response, such as increased proximal tubular sodium reabsorption, this abnormality of renal alpha-adrenergic receptors may contribute to some or all of the pathophysiologic derangements leading to hypertension in SHR.

Altered renal alpha 2-adrenergic receptor regulation in genetically hypertensive rats.

Renal alpha 1 and alpha 2-adrenergic receptors were quantified in Dahl salt-sensitive and salt-resistant rats, in Okamoto-Aoki spontaneously hypertensive rats (SHR), in Wistar Kyoto "normotensive" (WKY), and in Charles River rats made hypertensive by the Grollman ligature technique and by DOC-NaCl administration after unilateral nephrectomy. The effect of high dietary NaCl on renal alpha receptors was studied in Dahl, SHR, and WKY rats. Renal alpha 1 and alpha 2 receptor densities were higher (p less than 0.05) in SHR and in Dahl salt-sensitive rats than in their normotensive controls. High dietary sodium increased renal alpha 2 receptors and blood pressure in SHR, WKY and Dahl salt-sensitive, but not in resistant Dahl rats. A study of time relationships revealed that the increase in renal alpha 2 receptors preceded most of the blood pressure elevation due to high dietary sodium. Renal alpha-adrenergic receptor densities of surgical (Grollman) and endocrine (DOC-NaCl) forms of rat hypertension were not different from normotensive controls. Thus, renal alpha 2 receptor density and increase thereof by dietary sodium may be: 1) a biochemical marker for genetic forms of hypertension in the rat, and 2) closely linked to the basic mechanism of high blood pressure.

Altered renal alpha 2-adrenergic receptor regulation in genetically hypertensive rats

Altered renal alpha 2-adrenergic receptor regulation in genetically hypertensive rats

Dietary Sodium and Renal α2-Adrenergic Receptors in Dahl Hypertensive Rats

Dahl sodium-sensitive and resistant rats were fed low and high sodium diets. Renal plasma membrane alpha 2-adrenergic receptor concentrations were greater (p less than .05) in sensitive than in resistant rats while ingesting a low sodium diet. On a high sodium diet the alpha 2 receptor concentration increased (p less than .01) in sensitive but not in resistant rats. Since alpha 2 receptors are located in proximal tubules at sites where norepinephrine induces sodium reabsorption, we postulate that this genetically determined abnormal receptor regulation could lead to exaggerated sodium retention and possibly high blood pressure.

Effect of renal alpha-adrenergic stimulation on proximal tubular sodium reabsorption.

ARTICLESEffect of renal alpha-adrenergic stimulation on proximal tubular sodium reabsorption Gill JR Jr, and AG Casper Gill JR Jr, and AG CasperPublished Online:01 Nov 1972https://doi.org/10.1152/ajplegacy.1972.223.5.1201MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByLandscape of GPCR expression along the mouse nephronBrian G. Poll, Lihe Chen, Chung-Lin Chou, Viswanathan Raghuram, and Mark A. 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