Renal Alpha 2-adrenoceptors Research Articles

Factors that influence the risk of hypertension in obese individuals.

Obesity, which has reached epidemic prevalence, is now recognized as an independent risk factor for increasing blood pressure. The complex mechanisms of obesity-related hypertension are unclear, but several studies have provided evidence of a hypertensive shift in pressure natriuresis. Excess sympathetic outflow to the kidneys and changes in renal structure and function may both affect the renal pressure relationship. Other factors that may contribute to altered natriuresis include hyperinsulinemia, hyperleptinemia and activation of the renin-angiotensin system. Disruption of the renal alpha2 adrenoceptors or leptin receptor implicated in natriuresis control may also be an additive risk for the increase in tubular reabsorption in obesity hypertension. Recent advances have highlighted the importance of two adipocyte-derived hormones - leptin and angiotensinogen - in obesity hypertension. Leptin has direct central effects that increase sympathetic outflow to the kidney and the new concept of selective leptin resistance, suggests the maintenance of leptin-induced sympathetic activation in obesity, despite resistance to leptin metabolic effects. On the other hand, a recent study showed that angiotensinogen produced in the adipocyte is also relevant to blood pressure control. The article reviews the factors implicated in the disruption of blood pressure control in obesity. Further investigation on the time course of the disease would reveal the relative importance of each of the factors that influence the risk of hypertension in obese individuals.

Influence of the sympathetic nervous system on renal function during hypothermia.

Hypothermia increases preglomerular vasoconstriction leading to decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Since plasma catecholamine concentrations are increased during hypothermia, the present study was performed to determine the role of the renal sympathetic nervous system in the cold-induced renal vasoconstriction. In Inactin anaesthetized rats, hypothermia at 28 degrees C decreased GFR by 50% but failed to alter efferent renal sympathetic nerve activity (ERSNA). Since hypothermia causes shivering which could have influenced the ERSNA recording, Inactin anaesthetized rats were treated with pethidine or rats were anaesthetized with pentobarbital sodium or Saffan to eliminate cold-induced shivering. In these non-shivering rats, hypothermia produced a reversible decrease in ERSNA in association with a fall in GFR that was of a similar magnitude as in shivering rats. Further studies in Inactin anaesthetized rats showed that the fall in GFR was unaltered by renal denervation, bilateral adrenalectomy or intrarenal administration of the alpha 1-adrenoceptor antagonist prazosin. We conclude that cold-induced renal vasoconstriction is not due to an increase in ERSNA or adrenaline/noradrenaline-mediated activation of renal alpha 1-adrenoceptors.

Regulation of renal alpha2-adrenoceptor activity in Dahl salt-sensitive rats by dietary sodium changes

The objective of the study was to evaluate the concept that genetically predisposed salt-sensitivity contributes to an increased adrenergic susceptibility and renal alpha 2-adrenoceptor (A2) abnormality in Dahl salt-sensitive hypertensive rats. The results showed: i) After 2 months of Na-loading (8% NaCl) Dahl salt-sensitive (DSS) rats expressed increased sodium and water retention which paralleled gradual development of diastolic hypertension. Low Na diet (0.5% NaCl) does not prevent hypertension but delays its development. ii) The increased activity of the sympathetic nervous system (SNS), in DSS rats corresponded to the development of hypertension and was stimulated by Na-loading. It was assessed by plasma catecholamine levels and heart rate changes. iii) The increased density of renal A2 by 29% was upregulated by high sodium diet, and coupled with increased norepinephrine level by 53%, only in DSS but not in DSR rats. iv) No strain renal A2 and epinephrine differences between DSS and DSR were found in weanling, prehypertensive rats, or in the adult DSS and DSR on low Na diet. By mediating an enhanced receptor-coupled response, such as increased proximal tubular sodium reabsorption during sodium loading, a genetic abnormality of renal alpha 2-adrenoceptors may contribute to some of the pathophysiologic derangements leading to hypertension in Dahl salt-sensitive rats.

Adrenoceptors in SHR: Alterations in binding characteristics and intracellular signal transduction pathways

There is much data on altered adrenoceptor function in the heart, blood vessel and kidney from spontaneously hypertensive rats (SHR). The enhancement of vascular and renal alpha-adrenoceptor Function, I.e. vasoconstriction and retension of water and sodium, may contribute to the development and maintenance of the hypertension, whereas cardiac alpha-adrenoceptor may be of minor physiological significance. Alpha 1-adrenoceptor-mediated signal transduction as a whole is increased in SHR vascular tissues, but the intracellular signaling per receptor in the kidney seems to be decreased despite increased alpha 1-adrenoceptor density. On the other hand, cardiac and vascular beta-adrenoceptor responsiveness is attenuated in SHR. Reduced vasorelaxation medated by beta-adrenoceptors may also contribute to high blood pressure. The impaired cardiovascular beta-adrenoceptor function in SHR does not appear to be necessarily explained by alterations observed at receptor levels. Alterations in signal transduction should be also considered. Limited data on renal beta-adrenoceptor density and its signaling suggest decreased or unaltered cyclic AMP formation per receptor in SHR. We will review alterations in both binding characteristics and each component of intracellular signal transduction pathways in cardiovascular and renal adrenoceptors of SHR.

Alpha 2-adrenoceptors determine the response to nitric oxide inhibition in the rat glomerulus and proximal tubule.

Arginine-derived nitric oxide exerts control over the processes of glomerular filtration and tubular reabsorption. The tonic influence of nitric oxide over both of these is eliminated by renal denervation. The hypothesis that the renal nerves function, in this regard, via the activation of alpha 2-adrenoceptors was tested by renal micropuncture. The physical determinants of glomerular filtration and proximal tubular reabsorption were assessed in Munich-Wistar rats before and during the administration of the nitric oxide synthase inhibitor NG-monomethyl L-arginine (L-NMMA). In one set of studies, the systemic infusion of the alpha 2-agonist B-HT 933 rendered nephron GFR, nephron plasma flow, and proximal reabsorption sensitive to reduction by L-NMMA after renal denervation. In a second set of studies, the infusion of the alpha 2 receptor antagonist, yohimbine, to rats with renal nerves intact was found to suppress the effects of L-NMMA on nephron plasma flow and proximal reabsorption. The effects of L-NMMA on nephron GFR and nephron plasma flow, afferent and efferent arteriolar resistances, and proximal reabsorption correlated with the level of underlying alpha 2-adrenergic activity. The activation of renal alpha 2-adrenoceptors increases the influence of arginine-derived nitric oxide in the glomerulus and proximal tubule.

Differential sodium regulation between salt-sensitive and salt-resistant sabra rats is not due to any mutation in the renal α 2B-adrenoceptor gene

A defect in sodium modulation of density and agonist affinity of renal alpha 2-adrenoceptor exists in normotensive salt-resistant Sabra (SBN) rats when compared to hypertensive salt-sensitive (SBH). A highly conserved aspartic acid residue in the second helix has been implicated in sodium regulation of alpha 2-adrenoceptor-ligand interactions. As the alpha 2B-adrenoceptor subtype is preponderantly present in kidney of SBH and SBN rats, a mutation might distinguish this subtype between SBH and SBN rats. From this study, no difference between SBH and SBN alpha 2B-adrenoceptor gene could be demonstrated in terms of nucleotide sequence. These data suggest that in Sabra rats, the differential sodium regulation in density and agonist affinity between renal SBH and SBN alpha 2-adrenoceptor may have another origin than the alpha 2B-adrenoceptor encoding gene.

Ontogenic changes in renal response to alpha 1-adrenoceptor stimulation in sheep.

The present study was designed to examine the effect of direct intrarenal infusion of the alpha 1-adrenoceptor agonist, phenylephrine, on urinary flow rate (UFR) and on renal Na and Cl excretion in conscious and chronically instrumented fetal (128-133 days gestation, term 145 days), newborn (6-12 days), and adult sheep. Five different renal concentrations of phenylephrine, varying from 5 +/- 1 to 72 +/- 2 ng/ml, were studied. Low renal phenylephrine concentration (< or = 12 +/- 1 ng/ml) induced a significant renal vasoconstrictor response in fetuses but not in newborn and adult sheep. The effects of intrarenal phenylephrine infusion on UFR and fractional excretion of Na (FENa) was greater (P < 0.05) in newborn lambs than in fetal and adult sheep. At a renal concentration of phenylephrine between 9 +/- 1 and 12 +/- 1 ng/ml, the percent decrease in UFR was greater (P < 0.05) in newborn lambs (-19.1 +/- 4.7%) than in fetal (9.8 +/- 8.9%) and adult sheep (-3.3 +/- 3.9). The percent decrease in FENa at renal concentration of phenylephrine between 18 +/- 1 and 24 +/- 1 ng/ml was also significantly (P < 0.05) larger in newborn lambs (-20.2 +/- 2.8%) than in fetal (-8.0 +/- 3.1%) and adult sheep (-11.2 +/- 2.6%). In summary, the present results indicate that the fetal kidney has a limited ability to increase sodium reabsorption in response to stimulation of alpha-adrenoceptors and that the effect of renal alpha-adrenoceptor stimulation on urinary volume and urinary sodium excretion increases during the newborn period.

Renal alpha 2-adrenoceptors in New Zealand genetically hypertensive rats.

1. Renal alpha 1- and alpha 2-adrenoceptors were characterized in the New Zealand strain of genetically hypertensive (GH) rat and the Otago random-bred albino normotensive (NT) control rat at 4 and 12 weeks of age with [3H]-prazosin and [3H]-rauwolscine. 2. At 4 weeks of age, the density of alpha-adrenoceptors in NT and GH rats was similar to both the alpha 1- (193 +/- 11 vs 163 +/- 14 fmol mg-1 protein) and alpha 2- (347 +/- 34 vs 319 +/- 41 fmol mg-1 protein) adrenoceptor. At 12 weeks of age, GH rats had a greater density of renal alpha 1- (152 +/- 27 vs 238 +/- 17 fmol mg-1 protein) and alpha 2- (175 +/- 42 vs 350 +/- 23 fmol mg-1 protein) adrenoceptors compared to the NT rats. 3. Pre-incubation of kidneys from GH rats (12 weeks of age) with 1 and 10 microM clonidine decreased the density of receptors identified by unlabelled clonidine displacement of [3H]-rauwolscine to 77% and 56% of control. Pre-incubation with adrenaline, 2,6 dimethylclonidine or phenylephrine failed to alter binding. 4. Pre-incubation of kidneys from NT rats (12 weeks) or young GH rats (4 weeks) with 10 microM clonidine failed to alter displacement of [3H]-rauwolscine by unlabelled clonidine. 5. These studies demonstrate that in another strain of hypertensive rat, the GH rat, alpha 2-adrenoceptor density is increased as compared to the normotensive control at 12 but not 4 weeks of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual adrenergic control of renin during nonhypotensive hemorrhage in conscious dogs.

These experiments evaluated the contribution of renal alpha-adrenoceptors, renal beta-adrenoceptors, and extrarenal beta-adrenoceptors to increased plasma renin activity (PRA) during nonhypotensive hemorrhage in conscious dogs. Blood withdrawal at a rate of 16 g/kg body wt over 20 min increased PRA to nearly threefold control levels without decreasing mean arterial pressure. The PRA response to hemorrhage was reduced to a greater extent by simultaneous direct renal arterial (ira) infusion of phenoxybenzamine and propranolol than by propranolol alone. Phenoxybenzamine infusion ira did not block alpha-adrenoceptors located outside of the kidney. The PRA and heart rate responses to hemorrhage were both significantly reduced when propranolol was infused either ira or intravenously (iv) at a rate of 2 micrograms.kg-1.min-1 for 20 min followed by 0.5 microgram.kg-1.min-1 continuous infusion. Propranolol infusion at a lower rate (0.5 microgram.kg-1.min-1 for 20 min followed by 0.12 microgram.kg-1.min-1) had little effect on the magnitude of increase in PRA when infused either iv or ira. The calculated renal arterial plasma propranolol concentration was at least fivefold higher or more during ira than during iv propranolol infusion at each rate and was approximately the same during ira infusion at the lower rate (17.5 +/- 0.7 ng/ml) as during iv infusion at the higher rate (16.7 +/- 2.4 ng/ml). These data indicate that the hemorrhage-induced increase in PRA is mediated by renal alpha-adrenoceptors and extrarenal beta-adrenoceptors, whereas renal beta-adrenoceptors appear to play little or no role.

Autoradiographic Localization and Computerized Quantification of α1- and α2-Adrenoceptors in Spontaneously Hypertensive Rat Kidney: [3H]Bunazosin and [3H]Yohimbine Binding Studies

The autoradiographic localization of alpha 1- and alpha 2-adrenoceptors was identified in 22-week-old Wistar-Kyoto rat kidney, using alpha 1-selective ([3H]bunazosin) and alpha 2-selective ([3H]yohimbine) antagonists. [3H]Bunazosin binding was distributed predominantly over the cortex, less over the outer medulla and was absent from the inner medulla. [3H]Yohimbine binding was distributed predominantly over the medulla, less over the renal cortex and was absent from the inner medulla. In addition, the distribution of renal alpha-adrenoceptors was investigated in 3-, 7- and 22-week-old spontaneously hypertensive rats (SHRs) using a computerized image analysis system. Renal alpha-adrenoceptors were both found to be increased in SHRs at all ages tested compared with their respective controls and were increased in both the cortex and the outer medulla. The increase in renal alpha-adrenoceptors was already present in 3-week-old SHRs whose systolic blood pressures did not differ significantly from those of the controls. The results strongly suggest that these abnormalities of renal alpha-adrenoceptors may play a critical role in the development of hypertension in SHRs.

Sodium regulation in the affinity of renal alpha 2-adrenoceptors for epinephrine in Sabra salt-sensitive and salt-resistant rats.

Sodium ions markedly decreased in vitro renal alpha 2-adrenoceptor affinity for epinephrine in Sabra hypertensive (SBH) but not in normotensive (SBN) rats. Under these conditions, affinity of alpha 1-adrenoceptor for epinephrine was unchanged in SBH and SBN rats. If these data could be confirmed in vivo, the sodium ion, by acting as an inhibitor, could modify the effect of agonists on renal alpha 2-adrenoceptors in SBH rats. Conversely, the absence of sodium regulation in SBN rats might represent a genetically mediated change responsible for the resistance to the development of salt-induced hypertension.

Characterization of renal alpha-adrenoceptor subtypes in sheep during development.

Intrarenal arterial infusion of alpha 1-adrenergic agonists decreases renal blood flow, glomerular filtration rate, and water and sodium excretion to a greater extent in fetus and newborn than in adult sheep. In vitro renal vascular effects of alpha 1- and alpha 2-adrenergic agonists are also greater in fetus than newborn or adult. The present studies were designed to examine the ontogeny of renal alpha-adrenoceptor subtypes in sheep for whom the renal effects of alpha-adrenergic agonists have been described at similar postconceptional ages. With the use of radioligand-binding techniques, specific binding of [3H]prazosin (alpha 1-adrenergic antagonist), [3H]idazoxan, and [3H]rauwolscine (alpha 2-adrenergic antagonists) was studied in fetus, lamb, and adult sheep kidneys. The specific binding of the three radioligands was greatest in fetal and least in adult kidneys. Analysis of Scatchard plots revealed a greater renal alpha 1-adrenoceptor density in fetuses than in lamb or adults. Renal alpha 2-adrenoceptor density was also greater in fetuses than in lambs. These studies suggest that the increased renal alpha 1- and alpha 2-adrenergic effects in fetal sheep are related to increased alpha-adrenoceptor density. Competition experiments and rank adrenergic antagonist potency suggested the presence of only the alpha 1b-adrenoceptor in fetal and adult sheep kidneys. The alpha 2-adrenoceptor that was found only in the fetal sheep had a low affinity to rauwolscine, which is unlike that described in most species for alpha 2-adrenoceptors.

Modulation of vasopressin antidiuretic action by renal alpha 2-adrenoceptors

It has been almost 40 years since the diuretic effect of alpha-adrenoceptor agonists was first demonstrated. Two possible mechanisms were proposed: inhibition of vasopressin secretion and antagonism of the cellular hydrosmotic actions of vasopressin. The debate could not be settled then for the lack of appropriate experimental models and pharmacological tools. Advances made in adrenoceptor pharmacology in the 1970s such as 1) subdivision of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes; 2) development of selective agonists and antagonists; and 3) localization of both adrenoceptor subtypes in the kidney, including the proximal and collecting tubules, stimulated new research. With regard to renal adrenoceptors, selective alpha 2-agonists have been shown to induce diuresis in dogs and rats. Whereas in the dog the increase in urine flow results mostly from an increase in osmolal clearance, in the rat the diuresis results in large part from an increase in the excretion of solute-free water. In vitro studies on isolated collecting tubules from rats and rabbits (none from dogs) have shown that alpha 2-agonists inhibit vasopressin-induced adenosine 3',5'-cyclic monophosphate formation and that this effect is mediated by the inhibitory guanine nucleotide regulatory protein and abolished by pertussis toxin treatment. In vivo evidence in support of such a mechanism was presented from conscious Brattleboro homozygous rats in which a selective alpha 2-agonist inhibited the antidiuretic effect of exogenous vasopressin, and this effect was abolished by pertussis toxin. The physiological importance of renal alpha 2-adrenoceptors was identified by use of adrenal medullectomized rats and the alpha 2-antagonist, yohimbine.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered Renal α-Adrenoceptor Density Induced by Prolonged NaCl and DOCA Administration in Spontaneously Hypertensive Rats

This study examines the effects of a 6-week exposure to 1% NaCl in tap water with and without desoxycorticosterone acetate (DOCA) on renal alpha adrenoceptors and systolic blood pressure (SBP) in spontaneously hypertensive adult rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. On normal sodium intake, SHR had higher renal alpha 1- (p less than 0.05) and alpha 2-adrenoceptor densities (p less than 0.001) and SBP (p less than 0.001) than WKY rats. Although WKY rats given either 1% NaCl, DOCA, or DOCA plus 1% NaCl developed hypertension after 6 weeks of treatment, only 1% NaCl administration for the same period produced an increase in the alpha 1-adrenoceptor density when compared to the control (p less than 0.001). In SHR, ingestion of 1% NaCl or DOCA plus 1% NaCl increased the already elevated alpha 2-adrenoceptor density (p less than 0.001) and SBP even more in this strain after 6 weeks of treatment. Equilibrium dissociation constants (Kd), however, were similar for both classes of receptors in experimental and control rats. The results of this study indicate that only the combination of 1% NaCl in tap water and DOCA administration is effective in accelerating hypertension in adult SHR. On the other hand, in this form of genetic rat hypertension, exaggerated sodium intake with or without DOCA administration could presumably be correlated with the increased renal alpha 2 adrenoceptors observed in these animals.

α‐ADRENOCEPTOR PROPERTIES IN RAT STRAINS SENSITIVE OR RESISTANT TO SALT‐INDUCED HYPERTENSION

Cerebral and renal alpha 2-adrenoceptors are implicated in the control of sympathetic activity and of sodium reabsorption respectively. In addition, sodium ions play an important role in the regulation of either alpha 2-adrenoceptor densities and affinities for adrenergic agonists. In the present study, alpha-adrenoceptor properties were investigated in genetically predetermined salt-sensitive and salt-resistant Dahl and Sabra rats. Cerebral alpha 2-adrenoceptor densities were higher in salt-resistant than in salt-sensitive Dahl and Sabra rats. In contrast, renal alpha 2-adrenoceptor density was higher in salt-sensitive than in salt-resistant rats. No difference in cerebral and renal alpha 1-adrenoceptor densities was observed between Dahl and Sabra substrains. Noradrenaline content in cerebral and renal cortex were also similar in both these rat substrains. Sodium ions markedly increased cerebral and renal high-affinity alpha 2-adrenoceptor densities in salt-sensitive but not in salt-resistant rats. Cerebral and renal alpha 1-adrenoceptor densities were unchanged in salt-sensitive and salt-resistant substrains of Dahl and Sabra rats. In addition, sodium ions reduced the affinity of adrenaline for renal alpha 2-adrenoceptors in salt-sensitive rats but not in salt-resistant rats. We can conclude that there exist genetically determined differences in the densities and properties of cerebral and renal alpha 2-adrenoceptors between salt-sensitive and salt-resistant rat strains. Abnormal densities of alpha 2-adrenoceptors may play a primary role in the role in the development of hypertension in salt-sensitive animals. These results also suggest an association between absence of sodium regulation of alpha 2-adrenoceptors and resistance to salt-induced hypertension. The absence of sodium regulation in salt-resistant rats may be linked either to a particular receptor conformation or to an abnormal structure of the receptor system. This property may represent a genetically-mediated change responsible for the resistance to the development of salt-induced hypertension.

Adrenergic control of renin during dietary sodium deprivation in conscious dogs

These experiments evaluated the contribution of alpha- and beta-adrenergic stimulation to plasma renin activity (PRA) during early and long-term dietary sodium restriction, compared with normal sodium intake. Uninephrectomized conscious dogs with catheters in the aorta, vena cava, and remaining renal artery were studied during normal sodium diet (approximately 70 meq/day), after 2-3 days of low-sodium diet (5-7 meq/day), and after greater than or equal to 2 wk of low-sodium diet. Direct renal arterial (ira) infusion of phenoxybenzamine plus propranolol decreased PRA by similar proportions (39-48%) during all three states of dietary sodium intake. The PRA achieved after adrenergic blockade remained higher (P less than 0.05) during early and long-term sodium restriction than during normal sodium intake. The effect on PRA of ira infusion of propranolol alone was not different from that of phenoxybenzamine plus propranolol during normal or low-sodium diet, and the magnitude of decrease in PRA during low-sodium diet was the same whether propranolol (1 microgram.kg-1.min-1) was infused ira or intravenously. In summary, beta-adrenergic stimulation accounts for similar proportions of PRA during early and long-term dietary sodium restriction and during normal sodium intake. Renal alpha-adrenoceptors appear to play little or no role in control of PRA under these conditions.

α- and β-Adrenoceptors in Hypertension. I. Cardiac and Renal α1-, β1, and β2-Adrenoceptors in Rat Models of Acquired Hypertension

To determine whether adrenoceptor changes in genetic hypertension occur primary or secondary to blood pressure elevation, we measured cardiac and renal alpha 1- (by [125I]Be 2254 binding) and beta 1- and beta 2-adrenoceptors (by (-)-[125I]iodocyanopindolol binding) densities in various rat models of acquired hypertension (Dahl S rats on a high-sodium diet, 1-clip-1-kidney (1C-1K) renal hypertensive and DOCA-salt hypertensive rats) in comparison with genetically identical age-matched untreated rats. In addition, alpha 1-adrenoceptors were assessed in spontaneously hypertensive rats (SHR) and in SHR treated with the immunosuppressant cyclosporin A. In heart, no clear pattern of changes in alpha 1- or beta 1- and beta 2-adrenoceptors was obtained. In kidney, however, beta 1- and beta 2-adrenoceptors were increased in all models of hypertension, and a good correlation between renal beta-adrenoceptors and systolic blood pressure was found. In contrast, renal alpha 1-adrenoceptors were only increased in SHR but not in any form of acquired hypertension. Thus, renal beta-adrenoceptor increases probably occur secondary to blood pressure elevation, whereas alpha 1-adrenoceptor increases appear to be associated with genetic hypertension. Because renal alpha-adrenoceptors are linked to tubular sodium reabsorption, we suggest that an increase in renal alpha 1- (and alpha 2)-adrenoceptors may be a very early step in the development of genetic hypertension.

α- and β-Adrenoceptors in Hypertension. II. Platelet α2- and Lymphocyte β2-Adrenoceptors in Children of Parents with Essential Hypertension. A Model for the Pathogenesis of the Genetically Determined Hypertension

To study whether changes in alpha- and beta-adrenoceptors in human essential hypertension (EHT) might be genetically determined, we assessed platelet alpha 2- and lymphocyte beta 2-adrenoceptor density in 48 normotensive children of normotensive parents (NT) and in 41 normotensive children with one EHT-parent. Both groups did not differ in age, body weight and height, blood pressure, heart rate, plasma catecholamine levels, plasma renin activity (PRA), and lymphocyte beta 2-adrenoceptor density. Platelet alpha 2-adrenoceptor density, however, was in EHT-children significantly higher than in NT-children. In NT-children, platelet alpha 2-adrenoceptors were significantly, inversely correlated with PRA, indicating that they might mirror renal alpha 2-adrenoceptors which inhibitorily regulate renin release. In contrast, in EHT-children PRA was not at all related to platelet alpha 2-adrenoceptors, suggesting an early (even in the normotensive stage) disturbance of the alpha 2-adrenoceptor-mediated regulation in renin release. From these results and those obtained in the experimental rat models of acquired hypertension, a model for the pathogenesis of the genetically determined hypertension is proposed in which a very early step in the development of hypertension is a genetically determined increase in renal alpha-adrenoceptors that causes enhanced sodium retention. This initiates a chain of events that finally results in increased peripheral vascular resistance and, hence, blood pressure. On the other hand, beta-adrenoceptor changes seem to be secondary phenomena due to the elevation in blood pressure.

Renal α-Adrenoceptor Density and Blood Pressure in Shr Rats Exposed Chronically to Prazosin and/or Yohihbine

In the present study we evaluated the effect of selective alpha 1 and alpha 2-adrenoceptors blockade on the development of hypertension and on renal alpha-adrenoceptor densities in the spontaneously hypertensive rats (SHR). In these rats, daily intraperitoneal administration of 0.1 mg/kg of prazosin, yohimbine or prazosin + yohimbine for seven weeks significantly retarded the development of hypertension. In an attempt to characterize the relationship between changes in blood pressure and the renal alpha-adrenoceptor number after a prolonged alpha-blockade in the SHR, we have used 3H-prazosin and 3H-yohimbine as the selective ligands for alpha 1 and alpha 2-adrenoceptors. Saturation studies showed that renal alpha 1 and alpha 2-receptor densities were significantly decreased by prazosin and yohimbine, respectively, in SHR. Equilibrium dissociation constants (KD), however, were similar for both classes of receptors in experimental and control rats. In WKY rats, to the contrary, only prolonged administration of yohimbine and prazosin + yohimbine for seven weeks decreased the number of 3H-binding sites, and this decrease consisted in a Bmax change rather than an affinity (KD) change. Thus, the study provides evidence that the elevated blood pressure in the SHR is related, at least in part, to an abnormality in the adrenergic system control.

Tonic inhibition of renal response to vasopressin by a pertussis toxin substrate

The putative role of the inhibitory guanine nucleotide binding protein (Gi) in modulating the renal response to vasopressin was investigated using islet activating protein (IAP). IAP treatment in rats in vivo abolished the capacity of alpha 2-adrenoceptors to reverse vasopressin-induced adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in microdissected cortical collecting tubule (CCT) segments. IAP pretreatment also caused a marked upward shift in the dose-response curve of vasopressin (10(-10) to 10(-4) M)-induced cAMP accumulation. Augmentation of the response to vasopressin in rat CCT was dependent on the in vivo dose of IAP and paralleled the loss in alpha 2-adrenoceptor responsiveness. In the isolated perfused kidney the antinatriuretic and antidiuretic effects of the V2-receptor agonist desamino-8-D-arginine vasopressin (DDAVP) (1 pM) were enhanced following IAP pretreatment. alpha 2-Adrenoceptor stimulation (30 nM epinephrine) inhibited the renal effects of DDAVP (1 pM) in kidneys from control but not IAP-pretreated rats. Interestingly, IAP pretreatment alone caused increased urine flow rate and enhanced excretion of sodium and chloride without affecting potassium excretion or renal hemodynamics in vitro. Our results suggest that an IAP substrate, probably Gi, 1) is required for signal transduction by renal alpha 2-adrenoceptors, 2) may tonically modulate the response to vasopressin in the CCT but not of parathyroid hormone in the proximal convoluted tubule, and 3) participates in renal water and electrolyte reabsorption independent of exogenous adenylate cyclase stimulation.