Interaction of renal beta 1-adrenoceptors and prostaglandins in reflex renin release

Anesthetized dogs with isolated carotid sinus preparation were used to examine the mechanisms involved in the increase in renin secretion rate produced by carotid baroreceptor reflex renal nerve stimulation (RNS) at constant renal perfusion pressure. Lowering carotid sinus pressure by 41 +/- 5 mmHg for 10 min increased mean arterial pressure and heart rate, caused no or minimal renal hemodynamic changes, decreased urinary sodium excretion, and increased renin secretion rate. Metoprolol, a beta 1-adrenoceptor antagonist, given in the renal artery, did not affect the decrease in urinary sodium excretion but attenuated the increase in renin secretion rate, from 1,764 +/- 525 to 412 +/- 126 ng/min (70 +/- 8%). Indomethacin or meclofenamate, prostaglandin synthesis inhibitors, did not affect the decrease in urinary sodium excretion but attenuated the increase in renin secretion rate, from 1,523 +/- 416 to 866 +/- 413 ng/min (51 +/- 18%). Addition of metoprolol to indomethacin-pretreated dogs attenuated the increase in renin secretion rate from 833 +/- 327 to 94 +/- 60 ng/min (86 +/- 10%). These results indicate that reflex RNS at constant renal perfusion pressure results in an increase in renin secretion rate that is largely mediated by renal beta 1-adrenoceptors and is partly dependent on intact renal prostaglandin synthesis. The beta 1-adrenoceptor-mediated increase in renin secretion rate is independent of and not in series with renal prostaglandins.     

Receptor recruitment: a mechanism for interactions between G protein-coupled receptors

There is a great deal of evidence for synergistic interactions between G protein-coupled signal transduction pathways in various tissues. As two specific examples, the potent effects of the biogenic amines norepinephrine and dopamine on sodium transporters and natriuresis can be modulated by neuropeptide Y and atrial natriuretic peptide, respectively. Here, we report, using a renal epithelial cell line, that both types of modulation involve recruitment of receptors from the interior of the cell to the plasma membrane. The results indicate that recruitment of G protein-coupled receptors may be a ubiquitous mechanism for receptor sensitization and may play a role in the modulation of signal transduction comparable to that of the well established phenomenon of receptor endocytosis and desensitization.     

Effect of dietary sodium intake on the responses to bicuculline in the paraventricular nucleus of rats

The tachycardic, pressor, and renal sympathoexcitatory responses produced by administration of the gamma-aminobutyric acid antagonist bicuculline into the paraventricular nucleus of the rat are attenuated by the administration of losartan, an angiotensin II type 1 receptor antagonist, into the ipsilateral rostroventrolateral medulla. Therefore, excitatory synaptic inputs to pressor neurons in the rostroventrolateral medulla that arise from activation of the paraventricular nucleus are mediated predominantly by the action of angiotensin II on angiotensin II type 1 receptors. To examine whether such responses are influenced by physiological changes in the activity of the renin-angiotensin system, we measured heart rate, arterial pressure, and renal sympathetic nerve activity responses to the administration of bicuculline in the paraventricular nucleus in normal rats that were fed low-, normal-, and high-sodium diets and in rats with congestive heart failure. The rank order of both plasma renin activity and renal sympathoexcitatory responses was congestive heart failure>low-sodium diet>normal-sodium diet>high-sodium diet. The rank order of pressor and tachycardic responses exhibited a similar trend, but the differences between the groups were smaller and not statistically significant. The results indicate that the renal sympathoexcitatory responses to activation of the paraventricular nucleus are modulated by physiological alterations in the activity of the renin-angiotensin system.     

Inhibition of prostaglandin E2 secretion. Failure to abolish autoregulation in the isolated dog kidney.

We studied the role of renal prostaglandins in the regulation of glomerular filtration rate (GFR) and renal blood flow (RBF) in the isolated dog kidney. Indomethacin or meclofenamate, 2 mg/kg of body weight, suppressed renal prostaglandin E2 (PGE2) secretion, measured by radioimmunoassay, to zero within 20 minutes; the effect persisted for the duration of the study. When renal arterial pressure (PRA) was maintained at 104 mm Hg both drugs caused a sharp decrease in sodium excretion and RBF with redistribution of flow from inner to outer cortes we examined autoregulation of GFR and RBF over the pressure ranges of 150-100 and 150-75 mm Hg, respectively, after inhibition of PGE2 secretion and under control conditions. deltaGFR/deltaPRA (ml/min per mm Hg) was 0.020 +/- 0.017 in the indomethacin group, 0.152 +/- 0.055 in the meclofenamate group, and 0.086 +/- 0.017 in the control group. The change in GFR for the indomethacin group was significantly less than that for meclofenamate (P less than 0.01) and control groups (P less than 0.025); the latter two groups were not statistically different from each other (P greater than 0.1). There was no significant difference (P greater than 0.1) between the three groups with respect to deltaRBF/deltaPRA, which measured 0.288 +/- 0.046, 0.370 +/- 0.112, and 0.438 +/- 0.123 ml/min per mm Hg in the indomethacin, meclofenamate and control groups, respectively. Renal was lowered from 150 to 75 mm Hg. The observation that inhibition of prostaglandin synthesis promotes a redistribution of RBF from inner to outer cortex suggests that renal prostaglandins may participate in the regulation of medullary blood flow. However, since autoregulation of GFR and RBF remained intact despite inhibition of prostaglandin secretion, these data argue against a role for renal prostaglandins in regulating whole kidney GFR and RBF.     

Selective central alpha-2 adrenoceptor control of regional haemodynamic responses to air jet stress in conscious spontaneously hypertensive rats

The role of central nervous system alpha 2-adrenoceptors in the regulation of peripheral sympathetic outflow to regional vascular resistance beds during environmental stress was examined in conscious chronically instrumented spontaneously hypertensive rats (SHR). SHR were instrumented with pulsed Doppler flow probes on the renal and mesenteric arteries and the lower abdominal aorta. The mean arterial pressure (MAP), heart rate and regional vascular resistance responses to air jet stress were determined before and after cumulative administration of the alpha 2-adrenoceptor agonist, guanabenz, into the lateral cerebral ventricle in doses of 5 and 25 micrograms. Compared with intracerebroventricular (i.c.v.) administration of isotonic saline vehicle which did not affect baseline systemic and regional haemodynamic measurements, guanabenz produced significant decreases in baseline MAP and heart rate but did not affect regional vascular resistances. During air jet stress, the characteristic pattern of the classic defense reaction with an increase in MAP, heart rate, renal and mesenteric vascular resistances and a decrease in hindquarters vascular resistance was observed and was not affected by i.c.v. administration of isotonic saline vehicle. Guanabenz did not affect the MAP, heart rate or renal vascular resistance responses to air jet stress. The air jet stress-induced increase in mesenteric vascular resistance was reduced by 25 micrograms guanabenz. The air jet stress-induced decrease in hindquarters vascular resistance was converted to an increase by 25 micrograms guanabenz. These results demonstrate that the regulation of environmental stress-stimulated sympathetic neural outflow to different vascular beds may be independently controlled by central nervous system alpha 2-adrenoceptors.     

Modulation of reflex renal vasoconstriction by increased endogenous renal prostaglandin synthesis

The effect of increased endogenous renal prostaglandin synthesis on the reflex renal vasoconstrictor response to stimulation of skeletal muscle somatic receptors and their afferents was examined in anesthetized dogs with bilateral carotid artery occlusion and vagotomy. Acute ureteral occlusion and indomethacin were used to acutely increase and decrease, respectively, endogenous renal prostaglandin synthesis. Graded electrical stimulation of the afferent sciatic nerve or antegrade femoral arterial injection of capsaicin elicited a frequency dependent reduction in renal blood flow accompanied by increases in mean arterial pressure and heart rate. Acute ureteral occlusion attenuated (circa 50%) the renal vasoconstrictor response but did not affect the increases in mean arterial pressure or heart rate. Administration of indomethacin during continued ureteral occlusion restored the renal vasoconstrictor responses to the preureteral occlusion level. These results indicate that the increase in endogenous renal prostaglandin synthesis during acute ureteral occlusion specifically attenuates the reflex renal vasoconstrictor response to stimulation of skeletal muscle somatic receptors and their afferents.     

Arterial baroreceptor reflex function in borderline hypertensive rats.

With increased dietary NaCl intake (8% NaCl), the borderline hypertensive rat develops hypertension, thus expressing the phenotype of the spontaneously hypertensive parent. Since arterial baroreceptor reflex function is impaired in the spontaneously hypertensive parent, it was the objective of this study to examine arterial baroreceptor reflex function in the borderline hypertensive rat made hypertensive by increased dietary NaCl intake. Borderline hypertensive rats were fed either 1% or 8% NaCl from age 4 to 16 weeks. Borderline hypertensive rats fed 8% NaCl (n = 10) were hypertensive compared with borderline hypertensive rats fed 1% NaCl (n = 11) (141 +/- 3 versus 120 +/- 4 mm Hg, p less than 0.01). They were chronically instrumented for the recording of arterial pressure, heart rate, and renal sympathetic nerve activity. The percent change from control in heart rate and renal sympathetic nerve activity resulting from increases (phenylephrine) and decreases (nitroglycerine) in arterial pressure were measured in conscious freely moving animals. With respect to arterial baroreceptor reflex control of heart rate, 8% NaCl borderline hypertensive rats had a similar range (75 +/- 4%) and maximal gain (-2.72 +/- 0.24%/mm Hg) as 1% NaCl borderline hypertensive rats (70 +/- 4%; -2.78 +/- 0.50%/mm Hg). With respect to arterial baroreceptor reflex control of renal sympathetic nerve activity, 8% NaCl borderline hypertensive rats had values for range (205 +/- 22%) and maximal gain (-3.92 +/- 0.93%/mm Hg) that were not significantly different from those for 1% NaCl borderline hypertensive rats (167 +/- 33%, -2.76 +/- 0.62%/mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Central adrenergic receptor control of renal function in conscious hypertensive rats

The role of central nervous system alpha-adrenergic and beta-adrenergic receptors in the increased renal sympathetic nerve activity and antinatriuresis resulting from environmental stress (air stress) in conscious spontaneously hypertensive rats (SHR) was examined. Intracerebroventricular administration of the alpha 2-adrenergic receptor agonist clonidine (1, 5, and 15 micrograms) prevented the effects of air stress on renal sympathetic nerve activity and urinary sodium excretion. Clonidine, 5 and 15 micrograms, lowered baseline mean arterial pressure and renal sympathetic nerve activity and increased baseline urine flow rate and urinary sodium excretion; clonidine, 1 micrograms, had no effect on these baseline levels. Intravenous administration of 5 micrograms, but not 1 microgram of clonidine, abolished the renal responses to air stress. Intracerebroventricular administration of alpha 2-adrenergic receptor antagonists (yohimbine, rauwolscine) reversed the effects of clonidine, alpha 2-adrenergic receptor blockade alone, alpha 1-adrenergic receptor blockade (20 micrograms prazosin), or combined alpha 1-adrenergic and alpha 2-adrenergic receptor blockade (30 micrograms phenoxybenzamine) had no effect on the renal sympathetic nerve activity or antinatriuretic responses to air stress. Intracerebroventricular, but not intravenous, administration of the beta 2-adrenergic receptor antagonist ICI 118551 (30 micrograms) prevented the increased renal sympathetic nerve activity and antinatriuretic responses to air stress. In contrast, intracerebroventricular administration of the beta 1-adrenergic receptor antagonist atenolol (30 micrograms) had no effect on the renal responses to air stress. These results indicate that the increased renal sympathetic nerve activity and antinatriuresis resulting from environmental stress in conscious SHR can be prevented by pharmacological stimulation of central alpha 2-adrenergic receptors or by blockade of central beta 2-adrenergic receptors.     

Sodium responsiveness of central alpha 2-adrenergic receptors in spontaneously hypertensive rats

The responsiveness of central nervous system alpha 2-adrenergic receptors in the neural control of renal function was compared in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) on normal or high sodium intake (3-4 weeks of 1% NaCl for drinking). The responsiveness of central alpha 2-adrenergic receptors was determined by comparing among groups the dose-response curves for the effects of cumulative intracerebroventricular injections of guanabenz (5, 25, and 125 micrograms) on changes in mean arterial pressure, renal sympathetic nerve activity, and urinary sodium excretion. Guanabenz altered mean arterial pressure similarly in SHR on normal or high sodium intake and in WKY on normal or high sodium intake. High sodium intake shifted the guanabenz-renal sympathetic nerve activity and guanabenz-urinary sodium excretion dose-response curves to the left in SHR and to the right in WKY. The dose-response curves between SHR and WKY on normal sodium intake were similar. Surgical renal denervation or pretreatment with an alpha 2-adrenergic receptor antagonist (rauwolscine, 30 micrograms i.c.v.) attenuated the ability of guanabenz to inhibit renal sympathetic nerve activity or increase urinary sodium excretion in SHR and WKY on either normal or high sodium intake. We conclude that the responsiveness of central nervous system alpha 2-adrenergic receptors regarding the neural control of renal function is increased by high sodium intake in conscious SHR, but not in conscious normotensive WKY.     

Gene transfer of extracellular superoxide dismutase reduces arterial pressure in spontaneously hypertensive rats: role of heparin-binding domain

Oxidative stress may contribute to hypertension. The goals of this study were to determine whether extracellular superoxide dismutase (ECSOD) reduces arterial pressure in spontaneously hypertensive rats (SHR) and whether its heparin-binding domain (HBD), which is responsible for cellular binding, is necessary for the function of ECSOD. Three days after intravenous injection of an adenoviral vector expressing human ECSOD (AdECSOD), mean arterial pressure (MAP) decreased from 165+/-4 mm Hg (mean+/-SE, n=7) to 124+/-3 mm Hg (n=7) in adult anesthetized SHR (P<0.01) but was not altered in normotensive Wistar-Kyoto rats. Cardiac output was not changed in SHR 3 days after AdECSOD. Gene transfer of ECSOD with deletion of the HBD (AdECSODDeltaHBD) had no effect on SHR MAP, even though plasma SOD activity was greater after AdECSODDeltaHBD than after AdECSOD. Immunohistochemistry revealed intense staining for ECSOD in blood vessels and kidneys after AdECSOD but not after AdECSODDeltaHBD. Impaired relaxation of the carotid artery to acetylcholine in SHR was significantly improved after AdECSOD. Cumulative sodium balance in SHR was reduced by AdECSOD compared with AdECSODDeltaHBD. Gene transfer of ECSOD also reduced MAP in conscious SHR, although the effect was not as profound as in anesthetized SHR. In summary, gene transfer of ECSOD, with a strict requirement for its HBD, reduces systemic vascular resistance and arterial pressure in a genetic model of hypertension. This reduction in arterial pressure may be mediated by vasomotor and/or renal mechanisms.