Central alpha 2-adrenoceptor responsiveness in borderline hypertensive rats.

Increased dietary NaCl intake increases the responsiveness of central nervous system alpha 2-adrenoceptors which regulate the neural control of renal function in spontaneously hypertensive rats (SHR) but not Wistar-Kyoto (WKY) normotensive rats. The borderline hypertensive rat (BHR) is the first filial offspring of the SHR and the WKY. With increased dietary NaCl intake, the BHR develops hypertension and expresses other characteristics of the hypertensive SHR parent. This investigation sought to determine whether increased dietary NaCl intake in the BHR enhances the responsiveness of central nervous system alpha 2-adrenoceptors. Six weeks of increased dietary NaCl intake (8% versus 1% NaCl) in BHR augmented the depressor, bradycardic, renal sympatho-inhibitory and diuretic responses to intracerebroventricular administration of graded doses (5, 25 and 125 micrograms) of the alpha 2-adrenoceptor agonist, guanabenz. The results suggest that the potential for an increased responsiveness of central nervous system alpha 2-adrenoceptors is genetically transmitted to the BHR by the SHR and may be exposed in the BHR by increased dietary NaCl intake.     

Enhanced inhibitory effect of alpha 2-adrenoceptor stimulation on the formation of cAMP in glomeruli of spontaneously hypertensive rats.

Renal alpha 2-adrenoceptors are known to be increased in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). To investigate whether this difference affects the second messenger system, we examined the effect of alpha 2-adrenoceptor stimulation on the formation of cAMP in microdissected glomeruli and proximal convoluted tubules obtained from the kidneys of SHR and WKY. The formation of glomerular cAMP, which was stimulated by parathyroid hormone (PTH), was inhibited by alpha 2-adrenoceptor stimulation. In contrast, the inhibitory effect of alpha 2-adrenoceptor stimulation on PTH-induced cAMP formation in proximal convoluted tubules was not significantly different between SHR and WKY. These results confirm the inhibitory action of alpha 2-adrenoceptors on the formation of cAMP in glomeruli and proximal tubules and suggest that the greater inhibitory effect on glomerular cAMP formation in SHR may reflect an increase in alpha 2-adrenoceptor density in SHR kidneys.     

Presynaptic alpha 2-adrenoceptor mediated regulation of norepinephrine release in perfused mesenteric vasculatures in young and adult spontaneously hypertensive rats

The present study was designed to evaluate the role of the presynaptic alpha 2-adrenoceptor in the pathogenesis of hypertension. Norepinephrine overflow during sympathetic nerve stimulation and its changes by presynaptic alpha 2-adrenoceptor inhibition were examined in the perfused mesenteric vasculatures of young and adult spontaneously hypertensive rats (SHR) compared with age-matched Wistar Kyoto rats (WKY). Electrical sympathetic nerve stimulation caused significantly greater overflow of endogenous norepinephrine from the adrenergic nerve terminals in young SHR than in age-matched WKY. Yohimbine, an alpha 2-adrenoceptor blocking agent, facilitated norepinephrine overflow from the adrenergic nerve terminals. The effects of yohimbine on norepinephrine overflow and pressor responses to electrical nerve stimulation were less in young SHR than in age-matched WKY. Norepinephrine overflow in adult SHR was similar to that in adult WKY, and differences in the effect of yohimbine on norepinephrine overflow between SHR and WKY were not marked at this chronic stage. These results suggest that enhanced norepinephrine overflow in the mesenteric vasculatures can be observed only in young SHR; this may be due in part to an impaired negative feed-back mechanism on the nerve terminals by presynaptic alpha 2-adrenoceptors.     

Dietary sodium restriction and pressor responsiveness to tyramine in spontaneously hypertensive rats.

OBJECTIVE: To determine in vivo whether in young spontaneously hypertensive rats (SHR) dietary sodium restriction decreases adrenergic transmitter release from the sympathetic nerve terminal. DESIGN: Dietary sodium restriction was initiated in young and mature SHR and Wistar-Kyoto (WKY) rats, and subsequently changes in pressor responsiveness to norepinephrine and to the indirectly acting sympathomimetic tyramine were determined in relation to their effects upon plasma catecholamines. RESULTS: In young SHR sodium restriction for 3-6 weeks prevented the development of hypertension, whereas in mature SHR sodium restriction did not affect blood pressure. Sodium restriction caused modest decreases in pressor responsiveness to the exogenous alpha-agonist, not different in young and mature SHR compared with WKY rats. In contrast, sodium restriction markedly inhibited pressor-responses to tyramine in young SHR and WKY rats, but not at all in mature rats. Tyramine increased plasma norepinephrine 5-10-fold. However, sodium restriction did not affect this response. The pressor response to tyramine was related to increases in total peripheral resistance, with minimal changes in cardiac output, and could be blocked by alpha 1-receptor blockade in rats on either control or low-sodium diets. CONCLUSIONS: These results show that sodium restriction causes only a small decrease in the pressor response to norepinephrine, but a more marked inhibition of the pressor response to tyramine in young SHR and WKY rats without affecting the plasma norepinephrine response to tyramine. These results suggest that dietary sodium can indeed affect presynaptic functions in vivo, but that plasma norepinephrine responses to tyramine may not reflect changes in arterial norepinephrine release, or that sodium restriction affects a co-transmitter rather than norepinephrine release per se.     

A functional study of the development of the cardiac sympathetic neuroeffector junction in the SHR

We studied the function of the cardiac sympathetic nerve varicosity in isolated right atrial preparations of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 4, 9, 14, 20 and 50 weeks of age. Cumulative concentration-atrial period response (C-R) curves to isoprenaline showed similar maximum response and sensitivity (EC50) at all ages but there was an age-related fall in resting atrial rate. Similar results were found for methoxamine (alpha 1-adrenoceptor agonist) although the maximum response was significantly less than for isoprenaline. The time-dependent recovery (T 1/2) of the fall in atrial period in response to sympathetic nerve stimulation from electrical field pulses (1-32 at 1 Hz) was enhanced by neuronal uptake inhibition by desipramine (0.1-1 mumol/l), to a similar degree at all ages. Pre-junctional alpha 2-adrenoceptor stimulation by clonidine caused progressively more inhibition of the number of field pulses-fall in period relationship with age. SHR atria were similar to WKY rat atria at all ages except for a further impairment of the development of pre-junctional alpha 2-adrenoceptors. These studies indicate that the function of the cardiac sympathetic varicosity matures early (by 4 weeks) and overall there is very little impairment in SHR versus WKY rat atria.     

Decrease in alpha 1-adrenoceptor reserve in mesenteric arteries isolated from spontaneously hypertensive rats

The characterization of alpha-adrenoceptor-mediated contractile responses and the effects of the calcium channel blocker nifedipine on these responses were investigated in mesenteric arterial strips from 13-week-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Contractile responses to the alpha-adrenoceptor agonists phenylephrine and clonidine were mediated through the activation of alpha 1-adrenoceptors. The dose producing a half-maximum response (ED50) for the agonists was higher in SHR than in WKY. Affinities of alpha 1-adrenoceptors were similar between the two strains. When arterial strips from both strains were treated with the same concentration of phenoxybenzamine, the maximum response to each agonist was weaker in SHR. The alpha 1-adrenoceptor occupancy-response relationship for phenylephrine was hyperbolic and less steep in SHR, while the relationship for clonidine was linear in SHR but not in WKY. Alpha 1-adrenoceptor occupancy at a half-maximum response to each agonist was greater in SHR. Nifedipine inhibited the maximum responses to the agonists more profoundly in SHR than in WKY. This inhibition was greater in the response to clonidine than in the response to phenylephrine in both strains. When the maximum response to phenylephrine was reduced to the same extent in both strains by treatment with different concentrations of phenoxybenzamine, the responses to phenylephrine were more susceptible to inhibition by nifedipine. Under these conditions, the effects of nifedipine were similar between SHR and WKY. These results suggest that alpha 1-adrenoceptor reserve is reduced in SHR mesenteric artery compared with WKY, which may be responsible for the greater inhibition by nifedipine of the alpha 1-adrenoceptor-mediated contractions in SHR.     

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.     

Renal dopamine receptor signaling mechanisms in spontaneously hypertensive and Fischer 344 old rats

Dopamine plays an important role in the regulation of renal sodium excretion. The activation of D1-like receptors located on the proximal tubules causes inhibition of tubular sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase activity. The D1-like receptors are linked via G proteins to the multiple cellular signaling systems namely adenylyl cyclase and phospholipase C (PLC). A defective renal dopamine receptor function exists in spontaneously hypertensive rats (SHR). In the proximal tubules of SHR, the stimulation of adenylyl cyclase and PLC caused by dopamine was significantly reduced in comparison with Wistar-Kyoto (WKY) rats. Also unlike the effects seen in WKY, D1-like receptor activation did not inhibit Na,K-ATPase and Na,H-exchanger activities in SHR. In addition, reduced quantity of Gq/11alpha proteins was detected in the basolateral membranes of SHR compared to WKY rats. Studies revealed that there may be a primary defect in D1-like receptors leading to an altered signaling system in the proximal tubules and reduced dopamine-mediated effect on renal sodium excretion in SHR. Recently, it has been shown that the disruption of D1A receptors at the gene level causes hypertension in mice. Similar to SHR, dopamine and D1-like receptor agonist failed to inhibit Na,K-ATPase activity in the proximal tubules of old Fischer 344 rats. Unlike the observations in SHR where D1-like receptors were equal to WKY rats, there is a 50% decrease in D1-like receptor number in basolateral membranes of the old rats compared to the adult rats. Dopamine was unable to stimulate G proteins in the basolateral membranes of old rats compared to the adult rats. It is suggested that a defective dopamine receptors/signaling system may contribute to the development and maintenance of hypertension. Also, the inability of dopamine to inhibit Na,K-ATPase may lead to a reduced renal sodium excretion in response to dopamine in old rats.     

Specific changes in hypothalamic alpha-adrenoceptors in young spontaneously hypertensive rats

Changes in the activity of hypothalamic and brain-stem adrenergic neurons have been reported in young spontaneously hypertensive rats (SHR) prior to the development of hypertension. We have measured central alpha- and beta-adrenoceptor concentrations in 4-week-old SHR and Wistar-Kyoto (WKY) controls by direct radioligand binding studies using [3H]prazosin (alpha 1), [3H]clonidine (alpha 2), and [125I]iodohydroxybenzlpindolol (beta). The concentration of alpha 2-adrenoceptors was significantly elevated in the hypothalamus of the SHR, 156.9 +/- 10.4 compared with WKY, 119.4 +/- 10.0 fmole/mg protein (n = 7, mean +/- SEM, p less than 0.0125). Alpha 2-adrenoceptor concentrations in both the brain stem and cerebral cortex were similar in the two groups of animals. The increase in hypothalamic adrenoceptors was specific for alpha 2-adrenoceptors, since similar concentrations of alpha 2- and beta-adrenoceptors were found in this region.     

Role of hypothalamic-renal noradrenergic systems in hypotensive action of potassium.

To clarify the role of the renal and hypothalamic noradrenergic systems in the antihypertensive actions of dietary potassium supplementation in salt-loaded spontaneously hypertensive rats (SHR), we measured systolic blood pressure and norepinephrine turnover, which was determined from the rate of decline of tissue norepinephrine concentration after the administration of alpha-methyl-p-tyrosine, in 5-week-old SHR or age-matched Wistar-Kyoto (WKY) rats eating normal-NaCl (0.66%) or high-NaCl (8%) diet with supplementation of 8% KCl. In WKY rats, neither high-sodium nor high-potassium diets had an effect on blood pressure with no change in renal or hypothalamic norepinephrine turnover. In SHR, however, salt loading accelerated the development of hypertension. Potassium supplementation did not affect blood pressure in normal-sodium SHR but attenuated the rise in blood pressure with salt loads. Correspondingly, renal norepinephrine turnover in SHR was increased compared with that of WKY rats, and salt loading further potentiated the increased turnover in the kidney; however, no changes in hypothalamic turnover occurred. Potassium supplementation attenuated the rise in blood pressure with salt loads and the increased renal turnover. Stimulation of sympathetic discharge by cold exposure after the administration of alpha-methyl-p-tyrosine produced marked depletion of norepinephrine in most tissues. The loss of norepinephrine was significantly greater in both kidney and hypothalamus of salt-loaded SHR than in those of normal-sodium SHR, but potassium could normalize this. Thus, potassium not only diminished the increased renal norepinephrine turnover in the kidney under normal conditions but also attenuated the augmented renal and hypothalamic norepinephrine turnover by cold stress in salt-loaded SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Central alpha-adrenoceptors during the development of hypertension in rats on high and low salt intake

Our purpose was to investigate the binding characteristics of central alpha-adrenoceptors during the early stages of the development of hypertension in rats on high and low salt (NaCl) intake. We measured alpha 1-[( 3H]prazosin) and alpha 2-[( 3H]rauwolscine) binding in membranes of the hypothalamus and medulla oblongata of six groups of young Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and subtotally nephrectomized WKY (SN) rats with mean arterial blood pressure (MAP) ranging from normotensive to hypertensive levels after 1 week of salt restriction or loading. In the hypothalamus the SN-high salt rats and both SHR groups had elevated alpha 1-number but there was no change in alpha 2-number. Moreover, MAP was positively correlated with mean hypothalamic alpha 1-number in the six groups. In the medulla oblongata alpha 1-number was unaffected. However, high salt diet influenced medullary alpha 2-binding in the opposite manner in WKY rats versus SN rats and SHR. In these latter groups the affinity was increased and the number decreased in response to high salt intake. Furthermore, a positive correlation between MAP and mean alpha 1:alpha 2 ratio existed in both the hypothalamus and the medulla of the six groups. The data suggest that hypothalamic alpha 1-binding capacity was increased in SHR due principally to a genetic condition which is mimicked by salt loading in the SN rats. Medullary alpha 2-adrenoceptors of WKY, which remained normotensive despite salt loading, responded differently to high salt intake than those of the SN and SHR, whose blood pressure rose significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular angiotensin II receptors in SHR

We investigated the density (Bmax) of angiotensin II (ANG II) receptors in the mesenteric vascular bed of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) control rats. In 12-week-old SHR, the Bmax and the dissociation constant (Kd) of ANG II binding sites were not different from those of WKY rats in the sodium replete state or after sodium depletion. In prehypertensive (4- and 6-week-old) SHR, the Bmax of the vascular ANG II receptors was significantly higher (p less than 0.05) than in age-matched WKY rats. This result could not be attributed entirely to differences in the circulating renin-angiotensin-aldosterone system in 4-week-old-rats. In 6-week-old WKY rats, the plasma renin activity was significantly higher (p less than 0.05), which may account in part for the higher density of ANG II binding sites in SHR. There was an age-related decrease in the number of ANG II receptors in SHR. The increased density of vascular ANG II receptors in young SHR may play a role in the development of high blood pressure in this model of spontaneous hypertension. The higher number of ANG II binding sites in young SHR is not selective for ANG II receptors, since an increased density of alpha 1-adrenergic receptors was also found in the mesenteric arteries of 4-week-old SHR.     

Alterations in renal endothelin-1 production in the spontaneously hypertensive rat.

Endothelin-1 inhibits sodium and water transport systems in the inner medullary collecting duct. Endothelin-1 levels are reduced in the medulla of spontaneously hypertensive rats (SHR), raising the possibility that decreased inner medullary collecting duct production of endothelin-1 could contribute to inappropriate sodium and water retention. In the current study, immunoreactive endothelin-1 was measured in the urine, blood, and eluates from cortex and outer and inner medulla of SHR before (age 3-4 weeks) and after (age 8-9 weeks) the development of hypertension and in age-matched Wistar-Kyoto (WKY) controls. There was no difference in endothelin-1 levels between prehypertensive SHR and WKY rats. In contrast, 8-9-week-old SHR had significantly reduced endothelin-1 in the urine and outer and inner medulla, but not in the cortex or serum compared with those of WKY controls. Furthermore, inner medullary collecting duct cells from 8-9-week-old SHR, either acutely isolated or cultured, released less endothelin-1 than did those from WKY rats. Finally, the level of endothelin-1 messenger RNA was only reduced in the inner medulla and in inner medullary collecting duct cells from 8-9-week-old SHR. In summary, renal medullary, and in particular terminal collecting duct, endothelin-1 production is reduced in SHR only after the development of hypertension. Such decreases in inner medullary collecting duct endothelin-1 production may contribute to the hypertensive state in SHR.     

Reduced calcium sensitivity of dihydropyridine binding to calcium channels in spontaneously hypertensive rats.

To explore the role of calcium channels in hypertension, dihydropyridine ([3H]PN200-110) binding to heart, brain, and skeletal muscle microsomes of 4-, 8- and 15-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was measured. At a constant Ca2+ ion concentration (pCa 3.0), maximal binding (Bmax) of dihydropyridine binding to heart and brain microsomes was significantly enhanced in 8- and 15-week-old SHR compared with WKY rats (p less than 0.01), whereas this phenomenon was not observed in 4-week-old SHR and WKY rats. Bmax and dissociation constant (Kd) values for skeletal muscle microsomes from SHR showed no difference compared with WKY rats irrespective of age. Dihydropyridine binding to heart microsomes, brain microsomes, and solubilized skeletal muscle microsomes exhibited strong calcium dependence. The Ca2(+)-dependent dihydropyridine binding curves for heart showed a Hill slope, and pK 0.5 values for 15-week-old SHR and WKY rats were 0.70 +/- 0.12 and 4.66 +/- 0.12 versus 0.72 +/- 0.12 and 5.66 +/- 0.08 (n = 4, mean +/- SD), respectively, indicating that 15-week-old SHR require 10-fold higher calcium concentration than WKY rats to promote dihydropyridine binding. The pK 0.5 values of calcium for brain and solubilized skeletal muscle calcium channels in 15-week-old SHR were also significantly lower than in WKY rats. This difference first became apparent in SHR and WKY rats as early as 4 and 8 weeks after birth. These results suggest that enhancement of calcium channel density might occur in the heart and brain of SHR in response to elevated blood pressure and that reduced calcium sensitivity of dihydropyridine binding to calcium channels might be a primary characteristic of this rat strain.     

An Impairment of Renal Tubular DA-1 Receptor Function as the Causative Factor For Diminished Natriuresis to Volume Expansion in Spontaneously Hypertensive Rats

It has been demonstrated that endogenous kidney dopamine (DA) contributes to the natriuretic response to acute volume expansion (VE). Several studies suggest that a defect in renal DA-ergic mechanism may play a role in genetic hypertension in humans and rats. The present study was designed to determine the role of renal DA and tubular DA-1 receptors in the natriuretic response to VE in age-matched spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats of 10–12 weeks of age. In pentobarbital-anesthetized rats, VE was carried out by intravenously infusing isotonic sodium chloride (5% body weight) over a period of 60 min. This maneuver evoked pronounced increases in urine output, urinary sodium excretion and urinary DA excretion. However, the natriuretic and diuretic response to VE was significantly reduced in SHR, although the increase in urinary DA excretion was similar in both SHR and WKY rats. During VE no significant changes in glomerular filtration rate or blood pressure were noted in either strain of animals, indicating the involvement of renal tubular mechanisms in the natriuretic response. In a separate group of SHR and WKY rats, pretreatment with DA-1 receptor antagonist SCH 23390 caused significant attenuation of the natriuretic and diuretic response to VE in WKY rats but not in SHR, suggesting that unlike WKY rats kidney DA was not contributing to the natriuretic response to VE in SHR. In another group of animals, the renal effects of exogenously administered DA-1 receptor agonist fenoldopam were examined. Fenoldopam (1 μg/kg/min) produced significant increases in urine output and urinary sodium excretion without causing any alterations in blood pressure or glomerular filtration rate in both SHR and WKY rats. However, the interesting observation was that fenoldopam-induced diuresis and natriuresis were significantly attenuated in SHR compared to the WKY rats. These results show that SHR are not able to eliminate an acute increase in sodium load as efficiently as WKY rats, which may be at least in part due to a defect in renal tubular DA-1 receptor function.     

Prostaglandin E2 inhibits noradrenaline release and purinergic pressor responses to renal nerve stimulation at 1 Hz in isolated kidneys of young spontaneously hypertensive rats

The effects of prostaglandin E2 (PGE)2 and the thromboxane A2 (TxA2) receptor agonist U-46619 on noradrenaline release and pressor responses to renal nerve stimulation (RNS) at 1 Hz were investigated in isolated kidneys of spontaneously hypertensive rats (SHR; 5-7 weeks) and age-matched Wistar-Kyoto rats (WKY). After incubation with 3H-noradrenaline, the renal nerves were stimulated. The stimulation-induced (S-I) outflow of radioactivity was taken as an index of noradrenaline release. Absolute S-I outflow of radioactivity was lower in SHR than in WKY but pressor responses to RNS were greater in SHR than in WKY. Tetrodotoxin (1 mumol/l) abolished S-I outflow of radioactivity and pressor responses to RNS in both strains. PGE2 (0.06 mumol/l) inhibited S-I outflow of radioactivity in SHR but not in WKY kidneys. PGE2 (0.6 mumol/l) inhibited S-I outflow of radioactivity in both strains. In SHR, PGE2 (0.6 mumol/l) decreased pressor responses to RNS, but increased them in WKY. In WKY, but not in SHR kidneys, pressor responses to RNS were markedly reduced by the alpha 1-adrenoceptor antagonist prazosin (0.1 mumol/l). The prazosin-resistant pressor responses to RNS were blocked by alpha, beta-methylene adenosine triphosphate (ATP; 1 mumol/l). In kidneys of SHR, pretreated with 6-OH-dopamine (50 mg/kg intravenously, 24 and 48 h before isolation of the kidneys) to destroy sympathetic nerve endings, pressor responses to RNS and S-I outflow of radioactivity were almost abolished. U-46619 (0.1 mumol/l) increased perfusion pressure in SHR and WKY kidneys and this effect was blocked by the TxA2 receptor antagonist daltroban (BM 13505; 3 mumol/l). U-46619 did not significantly modulate S-I outflow of radioactivity. The results suggest that activation of prejunctional PGE2 receptors in kidneys of SHR and WKY inhibits noradrenaline release. The prejunctional inhibitory PGE2 receptor mechanism on renal sympathetic nerves seems to operate more effectively in SHR than in WKY. There is no evidence for prejunctional TxA2 receptors in the kidneys of SHR or WKY. Pressor responses to RNS at 1 Hz in SHR kidneys seem to be due entirely to release of a purinergic co-transmitter from renal sympathetic nerves, and PGE2 possibly reduces pressor responses to RNS by inhibiting release of this purinergic co-transmitter.     

The characteristics of alpha-adrenoceptors mediating the renal nerve induced antinatriuresis and antidiuresis in hypertensive rats.

Selective alpha-adrenoceptor and calcium antagonists have been used to determine both the alpha 1-adrenoceptor subtype and the extracellular calcium requirement for renal nerve-mediated antinatriuresis and antidiuresis in deoxycorticosterone acetate (DOCA)-salt and two-kidney, one clip (2K1C) Goldblatt hypertensive rats. Stimulation of the renal nerves at low frequencies reduced urine flow and absolute and fractional sodium excretions by 40-60% in pentobarbitone anaesthetized control, sham-operated, DOCA-salt and 2K1C Goldblatt hypertensive rats. Administration of prazosin, but not idazoxan, inhibited the renal nerve-induced excretory responses in both models of hypertension, a result compatible with the involvement of alpha 1-adrenoceptors. By contrast, the calcium antagonist inhibited the renal nerve-dependent antinatriuresis and antidiuresis in DOCA-salt but not 2K1C Goldblatt hypertensive rats. These results showed that the renal nerves mediated their action via alpha 1-adrenoceptors, but that the postreceptor responses were dependent on extracellular calcium in DOCA-salt but not 2K1C Goldblatt rats.     

Functional Evidence of Inhibitory Reno-renal Reflexes in Spontaneously Hypertensive Rats

The experiments were performed to study the role of the renal nerves and the reno-renal reflexes in the control of water and sodium excretion in spontaneously hypertensive rats (SHR) compared to their normotensive controls, Wistar Kyoto (WKY) rats. Unilateral renal denervation in anaesthetized animals produced a slight, progressive decrease in arterial pressure in both WKY and SHR rats. The glomerular filtration rate temporarily increased in the kidney that underwent the denervation in the SHR group only. After unilateral renal denervation a sharp increase in water and sodium excretion from the ipsilateral kidney was observed in both WKY and SHR. One hour after the denervation, the percent changes in water and sodium excretion were smaller in WKY (+32 ± 19% and +24 ± 17%) than in SHR rats (+84 ± 15% and +93 ± 20%). In the kidney contralateral to the denervation a reduction in water and sodium excretion was observed and this reduction was prompter in SHR than in WKY rats. One hour after the denervation, the percent changes in water and sodium excretion were similar in WKY (-21 ± 8% and -18 ± 7%) and SHR (-19 ± 6% and -19 ± 7%). In control groups, sham denervation did not cause significant changes in glomerular filtration rate, and urinary water and sodium excretion. Arterial pressure slightly and progressively decreased in both control groups. Electrical stimulation of the efferent renal nerves performed in WKY and SHR produced similar decreases in renal blood flow, glomerular filtration rate, and water and sodium excretion in the two groups for the same frequencies of stimulation. As this finding indicates that renal targets in hypertensive rats are normally responsive to the neural drive, our data demonstrate that renal responses to unilateral renal denervation in hypertensive rats are equal to the responses observed in normotensive rats. Our results indicate that tonically active inhibitory reno-renal reflexes normally operate in spontaneously hypertensive rats.