The cardiovascular and renal functional responses to the 5-HT1A receptor agonist flesinoxan in two rat models of hypertension.

1. This study investigated the importance of renal sympathetic nerves in regulating sodium and water excretion from the kidneys of stroke prone spontaneously hypertensive and 2K1C Goldblatt hypertensive rats anaesthetized with chloralose/urethane (17.5/300 mg initially and supplemented at regular intervals), and prepared for measurement of renal function. 2. In stroke prone spontaneously hypertensive rats, flesinoxan, 30-1000 micrograms kg-1, i.v., caused graded reductions in blood pressure and heart rate of 74 +/- 5 mmHg and 63 +/- 9 beats min-1, respectively at the highest dose (P < 0.001). Renal blood flow did not change at any dose of drug while glomerular filtration rate fell by some 20% (P < 0.001) at the highest dose of drug, absolute and fractional sodium excretions, approximately doubled at 100 micrograms kg-1, and thereafter fell to below the baseline level at 1000 micrograms kg-1. 3. This pattern of excretory response was abolished following acute renal denervation when flesinoxan caused dose-related reductions in urine flow and sodium excretion, similar to that obtained by a mechanical reduction of renal perfusion pressure. 4. Flesinoxan administration (30-1000 micrograms kg-1, i.v.) into 2K1C Goldblatt hypertensive rats caused a maximum decrease in blood pressure and heart rate (both P < 0.001) of 34 +/- 3 mmHg and 20 +/- 6 beats min-1 and while renal blood flow and glomerular filtration rate were autoregulated, from 160 to 125 mmHg, there were dose-related decreases in urine volume and sodium excretion from the clipped and non-clipped kidneys of approximately 50-60% at the highest dose. 5. These findings suggest that in the stroke prone spontaneously hypertensive rat the renal nerves importantly control sodium and water reabsorption at the level of the tubules, whereas in 2K1C Goldblatt hypertensive rats, they play a minor role.     

A study in the rat of the renal actions of nitrendipine and diltiazem on the adrenergic regulation of calcium and sodium reabsorption.

In pentobarbitone-anaesthetized rats, intravenous administration of diltiazem at 5 micrograms kg-1 min-1 did not change blood pressure or renal blood flow but increased glomerular filtration rate by approximately 16%, urine flow by 85%, calcium excretion by 151% and absolute and fractional sodium excretions by 100% and 69%, respectively. A similar pattern of responses was obtained in renally denervated animals, except that calcium excretion did not change statistically. Diltiazem given at 20 micrograms kg-1 min-1 into renally innervated and denervated groups of animals depressed blood pressure between 15-17 mmHg but had no effect on renal haemodynamic or tubular function. Nitrendipine administered at 0.5 microgram kg-1 min-1 to renally innervated and denervated animals significantly depressed blood pressure in intact animals by 6 mmHg and in both groups did not change renal haemodynamics but caused similar increases in urine flow of between 79-98%, calcium excretion of between 87 and 125%, absolute sodium excretion of between 108 and 140% and fractional sodium excretion of between 83 and 170%. Infusion of nitrendipine at 1.0 micrograms kg-1 min-1 into intact or renally denervated animals decreased blood pressure by 18-20 mmHg and increased urine flow by 84-111%, calcium excretion by 85%, absolute sodium excretion by 81-137% and fractional sodium excretion by 52-102%. Stimulation of the renal nerves at low frequencies (0.8 to 1.5 Hz) caused minimal changes in renal haemodynamics but decreased urine flow by 27%, calcium excretion by 35%, absolute and fractional sodium excretions 32% and 36%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Attenuated renal response to moxonidine and rilmenidine in one kidney-one clip hypertensive rats.

1. I1 non-adrenoceptor, imidazoline receptor agonists, such as moxonidine, increase urine flow rate and sodium excretion following infusion into the renal artery. The functions of these agonists in genetic and acquired models of hypertension have not been determined. 2. We therefore studied the renal effects of two known non-adrenoceptor, imidazoline receptor agonists, rilmenidine and moxonidine, in 1K-1C hypertensive and 1K-sham normotensive rats. Rilmenidine (0, 3, 10, 30 nmol kg-1 min-1) or moxonidine (0, 1, 3, 10 nmol kg-1 min-1) was infused directly into the renal artery (30 gauge needle) of 1K-sham normotensive and 1K-1C hypertensive rats. 3. In 1K-sham normotensive rats, rilmenidine and moxonidine produced dose related increases in urine flow rate, sodium excretion and osmolar clearance. Both rilmenidine and moxonidine failed to increase urine flow rate, sodium excretion and osmolar clearance in 1K-1C hypertensive rats to the same extent as in 1K-sham animals. At comparable doses, rilmenidine had no effect, while moxonidine (3 and 10 nmol kg-1 min-1) did result in a small increase in urine volume and osmolar clearance which was less than that observed in the 1K sham control animals. 4. These studies indicate that the renal effects of non-adrenoceptor, imidazoline receptor stimulation are diminished in 1K-1C hypertensive rats compared with 1K-sham normotensive rats. Whether this decrease in activity of the natriuretic non-adrenoceptor, imidazoline receptors contributes to the increase in blood pressure in the 1K-1C acquired model of hypertension remains to be determined.     

The interaction between atrial natriuretic peptides and angiotensin II in controlling sodium and water excretion in the rat.

1. The present study was designed to determine how the natriuretic and diuretic actions of atrial natriuretic peptides were modulated by circulating angiotensin II. 2. In sodium pentobarbitone-anaesthetized rats, administration of bolus doses of atriopeptin III (1000 ng kg-1) had no effect on blood pressure, renal blood flow, or glomerular filtration rate but caused reversible increases (all P less than 0.001) in urine flow, of 53.9 +/- 14.4 microliters kg-1 min-1, absolute sodium excretion, of 13.4 +/- 2.9 mumol kg-1 min-1 and fractional sodium excretion of 3.26 +/- 0.74%. Similar effects were seen following a second dose of the atriopeptin III. 3. Following blockade of the renin-angiotensin system with captopril (900 micrograms kg-1 h-1), control levels of blood pressure and haemodynamics were unchanged but there were significant (all P less than 0.001) increases in urine flow, from 39.96 +/- 5.05 to 88.70 +/- 8.41 microliters kg-1 min-1, absolute sodium excretion, from 8.35 +/- 1.08 to 21.62 +/- 1.62 mumol kg-1 min-1 and fractional sodium excretion, from 3.82 +/- 0.23 to 5.34 +/- 0.32%. Under these conditions, atriopeptin III-induced increases in urine flow (110.2 +/- 8.7 versus 43.9 +/- 6.2 microliters kg-1 min-1) absolute (24.0 +/- 1.8 versus 9.3 +/- 1.2 mumol kg-1 min-1) and fractional (5.16 +/- 0.24 versus 2.08 +/- 0.33%) sodium excretions were significantly (P less than 0.001) greater.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal actions of atriopeptin III in genetic and renovascular models of hypertension in the rat

The renal actions of atriopeptin III were compared in sham control, spontaneous and Goldblatt (2-K 1-C) hypertensive rats. Atriopeptin III, administered at 125. 250 and 500 ng/kg or 1.0, 1.5 and 2.0 micrograms/kg, into sham control rats had no effect on blood pressure or renal haemodynamics but caused dose related increases in urine flow, absolute and fractional sodium excretions, from 44 to 248%. Similar excretory responses to this dose range of atriopeptin III were obtained in spontaneously hypertensive rats. Atriopeptin III given at 125, 250 and 500 ng/kg into 2-K 1-C Goldblatt hypertensive rats increased reversibly left kidney urine flow, absolute and fractional sodium excretion by between 55 and 74% which were similar responses to those of sham control left kidneys. By contrast, atriopeptin III had much smaller effects on water and sodium excretions of the right clipped kidneys. These results suggest that atrial natriuretic peptides may be useful in mobilising fluid in genetic hypertension but their usefulness may be restricted in renovascular forms of hypertension.     

An investigation into the alpha-adrenoceptor mediating renal nerve-induced calcium reabsorption by the rat kidney.

An investigation was undertaken in pentobarbitone-anaesthetized rats to determine the sub-type of alpha-adrenoceptor responsible for the renal nerve-induced increases in the reabsorption of calcium and sodium by the tubules of the kidney. Stimulation of the renal nerves at low frequencies (0.8-1.5 Hz) did not change either renal blood flow or glomerular filtration rate but significantly reduced urine flow by 32%, calcium excretion by 36% and absolute and fractional sodium excretions by 36% and 22%, respectively. In the presence of the selective alpha 1-adrenoceptor antagonist prazosin, renal nerve stimulation (2-3 Hz) caused a significant reduction in renal blood flow of 7% but did not change either glomerular filtration rate, urine flow, calcium excretion or absolute and fractional sodium excretions. During administration of the selective alpha 1-adrenoceptor antagonist, idazoxan, renal nerve stimulation (1.0-1.5 Hz) significantly reduced renal blood flow by 4% and glomerular filtration rate by 7%; at the same time there were significant falls in urine flow of 43%, calcium excretion of 43% and absolute and fractional sodium excretions of 41% and 37%, respectively. These results show that low frequency renal nerve stimulation causes an anticalciuresis, independent of renal haemodynamics, which represents an increase in tubular reabsorption of calcium. This effect was blocked by prazosin but not idazoxan which is consistent with the mediation of alpha 1-adrenoceptors. The neurally-induced antinatriuresis also appeared to be dependent on the activation of alpha 1-adrenoceptors.     

Influence of combined hypertension and renal failure on functional alpha(1)-adrenoceptor subtypes in the rat kidney

BACKGROUND AND PURPOSE: This study investigated whether the alpha(1)-adrenoceptor responsiveness of the renal vasculature was altered in the state of hypertension combined with renal failure. EXPERIMENTAL APPROACH: Male spontaneously hypertensive rats (SHR) received cisplatin (5 mg kg(-1) i.p.) to induce renal failure. Seven days later, the rats were anaesthetized and the reductions in renal blood flow (RBF) to electrical renal nerve stimulation (RNS) and intrarenal administration of three adrenoceptor agonists (noradrenaline, phenylephrine and methoxamine) were determined before and after amlodipine, 5-methylurapidil, chloroethylclonidine or BMY 7378. KEY RESULTS: In renal failure SHR (RFSHR), RBF and creatinine clearance were significantly reduced (approximately 70%), while urine output and fractional sodium excretion were four and twenty-fold higher, respectively, compared to SHR. Vasoconstrictions induced by RNS or the adrenoceptor agonists were greater in RFSHR than SHR, and these responses were blunted by 5-methylurapidil, BMY 7378 and amlodipine in the SHR, while chloroethylclonidine had no effect. In the RFSHR, all renal vasoconstrictions were reduced by amlodipine and BMY 7378 but 5-methylurapidil attenuated those caused by RNS, noradrenaline and methoxamine while those to phenylephrine were enhanced. Chloroethylclonidine potentiated renal vasoconstrictor responses to methoxamine and phenylephrine but not RNS or noradrenaline in RFSHR. CONCLUSIONS AND IMPLICATIONS: These findings suggest alpha(1A)- and alpha(1D)-adrenoceptors mediated the renal vasoconstrictor responses in SHR and RFSHR. In the RFSHR, other alpha(1)-adrenoceptor subtypes, for example, alpha(1B)-adrenoceptors appeared to play a greater role.     

The influence of changes in perfusion pressure and angiotensin II on the renal excretory responses to atrial natriuretic peptides.

The renal actions of atriopeptin III were examined in anaesthetised rats at differing perfusion pressures before and following blockade of the renin-angiotensin system. At normal perfusion pressure 1000 ng kg-1 atriopeptin III caused reversible increases in glomerular filtration rate, of 20%, urine flow, absolute and fractional sodium excretions of 51-93%. Reduction of left renal perfusion pressure to 80 mm Hg decreased glomerular filtration rate by 30% and urine flow, absolute and fractional sodium excretions by 80% while atriopeptin III administration only minimally changed these variables. Concomitantly, right kidney perfusion pressure rose by 15 mm Hg which significantly increased fluid output, while the atriopeptin III induced diuresis and natriuresis were significantly larger. During infusion of captopril 900 micrograms kg-1 h-1 when pressures at the left and right kidneys had been reduced and elevated, respectively, atriopeptin III caused larger excretory responses in both kidneys which were greater than without captopril. These result suggested that the atriopeptin III mediated natriuresis and diuresis were directly proportional to perfusion pressure and attenuated by angiotensin II.     

The action of atriopeptin III on renal function in two models of chronic renal failure in the rat.

1. The natriuretic and diuretic effects of atriopeptin III (125, 250 and 500 ng kg-1, i.v.) were studied in groups of rats anaesthetized with pentobarbitone which were either sham controls, unilaterally nephrectomized controls, adenine-fed or subtotal nephrectomy chronic renal failure models. 2. Atriopeptin III given at these doses to the sham control animals had no effect on blood pressure, renal blood flow or glomerular filtration rate but reversibly increased urine flow, between 46% to 54%, absolute sodium excretion, between 52% to 61%, and fractional sodium excretion, between 48% to 54% (all P values less than 0.05) from the lowest to the highest dose. The adenine-fed chronic renal failure group of rats had a reduced renal blood flow of between 30 and 75%, and glomerular filtration rate of approximately 20%, compared to the sham controls. Administration of atriopeptin at 125, 250 and 500 ng kg-1 to the animals with renal failure increased water and sodium excretion to the same degree as observed in the sham group of rats. 3. In the group of unilaterally nephrectomized rats, atriopeptin III, at 125, 250 and 500 ng kg-1 increased urine flow by 36%, 47% and 72%, respectively, absolute sodium excretion by 37%, 57% and 106%, respectively, and fractional sodium excretion by 46%, 45% and 102%, respectively. A similar pattern of responses was observed in the subtotal nephrectomy, chronic renal failure group in which filtration rate was approximately 4 times less than the controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alpha 1b-adrenoceptors mediate renal tubular sodium and water reabsorption in the rat.

1. It is known that activation of alpha 1-adrenoceptors causes renal vasoconstriction and increased tubular Na+ and water reabsorption, with the alpha 1a-subtype mediating the constrictor effect. 2. This study examines which subtype of alpha 1-adrenoceptors mediates tubular Na+ and water reabsorption in pentobarbitone-anaesthetized rats. In order to avoid systemic effects, phenylephrine (0.3 to 30 micrograms kg-1), methoxamine (0.1-10 micrograms kg-1) and vehicle were infused into the right renal artery (via the suprarenal artery) of three groups of rats. Two other groups of rats were continuously infused with the irreversible selective alpha 1b-adrenoceptor antagonist, chloroethylclonidine (3 mg kg-1 h-1) for 1 h, prior to the construction of dose-response curves to phenylephrine or methoxamine. Another group was continuously infused with the irreversible selective alpha 1a-adrenoceptor antagonist, SZL-49 (10 micrograms kg-1 h-1) for 1 h, prior to the construction of dose-response curves to phenylephrine. Mean arterial pressure (MAP), heart rate (HR), urine flow, Na+ and K+ excretion, and urine osmolality were monitored. 3. Phenylephrine and methoxamine did not affect MAP or HR but dose-dependently and significantly decreased urine flow, urine osmolality as well as Na+ excretion and, slightly increased K+ excretion, although this was significant only for phenylephrine. 4. The antidiuretic, antinatriuretic and kaliuretic effects of phenylephrine were abolished by pretreatment with chloroethylclonidine, but were not inhibited by SZL-49. The inhibitory effects of methoxamine on urine flow and Na+ excretion were also almost totally abolished by chloroethylclonidine. 5. Our results show that alpha 1b-adrenoceptors mediate renal tubular Na+ and water reabsorption.     

Differential renal responses to atrial natriuretic peptide in two-kidney, one clip goldblatt hypertensive rats

Bilateral renal clearance experiments were performed to examine the effects of synthetic rat atrial natriuretic peptide (ANP, atriopeptin II) on the arterial blood pressure (BP) and individual kidney function in anesthetized 2-kidney, 1 clip Goldblatt hypertensive rats (n = 14) and normotensive rats (n = 15). Bolus administration of graded doses of ANP from 2.5 to 10 micrograms/kg produced dose-related reductions in BP in hypertensive and normotensive rats. Despite profound reductions in BP, there were significant increases in glomerular filtration rate, urine flow, absolute and fractional excretion rates of sodium and potassium, osmolar clearance, and free water clearance in the nonclipped kidney, whereas no significant changes in these renal indices occurred in the clipped kidney. The enhanced renal responses were dose-dependent. The normal kidney responded to ANP with similar magnitude. When ANP was infused intravenously (0.3 microgram/kg.min i.v.) during 2 h, BP maximally reduced by 36 +/- 2 mm Hg (24 +/- 1%) in the hypertensive group and by 27 +/- 2 mm Hg (22 +/- 2%) in the control group. Again, there were distinct renal responses between the two kidneys of hypertensive rats. These results indicate that ANP effectively reduces BP and preferentially increases the excretory function of the nonclipped kidney without compromising the function of the clipped kidney in this hypertensive model.     

Role of angiotensin AT1 and AT2 receptors in mediating the renal effects of angiotensin II in the anaesthetized dog.

1. Experiments were performed using the selective AT1 receptor antagonist, GR117289, and the selective AT2 receptor antagonist, PD123177, to assess the relative importance of AT1 versus AT2 receptors in mediating the renal effects of angiotensin II (AII) in vivo, in salt-replete pentobarbitone-anaesthetized dogs. 2. The AT1 receptor antagonist, GR117289 (0.5 mg kg-1 + 1 microgram kg-1 min-1, i.v.), caused renal vasodilatation, characterized by a mean increase of 21 +/- 5% in renal blood flow, 45 min post-dose. GR117289 also caused a fall in mean blood pressure (12 +/- 4%), but despite this, sodium and urine excretion were not reduced. Indeed, there was a tendency for urine output and sodium excretion to increase, although the changes were not statistically significant. GR117289 caused a reduction in plasma aldosterone levels (-35 +/- 16%) 45 min post-dose, despite increasing plasma renin activity (+ 173 +/- 42%). In contrast to GR117289, the AT2 receptor antagonist, PD123177 (20 micrograms kg-1 min-1 intra-renal artery; i.r.a.) caused no significant change in blood pressure, renal blood flow, or sodium and urine excretion, indicating that the renal effects of endogenous AII in these salt-replete animals are mediated predominantly by AT1 receptors. 3. Intra-renal artery infusion of AII (1-300 ng kg-1 min-1) caused dose-related renal vasoconstriction, and decreases in urine output, sodium excretion, fractional excretion of sodium, and glomerular filtration rate (GFR).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of a converting enzyme inhibitor (captopril) and angiotensin II on fetal renal function.

1. Renal function was studied in chronically catheterized fetal sheep (119-128 days gestation), before and during treatment of the ewe with the angiotensin converting enzyme (ACE) inhibitor, captopril, which crosses the placenta and blocks the fetal renin angiotensin system. 2. An i.v. dose of 15 mg (about 319 micrograms kg-1) of captopril to salt-replete ewes followed by an infusion to the ewe of 6 mg h-1 (about 128 micrograms kg-1 h-1) caused a fall in fetal arterial pressure (P < 0.01), and a rise in fetal renal blood flow (RBF) from 67.9 +/- 5.6 to 84.9 +/- 8.3 ml min-1 (mean +/- s.e. mean) (P < 0.05). Renal vascular resistance and glomerular filtration rate (GFR) fell (P < 0.01); fetal urine flow (P < 0.01); fetal urine flow (P < 0.01) and sodium excretion declined (P < 0.05). 3. Ewes were treated for the next 2 days with 15 mg captopril twice daily. On the 4th day, 15 mg was given to the ewe and fetal renal function studied for 2 h during the infusion of captopril (6 mg h-1) to the ewe. Of the 9 surviving fetuses, 3 were anuric and 3 had low urine flow rates. When 6 micrograms kg-1 h-1 of angiotensin II was infused directly into the fetus RBF fell from 69 +/- 10.1 ml min-1 to 31 +/- 13.9 ml min-1, GFR rose (P < 0.05) and urine flow (P < 0.01) and sodium excretion increased in all fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of diltiazem and nifedipine on renal function in the rat.

The effect of intravenous administration of the calcium-entry blocking drugs, diltiazem and nifedipine, on renal haemodynamic and tubular function was examined in denervated kidneys of pentobarbitone-anaesthetized rats. Infusion of vehicle for the compounds had no effect on renal function which was stable for the duration of the experiments. Diltiazem was infused at 5, 10 and 20 micrograms kg-1 min-1. Blood pressure did not change following 5 micrograms kg-1 min-1 diltiazem but was significantly reduced, by 12 mmHg, after 10 micrograms kg-1 min-1 and by 17 mmHg after 20 micrograms kg-1 min-1. Renal blood flow was not affected by any dose of diltiazem while at the lowest dose of drug, glomerular filtration rate (g.f.r.) was significantly increased, by 24%. Absolute and fractional sodium excretion were increased significantly, 154% and 77% respectively, by 5 micrograms kg-1 min-1 diltiazem, 20% and 24% respectively, by 10 micrograms kg-1 min-1 diltiazem, but were unchanged by 20 micrograms kg-1 min-1. Infusion of nifedipine at 0.5, 1.0 and 2.0 micrograms kg-1 min-1 decreased systemic blood pressure by 9, 9 and 20 mmHg, respectively. Renal blood flow was increased (7%) by 1.0 microgram kg-1 min-1 only, while g.f.r. did not change at any dose. Urine flow, absolute and fractional sodium excretions were increased, 127%, 96% and 90% respectively, by 0.5 microgram kg-1 min-1 nifedipine, 127%, 197% and 194% respectively, by 1.0 microgram kg-1 min-1, while these variables remained unchanged by a dose of 2.0 micrograms kg-1 min-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Hoe 140, a bradykinin B2-receptor antagonist, on renal function in conscious normotensive rats.

1. The present study was designed to determine if endogenous kinins are involved in the regulation of arterial blood pressure and renal function in conscious rats given deoxycorticosterone enantate (DOC, 25 mg kg-1, s.c., weekly) or vehicle for two weeks. 2. The bradykinin B2-receptor antagonist, D-Arg[Hyp3,Thi5,D-Tic7,Oic8]- bradykinin (Hoe 140), at a dose of 300 micrograms kg-1, s.c., blocked the hypotensive effect of 300 ng kg-1 bradykinin i.a., but it did not alter the blood pressure lowering action of 300 ng kg-1 acetylcholine or prostaglandin E2. Inhibition of the response to bradykinin persisted up to 6 h after the administration of Hoe 140. 3. Administration of 300 micrograms kg-1 Hoe 140 s.c. four times a day did not alter mean blood pressure, renal blood flow, or renal function in rats given DOC-vehicle. However, it decreased urinary volume by 70% (from 48.2 +/- 3.8 to 14.3 +/- 3.7 ml 24 h-1, P less than 0.01) and urinary secretion of sodium by 54% (from 1.02 +/- 0.05 to 0.47 +/- 0.16 mmol 24 h-1, P less than 0.01) and potassium by 30% (from 2.93 +/- 0.15 to 2.04 +/- 0.15 mmol 24 h-1, P less than 0.05) in DOC-treated rats. Mean blood pressure, glomerular filtration rate and total renal blood flow remained unchanged. 4. Our results suggest that endogenous kinins play a role in the regulation of renal excretion of water and sodium in the presence of elevated levels of DOC.     

Cardiovascular effects of the novel arteriovenous dilator agent, flosequinan in conscious dogs and cats.

1. Flosequinan (BTS 49 465, 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) a novel arteriovenous dilator agent was orally effective in conscious renal hypertensive dogs and normotensive cats. The hypotensive potency of flosequinan was approximately ten times less than that of hydralazine in renal hypertensive dogs, 10 mg kg-1 and 20 mg kg-1 flosequinan causing similar falls in mean blood pressure to 1 mg kg-1 and 3 mg kg-1 hydralazine respectively. In normotensive cats, 5 mg kg-1 flosequinan caused similar falls to 0.5 and 1.0 mg kg-1 hydralazine. The onset of hypotensive effect after flosequinan appeared to be slightly slower than after hydralazine in the dog and slightly faster than hydralazine in the cat. 2. The degree of tachycardia and increase in plasma renin activity (PRA) for equivalent falls in mean blood pressure in both species was significantly less for flosequinan than for hydralazine (P less than 0.05). 3. In normotensive dogs, flosequinan, 10 and 20 mg kg-1 orally, caused a small but non-significant increase in sodium and chloride excretion and had little effect on urine volume whereas hydralazine, 1 and 3 mg kg-1 orally, caused a marked retention of sodium and chloride ions and a reduction in urine volume (P less than 0.01). 4. Neither flosequinan, 10 mg kg-1 orally, nor hydralazine 1 mg kg-1 orally, affected either glomerular filtration rate measured as creatinine clearance or effective renal plasma flow measured as p-aminohippuric acid clearance in normotensive dogs. 5. The lesser degree of tachycardia and increase in plasma renin activity together with a lack of sodium retaining activity associated with flosequinan suggest that this agent may have potential advantages over existing therapy as an antihypertensive in man.     

The renal functional responses to 5-HT1A receptor agonist, flesinoxan, in anaesthetized, normotensive rat.

1. The present study was designed to examine the effects of a centrally acting 5-HT1A receptor agonist, flesinoxan, on the cardiovascular system and renal haemodynamics and excretory function. 2. In chloralose-urethane anaesthetized Wistar rats, i.v. administration of bolus doses of flesinoxan, at 30, 100, 300 and 1000 micrograms kg-1, caused significant, dose-dependent decreases in mean arterial pressure, of 33 +/- 2 mmHg (P < 0.001) and heart rate of 57 +/- 9 beats min-1 (P < 0.001) at the highest dose used. Despite this substantial fall in perfusion pressure there were no meaningful changes in the renal excretion of water and sodium. In a second group of rats, reduction of renal perfusion pressure mechanically to the same values as observed in rats given flesinoxan (i.e. 100, 92, 84 and 76 mmHg) produced reductions in urine flow, absolute and fractional sodium excretions reaching a maximum of 74, 86 and 84% respectively (all P < 0.001) at the lowest pressure. These reductions were significantly larger than those seen in the previous group of animals. 3. In the group of rats subjected to renal denervation, flesinoxan produced changes in blood pressure and heart rate which were not different from those observed in intact animals. However, the reduction in pressure was accompanied by significant decreases in urine flow of 71%, absolute sodium excretion of 68% and fractional sodium excretion of 67% (all P < 0.001) at the highest dose, which were all significantly greater than the changes seen in the innervated animals but were not different from those observed when renal perfusion pressure was reduced mechanically.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dietary NaCl-induced hypertension in uninephrectomized Wistar-Kyoto rats: role of kidney function

This study tests the hypothesis that combination of unilateral nephrectomy and a high sodium chloride (NaCl) diet causes hypertension in otherwise normotensive Wistar-Kyoto (WKY) rats and that this hypertensive response is due to a deficit in the remaining kidney's function. Four-week-old male WKY rats underwent either a right nephrectomy or a sham operation. Two weeks later, the groups either were switched to a high (8%) NaCl diet or remained on the basal (0.72%) NaCl diet. At ages 3 and 6 months, hemodynamic parameters and renal excretory responses were measured, in the conscious animals, before and after administration of a 30-min isotonic saline challenge (5% of body weight). The high-NaCl diet increased arterial pressure in the uninephrectomized but not in sham-operated rats; the development of hypertension was associated with increases in baseline renal excretion of fluid and sodium and diuretic and natriuretic responses to the isotonic saline challenge. The increased diuresis and natriuresis in the hypertensive WKY rats were related to a significant reduction in renal tubular reabsorption and an associated increase in fractional excretion of fluid and sodium. The high-NaCl diet also increased renal excretion of fluid and sodium in the sham-operated rats; however, the uninephrectomized animals excreted much more fluid and sodium than did sham-operated rats. These data suggest that the combination of unilateral nephrectomy and dietary NaCl excess causes hypertension in the normotensive WKY rats, but the hypertensive response is not likely due to a functional deficit in the remaining kidney.     

Urinary Kallikrein Excretion in Normotensive and Spontaneously Hypertensive Rats

Abstract: Using single animals and repeated determinations at one week intervals the urine output, and sodium and kallikrein urinary excretion have been measured in normotensive, “moderate” spontaneously hypertensive (BP 150–179 mmHg) and “elevated” spontaneously hypertensive rats (BP > 180 mmHg). Both the groups of spontaneously hypertensive rats show higher water, sodium and kallikrein excretions than the normotensive animals. The group of “elevated” hypertensive rats shows the highest values. The results are discussed in the light of the interrelation between the kallikrein-kinin system and the prostaglandis.     

Effect of clonidine on renal sodium handling in spontaneously hypertensive rats

Up-regulation of kidney α2-adrenoceptor expression has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). This study was carried out to evaluate renal sodium excretion in response to clonidine administration in SHR and control normotensive Wistar-Kyoto (WKY) rats. SHR and WKY rats (12-week-old) were placed in metabolic cages for 4 days: the first 2 days in control conditions and the following 2 days under oral clonidine treatment (100 μg/kg body weight). Clonidine produced a similar reduction in systolic blood pressure values in SHR and WKY rats, although SHR remained hypertensive. At the end of the study SHR and WKY rats presented similar noradrenaline plasma levels. However, noradrenaline kidney tissue levels were significantly higher in SHR compared to WKY rats. Under control conditions, SHR presented lower urine flow compared to WKY rats. Clonidine produced a significant decrease in urine flow in WKY rats but not in SHR. Furthermore, clonidine also produced a significant reduction in urinary sodium, potassium, and creatinine excretion in WKY rats, but had no effect in SHR. In conclusion, in SHR the reduction in systolic blood pressure and sympathetic activity produced by clonidine was not accompanied by a decrease in urine volume and sodium excretion.