Effect of alpha-adrenoceptor blockade on the 0.4 Hz sympathetic rhythm in conscious rats

1. The present study examined the origin of the 0.4 Hz rhythm in renal sympathetic nerve activity (RSNA) in rats. It was anticipated that, after elimination of 0.4 Hz oscillations of arterial pressure (AP) by alpha-adrenoceptor blockade, the persistence or disappearance of a 0.4 Hz rhythm in RSNA would point to an endogenous (central oscillator) or baroreflex origin, respectively. 2. Arterial pressure and RSNA were recorded in seven conscious rats, before and after acute alpha-adrenoceptor blockade with phentolamine (5 mg/kg, i.v.). In each condition, power and coherence spectra were calculated over 15 min periods of rest. 3. In control conditions, highly coherent AP and RSNA oscillations were observed near 0.4 Hz. After phentolamine administration, spectral power in the mid-frequency (0.27-0.74 Hz) band was significantly reduced for both AP and RSNA and maximum power was shifted towards 0.7 Hz. 4. The disappearance of the RSNA rhythm at 0.4 Hz after phentolamine administration favours the hypothesis of a baroreflex origin. The new oscillation near 0.7 Hz can derive either from the activity of a previously unrecognized central oscillator or from a faster feedback mechanism involving cotransmitters of noradrenaline acting with shorter time constants (e.g. ATP).     

Renal function during onset of carbachol-induced hypertension in conscious rats

This study evaluated the changes in renal function that occur during the early phases of chronic infusion of carbachol into the lateral ventricle in conscious rats. Infusion of 1.0 micrograms/h of carbachol i.c.v. resulted in a prompt pressor response with mean arterial pressure rising 20 mm Hg within 15 min. The pressure remained elevated for the duration of a 2-hour infusion. Carbachol infusion at 0.5 micrograms/h induced a similar elevation in blood pressure, but the onset was delayed, reaching significance only after 30-60 min. The higher dose of carbachol was associated with a marked and sustained natriuresis, with sodium excretion increasing from 2.1 +/- 0.3 to 5.3 +/- 1.0 microEq/100 g min after 2 h, compared to 2.0 +/- 0.5 and 1.8 +/- 0.3 microEq/100 g min in vehicle-infused control animals. Sodium excretion did not change significantly in animals infused with carbachol at 0.5 microgram/h. There were no significant changes in glomerular filtration rate in any of the groups. Plasma levels of atrial natriuretic peptide (ANP) were not altered significantly by ventricular infusion of carbachol (188 +/- 99 before vs. 83 +/- 17 pg/ml after infusion). It is concluded that the pressor response to central carbachol infusion is not dependent on retention of sodium and water. The natriuresis observed with carbachol infusion can be dissociated from the pressor response, and is not mediated by ANP.     

Mechanisms of renal vasoconstriction following furosemide in conscious rats

Regional hemodynamics following intravenous injection of furosemide were studied in conscious rats instrumented with Doppler flowprobes. Furosemide caused a dose-dependent acute (within 3 min) transient increase in renal resistance (RR) followed by a later generalized vasoconstriction in the renal, mesenteric and hindquarter (HQR) vascular bed. With in vitro experiments a possible direct effect of furosemide on renal artery segments was excluded. The acute rise in RR was partly (approximately 40%) attenuated by pretreatment with phentolamine or prazosin, but not prevented by renal denervation, volume repletion or pretreatment with captopril, losartan, indomethacin, aminophylline, nifedipine, or a vasopressin V_1A-receptor-antagonist. However, the acute renal vasoconstriction was absent in water diuretic rats. The later vasoconstriction was blunted by captopril (RR+HQR), losartan (RR) and phentolamine (HQR) pretreatment. We conclude that the later generalized vasoconstriction following furosemide involves regional specific stimulation of angiotensin II and -adrenoceptors. The mechanism of the acute renal vasoconstriction could not be fully determined. Because of its absence in water diuretic rats, its rapid onset, transient nature and relative insensitivity for pharmacological tools in euvolemic rats, the acute increase in RR following furosemide may be caused by cell swelling as a result from dissipation of the renal medullary gradient. Correspondence to: Dr. B. J. A. Janssen at the above address     

Studies on the adrenomedullary dependence of kappa-opioid agonist-induced diuresis in conscious rats.

1. The dependence of kappa-opioid agonist-induced diuresis, upon an intact and functional adrenal medulla in conscious rats, was investigated in order to test the hypothesis that the diuresis is mediated by a blood-borne 'diuretic factor', of adrenomedullary origin, released by kappa-opioid receptor stimulation. 2. Confirming previous observations, adrenal demedullation significantly attenuated diuretic responses to the kappa-opioid agonists U50488H, ethylketocyclazocine (EKC) and tifluadom, but did not affect basal urine output, furosemide-induced diuresis or the antidiuretic response to the mu-opioid agonist, buprenorphine. Naloxone abolished U50488H-induced diuresis, confirming an involvement of opioid receptors. 3. Transfusion studies established that blood, from intact rats treated with U50488H, induced diuresis in intact and demedullated recipient rats, whether or not the recipients had been pretreated with naloxone. However, blood from demedullated rats treated with U50448H was unable to induce diuresis when administered to intact or demedullated recipients. 4. It is concluded that kappa-opioid agonist-induced diuresis is dependent upon an intact and functional adrenal medulla and appears to be mediated by a blood-borne 'diuretic factor' of adrenomedullary origin.     

Acute arteriolar vasoconstriction following furosemide in conscious spontaneously hypertensive rats

In a previous study in conscious spontaneously hypertensive rats (SHR), we observed an immediate decrease in the cardiac index (CI) and an increase in the total peripheral resistance index (TPRI) following the administration of furosemide. The present study was designed to evaluate the regional hemodynamic effects and the involvement of sinoaortic baroreceptors in the increase in TPRI. In SHR instrumented for the measurement of central hemodynamics, 8 mg.kg-1 furosemide decreased CI from 31.0 +/- 2.5 ml.min-1.100 g bw-1 by 9.5 +/- 1.3 ml.min-1.100 g bw-1 (n = 7). TPRI increased maximally from 5.7 +/- 0.8 by 2.7 +/- 0.5 mm Hg.min.100 g bw.ml-1. The effect on TPRI was not affected by sinoaortic denervation (SAD) to abolish arterial baroreflexes. However, furosemide induced a significantly greater decrease in CI (-12.6 +/- 1.2 ml.min-1.100 g bw-1; n = 7) after SAD. Furosemide effectively reduced the mean arterial pressure in SAD SHR (-21 +/- 9 mm Hg) but not in sham-denervated SHR. Furosemide (8 mg.kg-1) reduced renal, mesenteric and hindquarter blood flow to a comparable extent (approximately 20%) in intact SHR. The reduction in renal flow at 3.5 min after injection (-17.9 +/- 4.1%; n = 8) was significantly greater than the reduction in mesenteric (-7.1 +/- 4.7%) and hindquarter blood flow (-4.2 +/- 3.7%), suggesting that the renal bed responds faster. Thereafter, the flow reductions in the three beds were not different. The results show that furosemide causes a general vasoconstriction in conscious SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of reflex tachycardia following alpha-adrenoceptor blockade in conscious dogs: comparison of urapidil with prazosin

The effects of the alpha-adrenoceptor antagonists urapidil and prazosin were compared as to their ability to suppress or enhance baroreceptor-induced reflex changes in heart rate in conscious dogs. Bradykinin was injected as an intravenous bolus to elicit a vasodepressor response and reflex tachycardia, and angiotensin II was utilized to produce opposite effects via baroreceptor activation. Urapidil, which is an alpha 1- and alpha 2-antagonist, was infused intravenously at 2 and 5 mg/kg, and suppressed reflex tachycardia elicited by bradykinin at both dose levels. The suppression of reflex tachycardia elicited by bradykinin was not evident with intravenous prazosin (0.25 and 0.625 mg/kg), an alpha 1-antagonist. Reflex bradycardia elicited by angiotensin was not affected by urapidil but was enhanced by prazosin. Therefore, urapidil may have a selective effect in suppressing cardiac sympathetic reflexes with no apparent effect on vagal reflexes. Both urapidil and prazosin produced similar decreases in arterial blood pressure with no long-term effects on heart rate, and the degree of alpha-receptor postjunctional blockade by both agents was judged to be equivalent, as determined by intravenous phenylephrine injection. The suppression of reflex tachycardia by urapidil could be eliminated by guanethidine pretreatment, indicating that a cardiosympathoinhibitory effect by urapidil was involved.     

Daily variation in the effects of furosemide in rats.

Daily variation in the effects of furosemide, a loop diuretic agent, was examined in Wistar rats maintained under conditions of light from 7 a.m. to 7 p.m. and dark from 7 p.m. to 7 a.m. Furosemide (30 mg/kg) was given orally at 12 p.m., 4 a.m., 8 a.m., 12 a.m., 4 p.m. or 8 p.m. Urine was collected for 8 hr after furosemide administration, and urinary excretions of sodium and furosemide were determined. There were significant daily variations in the urine volume and urinary excretions of sodium and furosemide with a peak at 8 a.m. and a trough at 12 p.m. Significant correlations were observed between the urinary amount of furosemide and its diuretic effects (urine volume and urinary sodium excretion). These results suggest that the diuretic effects of furosemide show daily variations which are, at least in part, caused by the daily variation in the urinary excretion of furosemide.     

Effects of furosemide on renal haemodynamics and proximal tubular sodium reabsorption in conscious rats.

1. The effects of furosemide given as constant i.v. infusion (7.5 mg kg-1 h-1) or bolus injections (0.5, 7.5 and 120 mg kg-1) on renal haemodynamics and proximal tubular Na reabsorption were studied in conscious water diuretic rats. The clearance of Li (CLi) was used as marker for Na delivery from the proximal tubules, and clearance of [14C]-tetraethylammonium (CTEA) and [3H]-inulin (CIn) as markers for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively. 2. Furosemide caused a transient increase of RPF and GFR followed by a secondary decrease below baseline levels; the latter could in part be counteracted by volume replacement. The filtration fraction (FF = GFR/RPF) was not significantly changed by furosemide. Fractional proximal Na excretion (CLi/CIn) was significantly increased by all doses of furosemide independent of changes in RPF, GFR and FF. 3. The peak diuretic/natriuretic effect of furosemide was markedly potentiated by volume replacement, probably due to prevention of antinatriuretic mechanisms triggered by volume depletion. 4. It is concluded that following i.v. furosemide administration there is a biphasic change in renal haemodynamics in conscious, restrained rats, and that the inhibition of proximal Na reabsorption, as manifested by changes in fractional Li excretion, is not likely to be due to changes in total renal haemodynamics.     

The effects of alpha-adrenoceptor blockade on dopamine-induced renal vasodilation and natriuresis

Summary To establish the effects of alpha-adrenoceptor blockade on dopamine-induced changes in renal hemodynamics and sodium excretion, dopamine dose-response curves were performed without and with pretreatment with the selective postsynaptic alpha₁-adrenoceptor antagonist prazosin in normal volunteers and in patients with renal disease and moderately impaired renal function.Prazosin (1 mg p. o. every 4 h) in 7 volunteers did not significantly affect baseline values but impaired the response of effective renal plasma flow (ERPF) and filtration fraction (FF) to infusions of dopamine in doses ranging from 0.5 to 8 g/kg per minute and completely abolished the dopamine-induced increase in sodium excretion. In 7 patients with renal disease and a glomerular filtration rate (GFR) ranging from 38–85 ml/min pretreatment with prazosin did not affect baseline ERPF, GFR or FF or their response to dopamine infusion, but sodium excretion and its response to dopamine infusion were reduced (fractional excretion of sodium at baseline 1.78 without and 0.89 with prazosin pretreatment).We conclude that alpha₁-adrenoceptor blockade with prazosin abolishes the effects of exogenous dopamine on sodium excretion in normal man. Prazosin also impairs the renal vasodilatory action of dopamine. However, the effect on sodium excretion is not directly related to inhibition of dopamine-induced renal vasodilation since in patients with renal disease prazosin also markedly reduces sodium excretion but does not influence the renal hemodynamic effects of dopamine. Send offprint requests to A. J. Smit at the above address     

Renal versus hindquarter hemodynamic responses to vasopressin in conscious rats.

Experiments were performed on conscious rats to (a) compare the responsiveness of the renal and hindquarter vascular beds to infusions of exogenous arginine vasopressin (AVP), and (b) determine whether either bed demonstrates V2-vasopressinergic vasodilation when the vasoconstrictor properties of AVP are blocked. Rats were chronically instrumented with pulsed Doppler flow probes on either the left renal artery or the distal abdominal aorta as well as with femoral arterial and venous catheters. One series of experiments examined the vascular responses of these two beds to exogenous AVP infused intravenously (i.v.) at 0.2, 2.0, or 5.0 ng/min. The lowest infusion rate was associated with no detectable changes in mean arterial blood pressure (MAP), heart rate (HR), renal or hindquarter blood flow (RBF or HQBF), or vascular resistance in these beds. In contrast, the higher infusion rates caused a marked increase in MAP, a decrease in HR, and a reduction in HQBF; RBF was unaffected, however. A second series of experiments tested for the presence of a V2-vasodilatory influence during infusion of AVP at 5 ng/min by selectively blocking V1-vasopressinergic receptors or both V1- and V2-receptor types. Little evidence for V2-mediated vasodilation was found in either vascular bed, however. We conclude that although the renal vasculature appears relatively insensitive to exogenous AVP, this insensitivity probably is not due to vasodilation mediated by activation of V2-receptors.     

Renal tubular flow dynamics during angiotensin diuresis in the rat

1. Tubular size and lissamine green transit times were measured in rat kidneys undergoing a diuretic response to angiotensin II (0.5 mug/kg per min), and compared with the changes observed during diuresis induced by osmotic diuretics, noradrenaline and chlorothiazide.2. Angiotensin always caused a marked prolongation in proximal and distal tubular transit times; individual distal convolutions were coloured for prolonged periods, and lissamine green appeared in high concentration in distal tubules.3. Marked changes were observed in superficial tubular calibre during a stable diuretic response to angiotensin. Where distal tubular diameter was normal for the rate of urine flow, proximal tubular volume was generally reduced. In a number of experiments, however, distal tubules were markedly dilated, and in these cases proximal tubular volume was also often increased. Angiotensin may therefore be capable of causing a degree of internal hydronephrosis in the rat kidney.4. Prolongation of dye transit times, and the appearance of a concentrated lissamine green bolus in distal tubules, was suggestive of a decreased superficial nephron flow rate, indicating that the diuretic effect of angiotensin may take place only through deeper nephrons.     

Renal and depressor effects of SQ 29,072, a neutral endopeptidase inhibitor, in conscious hypertensive rats.

The depressor and renal responses to the neutral endopeptidase (NEP) inhibitor, SQ 29,072, were characterized in both the conscious spontaneously hypertensive rat (SHR) and the conscious deoxycorticosterone acetate (DOCA)/salt hypertensive rat. Inhibition of tissue NEP activity by pharmacologically active doses was also ascertained in both hypertensive models. Intravenous administration of 300 mumol/kg of SQ 29,072 significantly reduced mean arterial pressure (MAP), produced modest natriuretic and diuretic responses, and inhibited renal NEP activity by approximately 40% in conscious SHR. Doses of 100 and 300 mumol/kg of SQ 29,072 elicited greater depressor responses (-36 +/- 7 and -41 +/- 8 mm Hg, respectively) in DOCA/salt hypertensive rats than in SHR (-11 +/- 24 and -31 +/- 5 mm Hg, respectively). SQ 29,072 (300 mumol/kg, i.v.) also inhibited renal NEP activity to a greater extent (70%) in DOCA/salt hypertensive rats. Similarly, the depressor responses to exogenous ANP 99-126 (1, 3, and 10 nmol/kg, i.v.) were greater in DOCA/salt hypertensive rats (-16 +/- 4, -38 +/- 6, and -73 +/- 6 mm Hg, respectively) than in the SHR (0 +/- 6, -17 +/- 3, and -24 +/- 3 mm Hg, respectively). Finally, equidepressor doses of SQ 29,072 and ANP 99-126 both increased urine volume as well as sodium and cyclic GMP excretion in conscious DOCA/salt hypertensive rats. In conclusion, the profile of depressor and renal activities produced by SQ 29,072 was consistent with potentiation of endogenous ANP by inhibition of NEP in conscious SHR and DOCA/salt hypertensive rats.     

Vascular alpha-adrenoceptor blockade by E. coli endotoxin in the rat

It has been previously shown that Escherichia coli endotoxin (ENDO) reduces the pressor effect of phenylephrine. This work attempted to define precisely the involvement of vascular alpha-adrenoceptors in this action. The dose-response curves of three alpha-agonists noradrenaline, St 587 and B-HT 933 in pithed rats were shifted rightwards by pretreatment (i.v. injection of 10 and 100 micrograms/kg) with ENDO. ENDO 10 and 30 micrograms shifted the dose-response curve of noradrenaline in perfused rat kidney. It can be suggested that ENDO has a potent blocking action on vascular alpha-adrenoceptors without evident discrimination between alpha 1 and alpha 2 subtypes.     

The hemodynamic effects of cocaine during acute controlled hemorrhage in conscious rats

BACKGROUND: Cocaine is often associated with trauma; however, little is known about how its use alters the response to blood loss. The effect of cocaine on hemodynamics following acute hemorrhage was studied in a rat model. METHODS: Following baseline measurements, rats were administered either intravenous cocaine, or saline as a control. Both groups then underwent arterial catheter hemorrhage of 30% of total blood volume. Outcome variables include blood pressure, heart rate, hematocrit, pH, PCO2, PO2, and serum bicarbonate. RESULTS: Following hemorrhage, blood pressure decreased in both groups but the hypotension was significantly greater in the saline group than the intravenous cocaine group at 0 and 5 minutes posthemorrhage. Heart rate was increased significantly for the intravenous cocaine group compared to the saline group starting at 15 minutes postcocaine and lasting for the next 25 minutes. No difference was noted for hematocrit, pH, PO2, or serum bicarbonate. CONCLUSION: Although transient, cocaine blunted the hypotensive response to acute controlled hemorrhage and resulted in tachycardia.     

Renal effects of glucagon-like peptide in rats.

The present study examined the effects of recombinant glucagon-like peptide-1-(7-36)amide (rGLP-1) on renal hemodynamics and excretory function in innervated and denervated kidneys of anesthetized rats. Intravenous infusion of rGLP-1 at a dose of 1 microg x kg(-1) x min(-1) increased urine flow and Na(+) excretion 13-fold in the innervated kidney. The natriuretic and diuretic response to rGLP-1 was attenuated in the denervated kidney in which urine flow and Na(+) excretion only increased 3-fold. Fractional excretion of Li(+), an index of proximal tubular reabsorption, increased 219% in the innervated kidney but only 54% in the denervated kidney during infusion of rGLP-1. The diuretic and natriuretic response to rGLP-1 was associated with an increase in glomerular filtration rate (39%) in the innervated kidney, but it had no effect on glomerular filtration rate in the denervated kidney. These results indicate that the natriuretic and diuretic effects of rGLP-1 are due to inhibition of Na(+) reabsorption in the proximal tubule. It also increases glomerular filtration rate in kidneys with an intact renal innervation.     

Calcium entry and 5-HT2 receptor blockade in oliguric ischaemic acute renal failure: effects of levemopamil in conscious rats.

1. Unilateral left renal artery occlusion for 1 h in a group of 8 untreated female Sprague-Dawley rats resulted in oliguric acute renal failure (ARF) persisting for more than 6 h after reflow, i.e. after reperfusion of the kidney by removal of the arterial clamp. In a second group of 8 rats with left unilateral ARF the effects of levemopamil (L), a calcium entry blocker with 5-hydroxytryptamine2 (5-HT2) receptor antagonistic properties, were studied. Rats received L as a continuous infusion (6 mg kg-1 h-1) from 1 h before ischaemia until 6 h after reflow. 2. Endogenous creatinine clearance, an estimate of glomerular filtration rate (GFR), of left ischaemic kidneys of untreated rats was almost completely abolished and urine flow was 0.05 +/- 0.02 and 0.03 +/- 0.01 ml h-1 100 g-1 body weight (body wt.) at 2 and at 6 h of reflow, respectively. In contrast, left ischaemic kidneys of L-treated rats revealed significantly higher GFR (0.10 +/- 0.02 and 0.03 +/- 0.01 ml min-1 g-1 kidney weight (k.wt.); P < 0.01) and urine flow (0.51 +/- 0.05 and 0.15 +/- 0.04 ml h-1 100 g-1 body wt.; P < 0.05) at 2 and 6 h of reflow, respectively. 3. At 6 h of reflow, mitochondria from the cortex of left ischaemic kidneys of untreated rats showed significantly reduced ATP synthesis when compared to right intact kidneys (0.06 +/- 0.02 vs 0.26 +/- 0.02 mumol ATP mg-1 protein min-1 (P < 0.01)). In contrast, in L-treated rats, ATP synthesis of left ischaemic kidneys was largely preserved (0.17 +/- 0.01 mumol ATP mg-1 protein min-1). 4. Ischaemia of left kidneys resulted in a significant decrease in medullary Na-K-ATPase activity to 9.6 +/- 2.4 as compared to 20.4 +/- 3.7 mumol P(i) h-1 mg-1 protein in the intact right kidneys which was not prevented by L (9.4 +/- 2.4 mumol P(i) h-1 mg-1 protein). 5. In untreated rats the calcium content in cortical mitochondria from left ischaemic kidneys had risen 2 fold to 23.0 +/- 1.8 at 6 h of reflow as compared to 12.2 +/- 0.3 nmol mg-1 protein in right intact kidneys (P < 0.01). This rise in mitochondrial calcium was not significantly attenuated by treatment with L (19.9 +/- 1.7 nmol mg-1 protein). 6. The results show that L transiently converted oliguria into non-oliguria during the early phase after reflow in ischaemic ARF, i.e. after reperfusion following 1 h of complete interruption of renal perfusion. The present data suggest indirectly that the 5-HT2-antagonistic properties of L rather than its calcium channel blocking action maintains GFR at low level and protects mitochondrial function early after reflow in this model of ischaemic ARF.     

Mechanisms of phenylalanine-induced pressor effects in conscious rats

Phenylalanine and tyrosine reportedly decrease blood pressure in conscious restrained rats. However, tyrosine has recently been found to increase blood pressure in anesthetized animals, questioning the generality of findings obtained in restrained animals. The present study therefore evaluated the effects of phenylalanine on mean arterial pressure (MAP) and heart rate (HR) in unrestrained, conscious rats. Phenylalanine (0.32-1.33 mmol/kg i.p.) increased MAP and decreased HR, effects that were antagonized by carbidopa and prazosin but not by desipramine. In addition, both DOPA and tyrosine (1.33 mmol/kg) increased MAP. In contrast, phenylalanine-induced increases in plasma concentrations of its indirectly acting sympathomimetic amine metabolite, phenethylamine, were small and temporally unrelated to the phenylalanine-induced MAP elevation, and desipramine inhibited MAP increases produced by exogenous phenethylamine. These observations indicate that phenylalanine increases MAP in conscious, unrestrained animals by augmenting peripheral catecholamine synthesis and release rather than by affecting phenethylamine bioavailability.