Renal Vasoconstrictor Effects Research Articles

Effects of the non‐peptide, non‐selective endothelin antagonist, bosentan, on regional haemodynamic responses to NG‐monomethyl‐L‐arginine in conscious rats

1. Male, Long Evans rats (350-450 g) were chronically instrumented to allow monitoring of mean arterial blood pressure, heart rate and changes in renal, mesenteric and hindquarters haemodynamics. In the first experiment, animals (n = 8) were given a bolus i.v. injection of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine hydrochloride (L-NMMA; 30 mg kg-1) on four consecutive days. Fifteen min prior to L-NMMA administration on the fourth day, the endothelin, ETA-, ETB-receptor antagonist, bosentan, was injected (30 mg kg-1, i.v.). Relative to the response on the third day, bosentan caused 33 +/- 4%, 24 +/- 3%, 14 +/- 3%, and 18 +/- 5% inhibition of the pressor, and renal, mesenteric and hindquarters vasoconstrictor effects of L-NMMA, respectively. 2. In the second experiment, bosentan was given 15 min before L-NMMA in a group of rats (n = 6) which had not received L-NMMA previously. Relative to the responses to L-NMMA on the first day in the previous experiment, bosentan caused a 30%, 24%, 18% and 27% inhibition of the pressor, and renal, mesenteric and hindquarters vasoconstrictor effects of L-NMMA, respectively. 3. The results indicate a significant contribution from endothelin to the haemodynamic effects of L-NMMA in conscious rats. However, since our previous studies have shown the renin-angiotensin and sympathoadrenal systems are not involved, it is likely that the major component of the cardiovascular response to L-NMMA in conscious rats is due to loss of vasodilator action of endothelial nitric oxide.

Eicosanoid modulation of the norepinephrine effect on blood pressure and renal hemodynamics in humans

The main objective of this study was to investigate the role of eicosanoids in modulating the effect of norepinephrine (NE) on blood pressure and renal hemodynamics during NE administration. Eight healthy volunteers were randomly assigned to three (1 week apart) infusion periods (180 min) with either dextrose 5% or NE, with or without indomethacin pretreatment. Pressor doses of NE induced marked alterations in renal hemodynamics and concomitant increases in eicosanoid excretion rates. The production of the vasodilatory prostacyclin (PGI 2), as reflected in the excretion rate of the stable metabolites 6-keto-prostaglandin (PG)F 1α and 2,3-dinor-6-keto-PGF 1α, was 2.7 times higher than that of the constrictor thromboxane (TX)A 2, which was measured as the stable derivative TXB 2. Indomethacin pretreatment blunted the NE-induced augmentation in eicosanoid excretion and resulted in further increases in arterial pressure and in renal vascular resistance. These results demonstrate that PGI 2 attenuates the systemic and the renal hemodynamic vasoconstrictor effect of NE in normotensive control normal subjects.

Stimulatory Effect of 8-Epi-PGF2α, An F2-Isoprostane, on Endothelin-1 Release

8-Epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) is an F2-isoprostane produced in vivo by a cyclooxygenase-independent, free radical-catalyzed lipid peroxidation mechanism. It exhibits renal vasoconstrictor effects by binding to a receptor related to, but distinct from, that of thromboxane A2 (TxA2). In cultured bovine aortic endothelial cells (BAECs), competitive binding assays using [3H]-8-epi-PGF2 alpha indicated the existence of two distinct binding sites. The Kd values were similar to those of cultured rat aortic smooth-muscle cells, suggesting that the high- and the low-affinity binding sites represent isoprostane and TxA2 receptors, respectively. 8-Epi-PGF2 alpha dose-dependently stimulated endothelin-1 (ET-1) secretion from BAECs. These increases were partially inhibited by a TxA2 receptor antagonist, consistent with the premise that isoprostanes and TxA2 recognize closely related receptors. The presence of specific binding sites for F2-isoprostanes on endothelial cells widens the scope of the possible pathophysiologic significance of these eicosanoids, released during oxidant injury, to include alteration of endothelial cell biology. The release of ET-1 by 8-epi-PGF2 alpha may help to explain the large increases in plasma and urinary concentrations for both ET-1 and 8-epi-PGF2 alpha in patients with hepatorenal syndrome.

Influence of sodium diet on L-NAME effects on renin release and renal vasoconstriction

The intervention of the L-arginine-NO pathway in renal vasodilation and renin secretion was studied in an isolated perfused rat kidney model. NG-nitro-L-arginine methyl ester (L-NAME, 1-25 microM), an inhibitor of nitric oxide (NO) synthesis, caused a dose-dependent increase in perfusion pressure (PP) and a dose-dependent decrease in renal perfusate flow. Renin was inhibited independently of the rise in PP, since the effect of L-NAME on renin release was the same when PP was maintained constant. Exposure of rats to low [salt depleted (SD)] or high [salt repleted (SR)] salt intake for 1 mo influenced the renal vascular response to L-NAME (3 microM). Isolated SR rat kidney vasculature vasoconstricted to a greater extent after inhibition of NO synthase than did that of SD kidneys. A similar fall in renin release was observed after L-NAME in both groups, despite a higher renin secretion rate in SD than in SR rats. These results suggest that NO-dependent vasodilation counteracts the renal vasoconstrictor effect of sodium loading.

Distribution and functional role of renal ET receptor subtypes in normotensive and hypertensive rats

Experiments were designed to compare the distribution and physiological roles of endothelin (ET) receptor subtypes, ETA and ETB, in the kidneys of normotensive Sprague-Dawley (SD) and spontaneously hypertensive (SH) rats. Using [125I] ET-1 and subtype-selective ligands sarafotoxin 6c (S6c, ETB-selective agonist) and BQ123 (ETA-selective antagonist), the distribution of ETA and ETB receptors in SD rat kidney cortex, outer medulla and papilla was calculated to be 50:50, 30:70 and 10:90, respectively. The ET receptor subtypes in outer medulla and papilla of age-matched SH rats were similar to those of SD. However, in the cortex of SH rats, the ratio of ETA to ETB was 25:75 compared to 50:50 in SD rats. In addition, the affinity of the ET receptors was also higher in SH rats (117 pM vs. 235 pM). In the conscious SD rats, bolus i.v. injections of ET-1 and S6c elicited similar dose-dependent decrease in renal blood flow (RBF), which were unaffected by the infusion of the selective ETA receptor antagonist, BQ123. The SH rats were more sensitive to the renal vasoconstrictor effect of S6c and ET-1. Also, the dose-response curve to S6c was shifted to the left when compared to ET-1; however, BQ123 infusion abolished this difference. In renal clearance studies, BQ123 infusions decreased RBF and glomerular filtration rate (GFR) only in SH rats, and the fractional excretion of sodium only in SD rats. The combined data indicate that the distribution and functional roles of ETA and ETB receptor subtypes are altered in the kidneys of SH rats.

Effects of ANG II, ETA, and TxA2 receptor antagonists on cyclosporin A renal vasoconstriction

The renin-angiotensin system, endothelin (ET), and vasoconstrictor prostaglandins have been reported in separate studies to mediate the renal vasoconstrictor effect of cyclosporin A (CsA). However, direct comparison of the relative importance of these potential mediators has not been performed. In this study, the attenuating effects of comparable agonist-inhibiting doses of receptor antagonists for angiotensin II (ANG II), DuP-753 at 2.5 mg/kg, for ETA, BQ-123 at 0.5 mg/kg, and for thromboxane A2 (TxA2), SQ-29,548 at 1.6 mg.kg-1.h-1, or saline vehicle on acute CsA (20 mg/kg) renal vasoconstriction were compared in anesthetized Sprague-Dawley rats. All three receptor antagonists significantly limited the CsA-induced increase in renal vascular resistance; however, BQ-123 and SQ-29,548 were more effective than DuP-753. Because all three receptor antagonists demonstrated at least some attenuation of CsA-induced renal vasoconstriction, the potential role of acute CsA-related nitric oxide synthase (NOS) inhibition and nonspecific heterologous effects of specific receptor antagonists on other agonists were determined to exclude the possibilities that there was a general increased agonist sensitivity and that detection of a single or primary constrictor mediator was obscured by "crossover" receptor antagonist effects. CsA significantly reduced renal blood flow (39%) in the presence of the NOS inhibitor, N omega-nitro-L-arginine methyl ester, and there was negligible indication that receptor antagonists had nonspecific effects. It is concluded that CsA-induced renal vasoconstriction is complex and involves activation of multiple constrictor agonists independently or sequentially.

Effects of an ET1‐receptor antagonist, FR139317, on regional haemodynamic responses to endothelin‐1 and [Ala11,15]Ac‐endothelin‐1 (6–21) in conscious rats

1. In conscious, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, we compared responses to the putative, selective ETB-receptor agonist, [Ala1,3,11,15]endothelin-1 (ET-1), obtained from two sources (Microchemical Laboratory, Cambridge (MLC) and Neosystem Laboratory, France (NLF)). [Ala1,3,11,15]ET-1 (0.15, 0.3, 1 and 10 nmol kg-1) from MCL caused dose-dependent pressor effects, accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances; there was an initial hyperaemic vasodilatation in the hindquarters which was not dose-dependent, and only with the highest dose was there a subsequent vasoconstriction. There was no significant initial depressor response to [Ala1,3,11,15]ET-1 from MLC at any dose. However, the peptide from NLF exerted dose-dependent depressor and hindquarters vasodilator actions, and subsequent pressor effects. The difference between the two peptide preparations remains unexplained, but it appears that the [Ala1,3,11,15]ET-1 from MLC may activate ETB-receptors mediating vasoconstriction, more effectively than those mediating vasodilatation. 2. We also assessed responses to the putative ETB-receptor agonist, [Ala11,15]Ac-ET-1 (6-21) (BQ-3020), and determined the effects of the selective ETA-receptor antagonist, FR139317, on responses to ET-1 and BQ-3020 at doses matched for their initial depressor and subsequent pressor effects (ET-1, 0.5 nmol kg-1, BQ-3020, 10 nmol kg-1), and also at doses that did not affect mean arterial blood pressure, but which were matched for their renal vasoconstrictor effects (ET-1, 7.5 pmol kg-1; BQ-3020, 0.15 nmol kg-1). 3. BQ-3020 (0.15, 0.3 and 1 nmol kg-1) had dose-dependent pressor effects accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances. BQ-3020 at a dose of 10 nmol kg-1 elicited an initial depressor response which coincided with an attenuated mesenteric vasoconstrictor effect, accompanying a marked hindquarters vasodilatation. Hence, it appears that BQ-3020 may activate both vasoconstrictor and vasodilator ETB-receptors. 4. FR139317 (0.5 mumol kg-1) caused attenuation of the pressor, and renal, mesenteric and hindquarters vasoconstrictor effects of ET-1 (0.5 nmol kg-1) and of BQ-3020 (10 nmol kg-1), but the reductions of the pressor and renal vasoconstrictor effects of ET-1 were greater than those of BQ-3020. However, in the presence of FR139317, significant pressor and renal, mesenteric and hindquarters vasoconstrictor responses to ET-1 and BQ-3020 still occurred, and the initial depressor and hindquarters vasodilator responses to both peptides were unchanged. 5. ET-1 at a dose of 7.5 pmol kg-1 and BQ-3020 at a dose of 0.15 nmol kg-1 had similar renal vasoconstrictor effects. However, the response to ET-1 was almost abolished by FR139317 whereas that to BQ-3020 was unaffected. Moreover, under these conditions, the mesenteric vasoconstrictor and hindquarters vasodilator responses to ET-1 and to BQ-3020 were not changed by FR139317.6. Collectively, these results are consistent with the haemodynamic effects of ET-1 and BQ-3020 involving ETA-receptors or ETB-receptors, or ETA- and ETB-receptors, depending on the dose of agonist and the regional haemodynamic effect considered.

Regional haemodynamic effects of carbachol injected into the hypothalamic paraventricular nuclei of conscious, unrestrained rats

Carbachol was injected into the hypothalamic paraventricular nuclei (PVN) of conscious, unrestrained Long Evans rats, chronically instrumented with intravascular catheters and pulsed Doppler probes to assess changes in regional haemodynamics. Bilateral microinjections of carbachol (1 ng-1 μg) produced increases in blood pressure, bradycardias and vasoconstrictions in renal, superior mesenteric and hindquarters vascular beds. In the presence of phentolamine, the bradycardic and hindquarters vasoconstrictor responses to carbachol were unchanged while the pressor response was smaller due to a reduction in the renal and the superior mesenteric vasoconstriction. In the presence of propranolol, the bradycardic response was reduced, but the pressor and renal vasoconstrictor responses were potentiated, whereas the superior mesenteric and hindquarter vasoconstrictions were not changed significantly. In the presence of phentolamine and propranolol, the heart rate and pressor responses, as well as the renal vasoconstriction, were unchanged, whereas the superior mesenteric vasoconstriction was reduced and the hindquarters vasoconstriction was potentiated. Together these results are consistent with an involvement of the sympathoadrenal system in the pressor response to carbachol injected into the PVN of untreated animals. They indicate that α-adrenoceptor-mediated vasoconstriction in the superior mesenteric vascular bed is a particularly important component in that regard. In the presence of the vasopressin antagonist, d(CH 2) 5(Tyr(Et))DAVP, alone or in combination with phentolamine and propranolol, the pressor response to carbachol was substantially reduced, while the renal and superior mesenteric vasoconstrictor effects were completely abolished; the bradycardia was not significantly affected by this treatment. These results indicate an important involvement of vasopressin in the cardiovascular responses to carbachol injected into the PVN of untreated animals. Moreover, in the presence of the vasopressin antagonist the hindquarters vascular bed showed a vasodilatation following PVN injection of carbachol; this effect was reversed to a vasoconstriction following combined i.v. pretreatment with the vasopressin antagonist, phentolamine and propranolol and hence was possibly due to circulating adrenaline acting on vasodilator β 2-adrenoceptors. However, there was a residual hindquarters vasoconstriction raising the possibility that non-adrenergic, non-vasopressinergic vasoconstrictor mechanisms were influencing that vascular bed.

A renal vasodilator effect of angiotensin II revealed by dual thromboxane inhibition.

Angiotensin II (AII) stimulates arachidonate release from renal endothelial and other cells. Arachidonate is then metabolized by cyclooxygenase to prostaglandin (PG) H2, then PGI2 and thromboxane A2 (TXA2). PGH2 and TXA2 activate the same receptor and should augment AII-mediated vasoconstriction, whereas PGI2 is a vasodilator. We had previously shown that inhibiting TXA2 synthesis with furegrelate (FRG) redirects PGH2 metabolism toward PGI2, causing renal vasodilation. Because TXA2 synthesis inhibition may be incomplete and unmetabolized PGH2 may cause vasoconstriction, we reasoned that adding a PGH2/TXA2 receptor antagonist (BMS 180,290, formerly SQ 29548 (SQ)) to furegrelate should cause further renal vasodilation in the presence of AII. Eight groups of 10 Sprague-Dawley rats received 120-min intravenous infusions of vehicle, FRG (2 mg.kg-1 plus 2 mg.kg-1.h-1), SQ (2 mg.kg-1 plus 2 mg.kg-1.h-1), FRG plus SQ, AII (10 ng.kg-1.min-1), AII plus FRG, AII plus SQ, or AII plus FRG plus SQ. Mean arterial pressure (MAP), p-[14C]aminohippurate clearance (CPAH), and [3H]insulin clearance were averaged for each rat for the final 90 min in three clearance periods. MAP did not change with any treatment. Estimating renal vascular resistance as MAP/CPAH confirmed a renal vasoconstrictor effect of this dose of AII: 58.1 +/- 6.3 vs. 47.3 +/- 6.8 (arbitrary units) with the vehicle (p < 0.05). FRG, SQ, or their combination did not affect renal vascular resistance, but adding FRG or SQ to AII prevented AII-mediated renal vasoconstriction. Adding both to AII caused net renal vasodilation to 24.8 +/- 2.6 (p < 0.05 vs. vehicle). Inulin clearance changed in the same direction in all groups, but the changes were less marked. We conclude that stimulation of renal arachidonate release by AII combined with TXA2 synthesis inhibition and receptor antagonism results in vasodilation. This renal effect could be due to increased and unopposed renal vasodilator PG (principally PGI2) action.

Acute and chronic effects of thromboxane A2 inhibition on the renal hemodynamics in streptozotocin-induced diabetic rats

We examined acute and chronic effects of thromboxane (TX) A2 inhibition on the renal hemodynamics at early and late stage of untreated streptozotocin (STZ)-induced diabetic rats. Two weeks and 28 weeks after the induction of diabetes, renal blood flow (RBF) under anesthesia was measured with an electromagnetic flowmeter before and after TXA2 inhibition. In two-week-old diabetic rats, a specific TXA2 synthetase inhibitor, OKY-046, or a specific TXA2 receptor antagonist, Sulotroban, increased renal vascular resistance (RVR) and ameliorated the hyperperfusion. The renal vasoconstrictive effect of OKY-046 was blunted by an angiotensin converting enzyme (ACE) inhibitor, MK422, or an angiotensin II receptor antagonist, Saralasin. On the contrary, OKY-046 ameliorated the renal hypoperfusion by decreasing RVR in 28-week-old diabetic rats. Chronic oral administration of OKY-046 ameliorated not only the renal hyperperfusion but increased urinary albumin excretion (UAE) at two weeks, but also the renal hypoperfusion, filtration fraction and UAE at 24 weeks. It is suggested that TXA2 might, at least in part, play important roles in the hyperperfusion by modulating activity of the renin-angiotensin system at an early stage of untreated diabetic rats and in the hypoperfusion at the late stage of untreated diabetic rats, and that TXA2 is also involved in the increase of UAE. These results support roles for TXA2 in the progression of renal injury in STZ-induced diabetic rats.

Regional haemodynamic responses to pituitary adenylate cyclase‐activating polypeptide and vasoactive intestinal polypeptide in conscious rats

1. Regional haemodynamic responses to the homologous peptides, pituitary adenylate cyclase-activating peptide (1-27) (PACAP27) and vasoactive intestinal polypeptide (VIP) were assessed by giving 20 min infusions (1.5-15 nmol kg-1 h-1) in conscious, chronically-instrumented, Long Evans rats. 2. PACAP27 caused dose-dependent depressor and tachycardic effects associated with renal, mesenteric and hindquarters vasodilatations, although only in the latter vascular bed was there a sustained increase in flow. 3. VIP caused dose-dependent depressor and tachycardic effects that were not significantly different from those caused by equimolar doses of PACAP27. However, the hindquarters vasodilator effects of VIP (at 7.5 and 15 nmol kg-1 h-1) were greater than those of PACAP27 (at the same doses), and accompanied by reductions in renal and mesenteric flows and conductances. 4. In the presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 11 mumol kg-1 h-1), there was significant inhibition of the hindquarters vasodilator effects of PACAP27 and VIP (at 7.5 and 15 nmol kg-1 h-1). Under these circumstances the renal and mesenteric vasoconstrictor effects of VIP were abolished. 5. The beta 2-adrenoceptor antagonist, ICI 118551 (670 nmol kg-1 bolus, 335 nmol kg-1 h-1 infusion), reduced the matched hindquarters vasodilator responses to PACAP27 (15 nmol kg-1 h-1) and VIP (7.5 nmol kg-1 h-1), and also abolished the renal vasoconstrictor effects of VIP. 6. The AT1-receptor antagonist, losartan potassium (20 mumol kg-1), had no significant effect on the haemodynamic response to PACAP27 (15 nmol kg-1 h-1), but augmented the hypotensive action of VIP (7.5 nmol kg-1 h-1). This influence of losartan was associated with conversion of the renal and mesenteric vasoconstrictor effect of VIP to vasodilatation. 7. Our findings show that similar changes in mean systemic arterial blood pressure in response to PACAP27 and VIP conceal substantial differences in their regional haemodynamic actions. Although the hindquarters vasodilator effects of both peptides involve NO- and Beta2-adrenoceptor-mediated mechanisms,it appears that activation of the renin-angiotensin system contributes significantly to the haemodynamic effects of VIP, but not to those of PACAP27.

Evidence from receptor antagonists of an important role for ETB receptor‐mediated vasoconstrictor effects of endothelin‐1 in the rat kidney

1. To characterize the receptor subtype(s) mediating the renal vasoconstrictor effects of the endothelin (ET) and sarafotoxin (SX) peptides in the isolated perfused kidney of the rat, we have examined the effects of endothelin-1 (ET-1), sarafotoxin 6b (SX6b) and sarafotoxin 6c (SX6c) as agonists, BQ-123 and FR 139317 as selective ETA receptor antagonists, and PD 145065 as a non-selective (ETA and ETB) receptor antagonist. We have also compared in the anaesthetized rat the systemic pressor and renal vasoconstrictor effects of ET-1 and SX6c alone or after pretreatment with PD 145065. 2. In the isolated perfused kidney, ET-1, SX6b and SX6c all gave similar concentration-dependent increases in perfusion pressure. The ETA receptor selective antagonists, BQ-123 and FR 139317, both partially blocked the increase in perfusion pressure induced by ET-1. In contrast, PD 145065 completely blocked the increase in perfusion pressure caused by ET-1. 3. Indomethacin (10 microM) had no effect on the ET-1-induced increases in perfusion pressure but significantly reduced the vasoconstriction induced by low concentrations of SX6c, without affecting responses to high concentrations. In the anaesthetized rat, indomethacin (5 mg kg-1) did not modify the systemic pressor or renal vasoconstrictor effects of ET-1 or SX6c. 4. In anaesthetized rats, bolus intravenous injections of ET-1 or SX6c (0.1, 0.25, 0.5 or 1.0 nmol kg-1) produced initial transient depressor responses followed by sustained and dose-dependent increases in mean arterial pressure (MAP). Both peptides caused an equipotent fall in renal blood flow (RBF).PD 145065 (5 mg kg-1) partially antagonized the systemic pressor effects of ET-1 and SX6c but completely blocked the fall in RBF and rise in renal vascular resistance (RVR) induced by ET-1 and SX6c. PD 145065 also antagonized the transient depressor effect following the bolus administration of either ET-1 or SX6c.5. These results indicate that ET/SX induced renal vasoconstriction is mediated via ETA and ETB-like receptors with ETB receptors having a predominant role in vivo. This may be of therapeutic relevance for an ETA receptor-selective antagonist may offer only limited protection against the deleterious renal effects of endogenous ETs.

Regional and cardiac haemodynamic effects of NG, NG,dimethyl‐l‐arginne and their reversibility by vasodilators in conscious rats

1. A series of experiments was carried out on 3 separate groups of male Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, to compare the effects of NG,NG, dimethyl-L-arginine (ADMA) and NG-monomethyl-L-arginine (L-NMMA), and their reversibility by the nitric oxide donors, S-nitroso-N-acetyl-penicillamine (SNAP), S-nitroso-glutathione (SNOG), sodium nitroprusside (SNP), and the vasodilator, hydralazine. 2. As previously reported for L-NMMA, ADMA (1-100 mg kg-1) caused dose-dependent pressor and bradycardic effects, accompanied by renal, mesenteric and hindquarters vasoconstrictions. The magnitude and duration of these effects were similar for ADMA and L-NMMA, consistent with their being equipotent inhibitors of nitric oxide synthase. 3. Infusion of SNAP or SNOG (300 micrograms kg-1 h-1) after injection of ADMA or L-NMMA (100 mg kg-1) reversed the pressor but did not abolish the vasoconstrictor, effects of ADMA or L-NMMA. However, a higher dose of SNAP (3 mg kg-1 h-1) caused complete reversal of the pressor and mesenteric haemodynamic effects of ADMA (100 mg kg-1), although its renal and hindquarters vasoconstrictor effects were not abolished. 4. Infusion of SNP (300 micrograms kg-1 h-1) after administration of L-NMMA (100 mg kg-1), caused complete reversal of its pressor and mesenteric and hindquarters haemodynamic effects, and reduced substantially its renal vasoconstrictor action; hydralazine (7.5 mg kg-1 h-1) was almost as effective as SNP in reversing all these variables. 5. In animals chronically instrumented for the measurement of cardiac haemodynamics, ADMA(100 mg kg-1) caused a pressor effect accompanied by a rise in central venous pressure, and reductions in heart rate, cardiac index, stroke index, peak aortic flow, maximum rate of rise of aortic flow and total peripheral conductance. The reversal of the pressor effect of ADMA by SNAP (300 microg kg-1 h-1) was accompanied by a reduction of central venous pressure below resting levels and a further diminution of stroke index; all other variables showed an increase, but they still remained below resting levels (with the exception of heart rate).6. Thus, following inhibition of NO synthesis, pharmacological intervention with NO donors, or other vasodilators, may cause normalisation of the mean arterial pressure without necessarily returning all associated cardiovascular variables to normal.

Role of muscarinic receptors in renal response to acetylcholine.

Renal arterial infusion of acetylcholine (ACh) (40 micrograms/min) in control dogs produced an ipsilateral increase in renal plasma flow (RPF) and in sodium excretion (UNaV) without a change in glomerular filtration rate (GFR). The increase in RPF and UNaV was maintained during the infusion of ACh. In indomethacin (Indo)-treated dogs (5 mg/kg) ACh produced a transient rise in RPF and UNaV, followed by a progressive decline in RPF and UNaV. The profound renal vasoconstriction was accompanied by a decline in GFR. To determine the role of the muscarinic receptor in the renal vasodilation and in vasoconstriction produced by ACh in Indo-treated dogs, atropine at 6, 60, and 600 micrograms/min was infused into the renal artery before and during the infusion of ACh. In Indo-treated dogs, all dosages of atropine prevented renal vasoconstriction by ACh. Renal arterial infusion of atropine at 600 micrograms/min completely inhibited the renal vasodilation produced by ACh. Atropine infused at 60 micrograms/min partially inhibited, whereas 6 micrograms/min atropine failed to inhibit, the renal vasodilation produced by ACh. Our data suggest that the renal vasodilator and vasoconstrictor effects of ACh in Indo-treated dogs are mediated by two separate types of muscarinic receptors.

Mediation via different receptors of the vasoconstrictor effects of endothelins and sarafotoxins in the systemic circulation and renal vasculature of the anaesthetized rat.

1. Using endothelin-1 (ET-1), endothelin-3 (ET-3), sarafotoxin 6b (SX6b) and sarafotoxin 6c (SX6c) as agonists and BQ-123 as a selective ETA receptor antagonist, we have examined the endothelin receptor subtypes mediating the systemic pressor and renal vasoconstrictor effects of the ET/SX family of peptides. 2. In anaesthetized rats, bolus intravenous injections of ET-1, ET-3, SX6b or SX6c (0.1, 0.25 and 0.50 nmol kg-1) produced initial transient depressor responses followed by sustained and dose-dependent increases in mean arterial pressure (MAP) with the following rank order of potency: SX6b > ET-1 >> SX6c > ET-3. In contrast, in the renal vasculature these peptides caused equipotent dose-dependent falls in renal blood flow (RBF) (ET-1 = ET-3 = SX6b = SX6c). 3. BQ-123 (1 mg kg-1, i.v. bolus) significantly reduced the systemic pressor effects of all the peptides but was largely ineffective against the renal vasoconstrictions. 4. These results indicate that although the systemic pressor effects of the ET/SX peptides are mediated via ETA receptors, the vasoconstriction in the kidney in vivo may be mediated predominantly via ETB-like receptors. This may be of therapeutic relevance, for an ETA-receptor-selective antagonist could offer only poor protection of the renal circulation from the deleterious effects of endogenously produced members of this peptide family.

Endothelin-mediated cardiorenal hemodynamic and neuroendocrine effects are attenuated by nitroglycerin in vivo.

Endothelin-1 may function pathophysiologically as a counterregulatory vasoconstrictor peptide that is modified in its activity by the opposing action of endothelium-derived relaxing factor(s) (EDRF). The present study determined in part the integrated cardiorenal and endocrine actions of pathophysiologic plasma concentrations of endothelin in the anesthetized dog. In addition, nitroglycerin, which inhibits vascular smooth muscle contraction by increasing cGMP in a mechanism similar to EDRF, acts like an endogenous nitrovasodilator. Therefore, we tested the hypothesis that nitroglycerin would effectively antagonize the cardiac and renal actions of exogenous endothelin. The results confirm that endothelin-1-mediated vasoconstriction in vivo is heterogenous with a greater renal than coronary action. Further, nitroglycerin effectively blocked endothelin-1-mediated coronary flow reductions, but only partially antagonized reductions in renal blood flow. Endothelin-1-induced reduction in cardiac output also was not antagonized by nitroglycerin despite its effects to preserve coronary blood flow. Nitroglycerin did, however, antagonize endothelin-induced elevations in plasma epinephrine, norepinephrine, and aldosterone. These results would suggest that in pathophysiologic states where endothelin-1 is elevated, such as hypertension or congestive heart failure, there is a major compromising of renal function, and also the production of cardiac ischemia. Since exogenous nitroglycerin is relatively ineffective in antagonizing the renal vasoconstrictive effects of endothelin, it may be that the endogenous vasodilating systems, such as ERDF and prostacyclin, are inadequate in such pathologic states to counter the vasoconstrictor effects of endothelin.

Vasoconstriction in the rat kidney induced by endothelin-1 is blocked by PD 145065.

We have previously shown that the receptors mediating the renal and systemic vasoconstrictor effects of endothelin-1 (ET-1) are of two distinct endothelin receptor subtypes. Here, we evaluate the effect of PD 145065, a nonselective endothelin receptor antagonist, on the renal vasoconstrictor effects of ET-1 in the rat kidney. ET-1 induced concentration-dependent increases in perfusion pressure in the isolated perfused kidney of the rat. The ETA receptor-selective antagonists BQ-123 (10 microM) and FR 139317 (10 microM) lowered the ET-1-induced rise in perfusion pressure by 57% and 61%, respectively, at 3 x 10(-10) M ET-1. By comparison, the ET-1-induced vasoconstriction was fully antagonized (96% inhibition) by PD 145065 (10 microM). In the anesthetized rat, ET-1 produced a dose-dependent increase in mean arterial pressure, which was attenuated by PD 145065. The initial depressor response to ET-1 was completely blocked by PD 145065, as were the reduction in renal blood flow and increase in renal vascular resistance induced by ET-1. These results suggest that both the ETA and a non-ETA receptor subtype play an important role in mediating the vasoconstrictor effects of ET-1 in the rat kidney.

Evidence for endothelin-induced renal vasoconstriction independent of ETA receptor activation.

Experiments were designed to examine the role of endothelin (ET) receptors, specifically ETA receptors, in mediating the renal vasoconstrictor effects of ET-1 in anesthetized Sprague-Dawley rats. Intravenous infusion of ET-1 at 25 pmol.kg-1 x min-1 for 60 min produced a significant increase in mean arterial pressure (20 +/- 7%) and decreases in renal plasma flow (-60 +/- 6%) and glomerular filtration rate (-47 +/- 6%). Renal vascular resistance was significantly increased from 17 +/- 1 mmHg.ml-1 x min.g kidney wt during control period to 54 +/- 11 mmHg.ml-1 x min.g kidney wt during the experimental period. A second group of rats was infused with both ET-1 and the specific ETA receptor antagonist BQ-123 (0.1 mg.kg-1 x min-1). ET-1-induced increases in mean arterial pressure were completely blocked by BQ-123 (the average change was -7 +/- 4%). However, the renal vasoconstrictor effects of ET-1 were not affected by the antagonist, since renal plasma flow and glomerular filtration rate were again significantly reduced (-54 +/- 4 and -56 +/- 6%, respectively). Once again, renal vascular resistance was significantly increased from 16 +/- 2 mmHg.ml-1 x min.g kidney wt during the control period to 33 +/- 5 mmHg.ml-1 x min.g kidney wt during the experimental period. In a third group, infusion of BQ-123 alone produced a significant decline in mean arterial pressure (-13 +/- 2%), with no significant changes in renal plasma flow or glomerular filtration rate, thus producing a significant decrease in renal vascular resistance (15 +/- 1 vs. 11 +/- 2 mmHg.ml-1 x min.g kidney wt).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of phospholipids on renal function.

The effects of two classes of phospholipids (PL) on renal function have been studied. Bolus injections of 1 ng (10 pmol) of lysophosphatidylcholine (LPC) caused natriuresis and diuresis in rats. Natriuretic activity was eliminated by substituting unsaturated bonds in the 1-acyl group and by removing the choline group on the sn-3 position. Natriuretic activity was not affected by substitution of 1-alkyl for 1-acyl groups. In the dog, LPC was natriuretic when given as a bolus of 3.0 micrograms/kg or as a constant infusion at 5 ng/kg/min. To explore further the effect of alkyl PLs on renal function, a series of studies with platelet activating factor (PAF) was performed. PAF injected directly into the renal artery (IR) in bolus doses of 0.5-10 ng/kg caused renal vasodilation that was blocked by a specific PAF receptor antagonist. This effect was not due to release of vasodilatory eicosanoids, dopamine, or nitric oxide (NO). PAF given IR as a continuous infusion at 2.5 ng/kg/min attenuated the renal vasoconstrictor effects of angiotensin II and norepinephrine but not vasopressin. This effect to attenuate vasoconstriction was blocked by the NO inhibitor N-monomethyl-L-arginine. These studies using picomolar amounts of PL suggest a physiologic role for these compounds in control of renal function.

Effect of Dipyridamole on Kidney Function in Cirrhosis

Adenosine is a potent endogenous renal vasoconstrictor. To investigate the sensitivity of the renal circulation to adenosine in cirrhosis, we evaluated kidney function and vasoactive hormones in 20 patients with cirrhosis before and after administration of dipyridamole (0.4 mg/kg, intravenously), a drug that increases extracellular levels of adenosine. In patients with ascites and increased plasma renin activity (6.9 +/- 4.0 ng/ml.hr [mean +/- S.D.]) (n = 7), dipyridamole induced marked reductions in renal plasma flow (from 623 +/- 294 to 374 +/- 188 ml/min, p = 0.03), glomerular filtration rate (from 89 +/- 22 to 48 +/- 16 ml/min, p = 0.009), urine volume (from 7.1 +/- 2.1 to 1.5 +/- 1.1 ml/min, p = 0.0001), free water clearance (from 4.0 +/- 1.7 to 0.4 +/- 0.6 ml/min, p = 0.001) and sodium excretion (from 28 +/- 36 to 7 +/- 15 mu Eq/min, p = 0.05) in the absence of changes in arterial pressure, plasma renin activity and levels of aldosterone, norepinephrine and antidiuretic hormone. In patients without ascites (n = 5) and in patients with ascites and normal plasma renin activity (0.9 +/- 0.5 ng/ml.hr) (n = 8), renal plasma flow and glomerular filtration rate did not change significantly after dipyridamole administration, whereas excretion of sodium and free water was reduced. These results indicate that in cirrhotic patients with ascites and overactivity of the renin-angiotensin system, dipyridamole induces renal vasoconstriction in the absence of changes in systemic hemodynamics, suggesting that these patients are particularly sensitive to the renal vasoconstrictor effect of endogenous adenosine.