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PubMed1975

Effect of beta-adrenergic blockade and inhibitors of angiotensin II and prostaglandins on renal autoregulation.

The role of the renin-angiotensin system and prostaglandins in renal autoregulation was investigated in dog kidneys in situ. Renal autoregulation during decreases in renal arterial pressure (RAP) was examined in animals pretreated with a competitive antagonist of angiotensin ii, [1-sarcosine, 8-glycine] angiotensin II, or one of two chemically dissimilar inhibitors of prostaglandin synthetase, indomethacin and meclofenamate. Because of recent evidence suggesting a role for an intrarenal beta receptor in regulating renin release, renal autoregulation was also examined in animals treated with the beta-adrenergic blocking agent propranolol. In all groups of animals constancy of glomerular filtration rate (GFR) and renal blood flow (RBF) was observed after substantial decreases in RAP to a range of 70-90 mmHg. These studies therefore do not provide evidence in support of a role for angiotensin II, prostaglandins, or an intrarenal beta receptor as mediators of the renal autoregulation of GFR or total RBF.

Angiotensin II↗

PubMed1975

Prostaglandin control of renal circulation in the unanesthetized dog and baboon.

Effects of indomethacin and meclofenamate, inhibitors of prostaglandin synthesis, were evaluated in the regulation of renal blood flow in conscious and anesthetized dogs and in tranquilized baboons, instrumented with arterial pressure catheters and renal blood flow probes. Indomethacin, 10 mg/kg, did not alter renal blood flow or resistance significantly in the conscious dog. In the anesthetized dog, however, indomethacin caused a reduction in renal blood flow (25 +/- 3% of control) and an elevation of renal vascular resistance (45 +/- 8% of control). Meclofenamate, 4 mg/kg, reduced renal flow (12 +/- 2%) and increased renal vascular resistance 15 +/- 4% in conscious dogs. In conscious dogs and tranquilized primates, indomethacin and meclofenamate reduced the reactive hyperemia in the renal bed after 15 s occlusion from a control of 36 +/- 5 ml to 6 +/- 2 ml, and after 45 s occlusion from a control of 98 +/- 9 ml to 17 +/- 5 ml. Methoxamine (10-50 mug/kg per min) and angiotensin II (0.03-0.12 mug/kg per min), infused in graded doses, induced significantly greater renal vasoconstriction in conscious dogs in the presence of indomethacin. Thus, in the conscious animal, prostaglandins appear to play only a minor role in the control of the renal circulation at rest, but are of greater importance in mediating the renal responses to reactive hyperemia and to vasoconstriction.

Angiotensin II↗

PubMed1975

Influence of inhibitors of prostaglandin synthesis on the canine pulmonary vascular bed.

The effects of two chemically dissimilar inhibitors of prostaglandin (PG) synthesis on vascular resistance and responses to pressor and depressor hormones were evaluated in the canine pulmonary vascular bed. Indomethacin or meclofenamate, 2.5-5 mg/kg iv, increased lobar arterial pressure. Since lobar blood flow was held constant and left atrial pressure did not change, the rise in pressure reflects an increase in vascular resistance. The rise in lobar pressure after indomethacin occurred in the absence of a change in lobar venous or translobar airway pressure. This agent enhanced the response to angiotensin but not to norepinephrine. Meclofenamate decreased responses to both agents. Indomethacin enhanced the dilator response to PGE1 and both indomethacin and meclofenamate increased the response to PGF2alpha. These data indicate that the rise in resistance after indomethacin or meclofenamate was the result of vasoconstriction in vessels upstream to the small veins, presumed to be small arteries. These data are consistent with the hypothesis that under resting conditions synthesis of a dilator prostaglandin may be important for the maintenance of the pulmonary vascular bed in a dilated state. However, results of the present study are not consistent with the postulate that prostaglandins modulate responses to norepinephrine but suggest that indomethacin and meclofenamate interfere with the inactivation of PGF2alpha and PGE1 in the lung.

Angiotensin II↗

PubMed1976

Renal effect of meclofenamate in presence and absence of superfusion bioassay.

Systemic blood pressure (SBP), renal blood flow (RBF), renal vascular resistance (RVR), and arterial and renal venous prostaglandin E (PGE) concentrations were determined in pentobarbital-anesthetized dogs.The effect of sodium meclofenamate infused into the renal artery was compared under two sets of conditions. In experiments carried out under control conditions, SBP, RBF, and RVR were stable and meclofenamate caused only a slight decrease in RBF (5.4%) and increase in RVR.

Animals↗

PubMed1976

Effect of prostaglandin synthetase inhibitors on renal blood flow in the rat.

Using a small-diameter electromagnetic flow transducer, the effect on the autoregulation of renal blood flow (RBF) of two structurally different prostaglandin synthetase inhibitors, indomethacin, 4 mg/kg BW, and meclofenamate, 5 mg/kg BW, was studied in nondiuretic rats anesthetized with either the oxybarbiturate, sodium pentobarbital, or the thiobarbiturate, Inactin. Regardless of the anesthetic agent, RBF remained relatively constant above a perfusion pressure of 105 mmHg. Treatment with either indomethacin or meclofenamate had no measurable effect on the autoregulatory response. Each agent, however, resulted in an increase in the renal vascular response to exogenous angiotensin II, an effect consistent with prostaglandin synthetase inhibition. Base-line RBF was significantly reduced by indomethacin or meclofenamate only in those animals that had previously received angiotensin. These results support the hypothesis that, in th rat, autoregulation of RBF occurs independently of prostaglandin activity, but that a relationship does exist between the renal vascular actions of angiotensin II and prostaglandins.

Angiotensin II↗

PubMed1998

Substance P and capsaicin release prostaglandin E2 from rat intrapulmonary bronchi.

We hypothesized that substance P and capsaicin would cause the release of prostaglandin E2 (PGE2) from intrapulmonary bronchi isolated from Sprague-Dawley rats. Substance P (1 microM) caused the release of PGE2, measured with enzyme immunoassay, from the isolated airway segments; PGE2 release was inhibited by the neurokinin (NK)1-receptor antagonist, RP-67580, by inhibition of cyclooxygenase with meclofenamate, and by removal of the epithelium. The release of PGE2 caused by capsaicin (1 microM) was similar in magnitude to that caused by substance P. The capsaicin-induced release of PGE2 was inhibited by desensitization of sensory nerves with capsaicin and by RP-67580, meclofenamate, and epithelial denudation. We conclude that activation of NK1 receptors on epithelium causes release of PGE2, which most likely represents the ultimate mediator of airway smooth muscle relaxation, produced by exogenous neuropeptides and by activation of the sensory nerve inhibitory system. Epithelial damage, such as that seen in asthmatic airways, would disrupt this protective system in the lungs, which could contribute to the development of airway disease.

Animals↗

PubMed2001

NO and prostaglandin interactions during hemodynamic stress in the fetal ovine pulmonary circulation.

Nitric oxide (NO) and prostacyclin (PGI(2)) are potent fetal pulmonary vasodilators, but their relative roles and interactions in the regulation of the perinatal pulmonary circulation are poorly understood. We compared the separate and combined effects of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition during acute hemodynamic stress caused by brief mechanical compression of the ductus arteriosus (DA) in chronically prepared fetal lambs. Nitro-L-arginine (L-NNA; NOS antagonist), meclofenamate (Mec; COX inhibitor), combined drugs (L-NNA-Mec), or saline (control) was infused into the left pulmonary artery (LPA) before DA compression. In controls, DA compression decreased pulmonary vascular resistance (PVR) by 43% (P < 0.01). L-NNA, but not Mec, treatment completely blocked vasodilation and caused a paradoxical increase in PVR (+31%; P < 0.05). The effects of L-NNA-Mec and L-NNA on PVR were similar. To determine if the vasodilator effect of PGI(2) is partly mediated by NO release, we studied PGI(2)-induced vasodilation before and after NOS inhibition. L-NNA treatment blocked the PGI(2)-induced rise in LPA blood flow by 73% (P < 0.001). We conclude that NO has a greater role than PGs in fetal pulmonary vasoregulation during acute hemodynamic stress and that PGI(2)-induced pulmonary vasodilation is largely mediated by NO release in the fetal lung.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2005

Partial renal ischemia elicits heterogeneous control of renal sympathetic nerve activity to ischemic and nonischemic regions of the kidney.

We tested the hypothesis that renal sympathetic nerve activity (RSNA) to the ischemic and nonischemic regions responded differently during partial ischemia of the kidney in pentobarbital-anesthetized cats. The renal artery divides into two branches at the front of the renal hilus: one branch perfuses predominantly the dorsal half of the kidney, and the other perfuses its ventral half. We identified the innervated area of a renal nerve bundle by supramaximal electrical stimulation and subsequently determined the changes in RSNA in response to occlusion of either renal arterial branch for 3 min. RSNA to the nonischemic region of the kidney gradually decreased by 23 +/- 4% during partial renal ischemia, whereas RSNA to the ischemic region of the same kidney showed no significant change. Crushing either all renal nerve bundles or only the renal nerve bundles terminated to the ischemic region abolished the decrease in RSNA to the nonischemic region. Furthermore, intra-arterial administration of a prostaglandin synthesis inhibitor (meclofenamate, 4 mg/kg) abolished the decrease in RSNA to the nonischemic region of the kidney. Following spinal transection at the level of T7, the inhibitory response in RSNA to the nonischemic region disappeared, whereas the RSNA to the ischemic region was markedly augmented by 47 +/- 17%. Thus it is likely that renal chemoreceptors activated during renal partial ischemia elicit heterogeneous control of renal sympathetic outflows to the ischemic and nonischemic regions of the same kidney, which may be determined by a net output between the supraspinal inhibitory and spinal excitatory reflexes.

Adrenergic Fibers↗

PubMed1981

Bradykinin effects on adrenergic transmission in the canine kidney: relation to prostaglandins.

We studied the action(s) of bradykinin at the renal vascular neuroeffector junction, and its relation to prostaglandin synthesis, by investigating the effect of the peptide on the renal venous output of the neurotransmitter and on the renal vasoconstrictor responses elicited by sympathetic nerve stimulation and by norepinephrine in pentobarbital-anesthetized dogs. Renal arterial infusion of bradykinin at 10 ng . kg-1 . min-1 increased blood flow to the kidney and inhibited the vasoconstrictor effect of renal nerve stimulation (1-8 Hz) and injected norepinephrine (0.06-0.5 micrograms). However, bradykinin did not alter the rise in venous output of norepinephrine elicited by nerve stimulation. Infusion of another vasodilatory peptide, substance P (2 ng . kg-1 . min-1) into the renal artery also increased blood flow to the kidney but failed to alter the vasoconstriction produced by either adrenergic stimulus. Pretreatment of dogs with an inhibitor of prostaglandin synthesis, either sodium meclofenamate or indomethacin (5 mg/kg), abolished the inhibitory effect of the kinin on renal vasoconstriction produced by adrenergic stimuli. These data suggest that bradykinin acts on postjunctional sites to reduce adrenergically induced vasoconstriction in the canine kidney by a mechanism dependent on prostaglandin synthesis.

Animals↗

PubMed1983

Suppressed basal antidiuretic hormone release during cyclooxygenase inhibition in conscious dogs.

Both in vitro and in vivo experiments suggest that prostaglandins may affect antidiuretic hormone (ADH) release centrally. In addition, other studies show that prostaglandins administered peripherally may cause ADH release. However, these latter studies have been flawed by hemodynamic alterations and the use of anesthetics, which make interpretation difficult. The present study was designed to test for involvement of prostaglandins produced outside the central nervous system in ADH release in conscious dogs. Administration of meclofenamate (2 mg/kg and 2 mg X kg-1 X h 1, iv) resulted in a consistent fall in plasma ADH levels in five dogs. This diminution of ADH release occurred with no change in systemic hemodynamics, arterial blood gases, or plasma osmolality, suggesting that prostaglandins are important mediators of basal ADH release in the conscious dog. Because meclofenamate does not cross the blood-brain barrier, prostaglandins produced outside the central nervous system appear to be involved in this process. The specific prostaglandin involved or the site of action of prostaglandins on ADH release is not clear at this time.

Animals↗

PubMed1984

Blood pressure control in pregnant rabbits: norepinephrine and prostaglandin interactions.

The relationship between norepinephrine (NE) and prostaglandins in the regulation of systemic blood pressure during pregnancy was examined in conscious rabbits. The arterial prostaglandin E2 (PGE2) concentration was higher in pregnant than in nonpregnant rabbits. Resting blood pressure was slightly lower in the gravid animals. The pressor response to incremental doses of intravenous NE was blunted in the pregnant rabbits. Meclofenamate, a cyclooxygenase inhibitor, failed to alter the resting blood pressure in either group of animals, although it reduced PGE2 levels more than 60% in the pregnant rabbits. The pressor response to NE was significantly increased only in the pregnant rabbits when the NE infusion was repeated following meclofenamate. Pregnant rabbits could also be differentiated from nonpregnant by their higher peripheral blood levels of NE and their uniform hypotensive response to alpha-adrenergic blockade. These observations define an altered responsiveness to both endogenous and exogenous NE in pregnant rabbits that appears to be related to an increase in vasodilator prostaglandins.

Animals↗

PubMed1986

Reduced osmotic and nonosmotic release of vasopressin after meclofenamate in the conscious dog.

Both in vivo as well as in vitro experiments suggest that prostaglandins (PG) may influence arginine vasopressin (AVP) release. Recent studies on conscious dogs have shown that cyclooxygenase inhibition with meclofenamate reduces basal AVP release as well as AVP release in response to hypoxia. The current experiments were performed in order to test whether PG synthesis inhibition affects osmotic- and nonosmotic-stimulated AVP release in a similar manner. Osmotic AVP release was tested by slowly infusing hypertonic saline intravenously in water-diuresing dogs and serially sampling plasma for AVP concentration. Experiments were performed both with and without meclofenamate (2 mg/kg and 2 mg X kg-1 X h-1 iv) pretreatment. AVP release to a comparable osmotic stimulus was greatly reduced after meclofenamate administration. Nonosmotic AVP release was tested by inducing systemic hypotension with an intravenous infusion of nitroprusside. Hypotension was associated with an increase in AVP concentration, which was partially blunted after meclofenamate administration. Experiments performed with only a saline vehicle administered showed no decrease in AVP release in response to comparable hypotension. The findings of these studies suggest that endogenous PG may be involved in both osmotic and nonosmotic AVP release in the conscious dog.

Animals↗

PubMed1987

Vasopressin responses to asphyxia and hemorrhage in newborn pigs.

Vasopressin may be important in maintenance of arterial pressure and redistribution of cardiac output in hypotensive and asphyxiated newborns. We used chronically instrumented, unanesthetized, 4-day-old pigs to investigate the effects of hypotensive hemorrhage and asphyxia on plasma vasopressin concentration and to determine the effects of cyclooxygenase inhibition on these responses. Asphyxia [arterial O2 partial pressure (PaO2) = 40-50 Torr, arterial CO2 partial pressure (PaCO2) = 60-80 Torr) increases plasma lysine vasopressin (LVP) from 2.2 +/- 0.8 to 52.4 +/- 15.0 microU/ml. Neither the baseline nor stimulated plasma LVP was affected by indomethacin (5 mg/kg) or meclofenamate (5 mg/kg). Hemorrhage (30 ml/kg) increased plasma LVP from 2.8 +/- 0.8 to 163.4 +/- 28.1 (20 min) and 135.1 +/- 18.5 microU/ml (60 min). The effects of vehicle and indomethacin (5 mg/kg) 20 min after hemorrhage on plasma LVP 60 min after hemorrhage were not different. Changes in plasma vasopressin caused by asphyxia and hemorrhage in the unanesthetized newborn pig are similar to the responses observed in adults of other species. This study does not suggest that prostanoids are involved in these responses in newborn pigs.

Animals↗

PubMed1989

Central interleukin 1-elicited hyperinsulinemia is mediated by prostaglandins but not autonomics.

This laboratory previously reported that centrally administered interleukin 1 (IL-1) in fasted pentobarbital-anesthetized rats elicited significant hyperinsulinemic and febrile responses. In characterizing this putative central mechanism for the regulation of pancreatic insulin secretion, hyperinsulinemia and fever elicited by IL-1 injected intravenously (iv) or intracerebroventricularly (icv) was totally eliminated by prior cyclooxygenase inhibition with indomethacin, ibuprofen, or meclofenamate but not lipoxygenase inhibition with propyl gallate or leukotriene receptor antagonism with LY 171883. Furthermore, central administration of prostaglandin E2 at 10 and 100 ng doses consistently evoked hyperinsulinemic, hypercorticotropinemic, and febrile responses in anesthetized rats maintained on isothermal pads. beta-Adrenergic and vagus nerves to the pancreatic beta-cells seemed likely candidates to mediate the enhanced secretion of insulin elicited by IL-1 acting centrally. However, pretreatment of rats with hexamethonium, propanolol, atropine, or bilateral subdiaphragmatic vagotomy all failed to reduce hyperinsulinemia after IL-1 iv or icv. This evidence suggests that the central mechanism for enhanced pancreatic insulin secretion elicited by IL-1 may depend on a humoral rather than autonomic neural efferent pathway. Moreover, the hyperinsulinemia is mediated in part by prostaglandins just like the well-studied febrile response.

Acetophenones↗

PubMed1990

Reduced renal perfusion pressure causes prostaglandin-dependent excitation of R2 chemoreceptors in rats.

The activity of multiunit preparations of afferent renal nerve activity (ARNA) and single R2 chemoreceptors was recorded during graded reductions in renal perfusion pressure (RPP) produced by tightening an aortic snare in anesthetized rats. In 13 multiunit preparations an initial RPP reduction from 117 +/- 2 to 101 +/- 2 mmHg caused ARNA to increase 29 +/- 5% above control. Further reductions in RPP produced a 65 +/- 11% increase in ARNA at 80 +/- 1 mmHg, 87 +/- 24% at 59 +/- 1 mmHg, and 127 +/- 38% at 37 +/- 1 mmHg (P less than 0.01 ARNA vs. RPP). Renal blood flow was measured by pulsed Doppler flowmeter in these rats and showed good autoregulation and minimal reduction (-4 +/- 2%) during the initial pressure drop. Ten single R2 chemoreceptors increased their firing rate by 129 +/- 4% when RPP was reduced from 109 +/- 2 to 85 +/- 2 mmHg and showed a peak response of 494 +/- 105% at 27 +/- 2 mmHg. The activity of 11 R2 receptors increased from 3.7 +/- 1.0 to 6.8 +/- 0.8 impulses/10 s when RPP was reduced from 112 +/- 4 to 79 +/- 2 mmHg. Prostaglandin blockade with indomethacin (6 rats) or meclofenamate (7 rats) caused a decrease in basal activity in the same units to 1.8 +/- 0.5 impulses/10 s and eliminated their excitatory response to a similar reduction in RPP (108 +/- 4 to 75 +/- 3 mmHg). These data support a role for R2 chemoreceptors in neurocirculatory reflexes elicited by reductions in RPP.

Afferent Pathways↗

PubMed1991

Inhibitory renorenal reflexes: a role for renal prostaglandins in activation of renal sensory receptors.

In anesthetized rats, activation of renal sensory receptors with a mechanical stimulus (increased ureteral pressure) and a chemical stimulus (renal pelvic perfusion with 0.9 M NaCl) results in an increase in ipsilateral afferent renal nerve activity and a reflex increase in contralateral urine flow rate and urinary sodium excretion, i.e., a contralateral inhibitory renorenal reflex. Because both interventions are known to increase renal prostaglandin (PG) synthesis, we examined whether renal PGs were involved in the renorenal reflex response to renal sensory receptor stimulation. In the first part, mechanical and chemical activation of renal sensory receptors was performed in the absence and presence of renal pelvic perfusion with indomethacin or meclofenamate (0.2 micrograms/min). Indomethacin inhibited the ipsilateral afferent renal nerve activity response to increased ureteral pressure (7 +/- 2 vs. 38 +/- 10%, P less than 0.01) and renal pelvic perfusion with 0.9 M NaCl (3 +/- 3 vs. 28 +/- 5%, P less than 0.01) and the contralateral diuretic and natriuretic responses in the absence of any renal hemodynamic changes. Similar effects were produced by meclofenamate. In the second part, mechanical and chemical activation of renal sensory receptors was performed in the presence of renal pelvic perfusion with vehicle, indomethacin, and indomethacin plus PGE2 (20 micrograms/min). Addition of PGE2 to the renal pelvic perfusate in indomethacin-treated kidneys restored the responses to mechanical and chemical activation of renal sensory receptors to levels not different from their pre-indomethacin control values. We conclude that PGs in the renal pelvic area are involved in inhibitory renorenal reflex responses to mechanical and chemical activation of renal sensory receptors.

Afferent Pathways↗

PubMed1993

Role of angiotensin II and prostaglandins in the regulation of uteroplacental blood flow.

This study was designed to determine the importance of the renin-angiotensin (RAS) and prostaglandin (PG) systems in regulating uteroplacental blood flow (UBF). Our objectives were to determine: 1) whether angiotensin II (ANG II) acts as a vasodilator or purely as a vasoconstrictor in the uteroplacental circulation, and 2) whether this circulation is capable of autoregulation. In chronically instrumented pregnant dogs (41-54 days gestation), ANG II was infused intravenously at increasing doses (8, 16, and 24 ng.kg-1 x min-1). Arterial pressure rose from 108 +/- 6 to 146 +/- 4 mmHg and UBF did not change but uterine vascular resistance (UVR) progressively increased. When the experiment was repeated while servo-controlling uterine arterial pressure, UBF fell at all doses, reaching 62 +/- 7% of control at the highest dose, and UVR increased as before. Meclofenamate (6 mg/kg i.v.) did not alter the dose-response curves. In separate experiments, uterine perfusion pressure was reduced in steps to 55 mmHg. UBF was well autoregulated down to approximately 85 mmHg, and neither captopril (14 micrograms.kg-1 x min-1) nor meclofenamate altered UBF autoregulation. Thus ANG II appears to act as a vasoconstrictor in the uteroplacental circulation and any preservation of UBF during ANG II appears to be due to the increased arterial pressure. Also, in the dog the uteroplacental circulation possesses a mild to moderate degree of autoregulatory capability, which does not appear to be dependent on the RAS or PGs.

Angiotensin II↗

PubMed1993

Endothelin-induced natriuresis and diuresis are pressure-dependent events in the rat.

The goal of the current study was to determine the mechanism by which doses of endothelin (ET) that do not markedly affect the glomerular filtration rate (GFR) cause a natriuresis and diuresis. ET was infused into pentobarbital-anesthetized female rats at 50 ng.kg-1.min-1 iv for 30 min. In controls (n = 6 rats; n = 5 in all other groups), ET increased mean arterial blood pressure (MAP) from 95 +/- 2 to 131 +/- 2 (SE) mmHg, Na excretion (UNa V) from 0.34 +/- 0.07 to 1.83 +/- 0.2 meq/min, and urine flow rate (V) from 13 +/- 1 to 24 +/- 3 ml/min (all P < 0.01 vs. baseline). At 15 min during infusion of ET, the GFR was not affected (2.1 +/- 0.1 to 2.2 +/- 0.1 ml/min) but modestly decreased to 1.8 +/- 0.1 ml/min at 30 min (P < 0.05 vs. baseline). Either removing the capsule from both kidneys during surgery or maintaining renal arterial pressure at baseline values with an adjustable clamp on the aorta above the right renal artery abolished the ET-induced increase in UNa V and V. Meclofenamate also did not alter the ET-induced increase in MAP, V, or UNa V. To determine the intrarenal site of action of ET, experiments were conducted with ET plus amiloride or with a combination of amiloride plus furosemide; there was a larger ET-induced diuresis and natriuresis in amiloride-treated rats and an even larger response with amiloride plus furosemide compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗