The effect of PGI2 on canine renal function and hemodynamics

The effect of prostaglandin I₂ (prostacyclin) on renal and intrarenal hemodynamics and function was studied in mongrel dogs to elucidate the role of this novel prostaglandin in renal physiology. Starting at a dose of 10^?8 g/kg/min, PGI₂ decreased renal vascular resistance and redistributed the blood flow away from the outer cortex (zone 1) and towards the juxtamedullary cortex (zone 4). At 3 × 10^?8 g/kg/min, the renal vascular resistance decreased even further, but at this dose the mean arterial blood pressure also declined 13% indicating recirculation of this prostaglandin. PGI₂ infusion at a vasodilatory dose resulted in natriuresis and kaliuresis. With a decline in filtration fraction, these changes were most likely secondary to the hemodynamic effects of this prostaglandin. Unlike PGE₂, PGI₂ had no direct effect on free water clearance indicating lack of activity at the collecting duct. PGI₂ may be the important renal prostaglandin involved in modulating renal vascular resistance and intrarenal hemodynamics as well as influencing systemic blood pressure.     

Skeletal muscle vasoconstriction produced by prostaglandin synthesis inhibitors; dependence on pump perfusion

A comparison was made of the effect of prostaglandin synthesis inhibitors (PGSI) on systemic blood pressure and hindlimb muscle vascular resistance of anesthetized dogs under different experimental conditions. When muscle blood flow was monitored using an extracorporeal or noncannulating electromagnetic blood flow probe, indomethacin (5 mg/kg i.v.) increased blood pressure slightly, but did not change vascular resistance. Administration of PGSI (indomethacin, meclofenamate, or naproxen, 5 mg/kg i.v.) after 2 hr of pump perfusion of the hindlimb caused a 22% increase in blood pressure, and 39% increase in vascular resistance 30 min afterwards. When administered immediately after instituting pump perfusion, indomethacin caused no significant change in blood pressure or vascular resistance at the 30 min interval, but at 60 min vascular resistance was increased. A similar vasoconstrictor response to indomethacin was obtained when it was infused in a lower dose intraarterially to the hindlimb, or when given i.v. after ligation of the renal pedicles. The results indicate that pump perfusion results in elaboration of a nonrenal prostaglandin(s) which maintains a vasodilator influence on the skeletal muscle vascular bed.     

The role of renal metabolism of PGE2 in determining its activity as a renal vasodilator in the dog.

Since the mammalian renal cortex avidly metabolizes prostaglandin E2 (PGE2), we examined the importance of renal metabolism of PGE2 in determining its renal vascular activity in the dog. We used 13, 14 dihydro PGE2 (DHPGE2) as a model compound to study this because DHPGE2 retains similar activity to the parent prostaglandin, PGE2, but is a poorer substrate than PGE2 for both the metabolism and the cellular uptake of the prostaglandins. Using dog renal cortical slices, we found that under similar experimental conditions, PGE2 was metabolized several-fold faster than DHPGE2. Both prostaglandins were metabolized to the 15 keto 13, 14 dihydro PGE2, which was positively identified using GC-MS. In vivo, we infused increasing concentrations of DHPGE2 into the renal artery of dogs and measured renal hemodynamic changes using radioactive microspheres. DHPGE2 was a potent renal vasodilator beginning at an infusion rate of 10(-9)g/kg/min. When compared to PGE2, DHPGE2 was about 10 times more potent in affecting renal vasodilation. The intrarenal redistribution of blood flow towards the inner cortex seen with DHPGE2 was identical to that seen with PGE2. We conclude that renal catabolism of PGE2 is very important in limiting the in vivo biological activity of PGE2, but regional differences in metabolism of PGE2 within the cortex are an unlikely determinant of the pattern of redistribution of renal blood flow.     

Effect of prostaglandin I2 on ovine placental vasculature.

The response of the placental circulations to prostaglandin I2 (maternal dose 20 microgram/kg, fetal dose 180 microgram/kg) was observed in 10 near-term sheep with chronically implanted vascular catheters. The blood flows before and 90 s after the injection of prostaglandin I2 were measured using radioactive microspheres. The injection of prostaglandin I2 to the mother decreased th blood pressure from 109 +/- 4 to 69 +/- 5 mmHg (P < 0.001) and increased the vascular resistance of the maternal cotyledons from 0.166 +/- 0.018 to 0.209 +/- 0.02 mmHg/(ml/min) (P < 0.001). The vascular bed of the non-cotyledonary uterus vasodilated as the resistance fell from 0.705 +/- 0.02 to 0.266 +/- 0.02 mmHg/(ml/min). (P < 0.001). Prostaglandin I2 caused the fetal arteriovenous pressure to fall from 37.6 +/- 1.35 to 26.0 +/- 1.6 mmHg. There was no significant change in the vascular resistance of the fetal cotyledons. We observed vasodilation in the fetal membranes as vascular resistance fell from 1.06 +/- 0.14 to 0.75 +/- 0.10 mmHg/(ml/min) (P < 0.001). The infusion of prostaglandin I2 significantly depressed the response of the placenta and uterus to norepinephrine. We have not proved that prostaglandin I2 plays a direct role in maintaining placental vascular homeostasis but it may modulate the response of this organ to exogenous vasoactive agents.     

Prostanoids and hypothermic renal preservation injury

The effect of 48 hours of hypothermic renal ischemia utilizing Euro-Collins flush and short term reperfusion on renal prostaglandin synthesis was studied in dogs. Hypothermic ischemia followed by 60 minutes of reperfusion in-vivo resulted in significant elevations in renal Thromboxane B2 (TXB2) production in the outer cortex, inner cortex, and medulla, relative to non-ischemic kidneys. Prostaglandin E2 (PGE2) and 6-keto Prostaglandin F1 alpha (6-K PGF1 alpha) production were not significantly affected by ischemia and reperfusion. Enhanced TXB2 production was not seen with ischemia alone (without reperfusion) or with reperfusion with O2 saturated buffer, indicating a blood born source or stimuli. Early postreperfusion renal blood flow after hypothermic ischemia followed a biphasic pattern; blood flow increased for the first 10 minutes of reperfusion to achieve normal values, and then steadily declined over the next 20 minutes. This pattern was not altered by the cyclooxygenase inhibitors Idomethacin (5 mg/kg, P.O.) or Mefenamic acid (10 mg/kg, I.V.). Administration of the TXA2 synthesis inhibitor CGS-12970 (3 mg/kg, I.V.) or the TXA2/endoperoxide receptor antagonist SQ-29548 (80 micrograms/min, I.A.) significantly increased renal blood flow during reperfusion but neither agent altered the basic time dependent pattern observed in the control group. These data indicate that 48 hours of hypothermic renal ischemia results in dramatic changes in intrarenal TXA2 synthesis at the time of reperfusion. Enhanced TXA2 production is not dependent on reoxygenation per se, but rather requires reperfusion with blood suggesting a circulatory source.(ABSTRACT TRUNCATED AT 250 WORDS)     

The renal haemodynamic and excretory actions of prostacyclin and 6-oxo-PGF1 alpha in anaesthetized dogs.

Intrarenal arterial (i.a.) infusions of prostacyclin (PGI2) at 30-300 ng/min to anaesthetized dogs reduced renal vascular resistance (RVR) and filtration fraction (FF), increased mean renal blood flow (MRBF) but did not alter mean arterial pressure (MAP)or glomerular filtration rate (GFR). The urinary excretion of sodium (UNaV), potassium (UKV) and chloride ions (UC1V) were increased through inhibition of net tubular ion reabsorption. PGI2 (3000 ng/min, i.a.) reduced MAP and increased heart rate. Intravenous (i.v.) infusions of PGI2 (3000 gn/min) reduced MAP, GFR, FF, urine volume and ion excretion, with elevation of heart rate. The measured variables were unaltered by 6-oxo-PGF1 alpha (10,000 ng/min i.a.). Treatment of the dogs with the PG synthetase inhibitor meclofenamic acid (2.5 mg/kg i.v.) did not antagonise the elevation of MRBF to PGI2 (300 ng/min i.a.). Thus the renal effects of PGI2 were due to a direct action rather than through conversion to 6-oxo-PGF1 alpha or through stimulation of endogenous renal PG biosynthesis and release.     

Bradykinin produces pulmonary vasodilation in fetal lambs: role of prostaglandin production

Bradykinin produces pulmonary vasodilation and also stimulates production of other pulmonary vasodilators, including prostaglandin I2 (PGI2) and endothelial-derived relaxing factor. In 12 chronically instrumented fetal lambs, we therefore investigated potential mediation of the bradykinin response by PGI2 or other cyclooxygenase products. A 15-min infusion of bradykinin (approximately 1 microgram/kg estimated fetal wt/min) increased fetal pulmonary blood flow by 522% (P less than 0.05) and decreased pulmonary vascular resistance by 86% (P less than 0.05); plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) concentration also increased (P less than 0.05). After cyclooxygenase inhibition by indomethacin (3 mg), bradykinin increased pulmonary blood flow by only 350% (P less than 0.05) and decreased pulmonary vascular resistance by 83% (P less than 0.05); plasma 6-keto-PGF1 alpha concentrations did not increase. The increase in pulmonary blood flow produced by bradykinin was greater before administration of indomethacin than after (P less than 0.05). These studies demonstrate that bradykinin produces fetal pulmonary vasodilation by at least two mechanisms, one dependent on and the other independent of PGI2 production, the latter mechanism predominating.     

PGl2 analogue mitigates the progression rate of renal dysfunction improving renal blood flow without glomerular hyperfiltration in patients with chronic renal insufficiency.

Renal blood flow decreases with the progression of chronic glomerulonephritis (CGN). This disease induces medullary ischemia and further renal dysfunction in patients with chronic renal insufficiency (CRI). Prostacyclin (PGI2), with its vasodilative action, increases renal blood flow (RBF) without increasing glomerular filtration rate (GFR). We therefore examined the possibility that PGI2 would mitigate the progression of renal dysfunction by increasing RBF in patients with CRI. Sixteen patients with progressive renal insufficiency (serum creatinine: 2.14+/-0.89 mg/dl) due to CGN were prospectively chosen for this study. The blood pressure was already under control using calcium channel blockers before and during this study in nine hypertensive patients. In the first 6 months the patients received a low-protein (0.6 g/kg/day) and low-salt (5.0 g/day) diet. In the next 6 months they received 60 microg/day of PGI2 analogue (Beraprost sodium) orally. GFR was determined by 24-hour creatinine clearance, and effective renal plasma flow (ERPF) was determined by 99mTc-MAG3 scintigraphy. Glomerular capillary pressure, the resistance ratio of afferent and efferent arterioles (R(A)/R(E)), and the other hemodynamic parameters from Gomez's estimation equation were determined at the start of this study, just before the administration of Beraprost and at the end of the study. The levels of GFR and ERPF were 34.6+/-12.4 and 140.6+/-52.1 ml/min at the start of this study respectively, and decreased to 28.0+/- 12.0 and 115.6+/-45.3 ml/min after the first 6 months without Beraprost. The levels of GFR and ERPF stayed at 28.1+/-15.7 and 119.2+/-57.6 ml/min after the next 6 months with Beraprost in the same patients. R(A)/R(E) increased in the first 6 months from 7.9+/-3.6 to 10.8+/-8.6, but remained constant during 6 months of Beraprost administration, at 10.5+/-8.0. These data indicate that PGI2 analogue diminishes the vascular resistance of glomerular afferent and efferent arterioles regulating the decrease of renal blood flow without glomerular hyperfiltration, thus mitigating the progression rate of renal dysfunction.     

Role of extrarenal and intrarenal converting enzyme inhibition in renal vasodilator response to intravenous captopril

Participation of intrarenal converting enzyme (ICE) in mediation of the renal vasodilator response to captopril (C) was studied in 7 anesthetized dogs. Blood pressure (BP), renal blood flow (RBF) and femoral blood flow (FBF) were measured and vasoconstrictor responses were elicited by i.a. injections of angiotensin (A) I to the renal and femoral vascular beds. The latter responses served as indices of intrarenal and skeletal muscle converting enzyme activity, respectively. Successive infusions of C were given i.a. to the kidney at 0.4, 0.8 and 1.6 μg/kg/min for 30 min each. RBF and renal vascular resistance (RVR) were unaffected by any of these doses of C. The % changes in RBF caused by A-I were reduced from 45 to 23, 20 and 17% by these successive doses of C, respectively; however, the decrements were not significantly different from each other. When C was administered i.v., 0.5 mg/kg, after the highest i.a. dose had been given, there was no further decrease in the response to A-I, suggesting maximal blockade of ICE obtainable by C. BP, RBF and RVR were further affected by the i.v. administration of C. BP decreased from 146 to 136 mm Hg (P<0.05), RBF increased from 240 to 290 ml/min (P<0.01) and RVR decreased from 32 to 24 mm Hg/ml/min/g (P<0.01). These results suggest that ICE plays a minor role in the renal vasodilator response to C, and implicate an influence of circulating peptides on the kidney.     

Cardiac inotropic effects of leukotriene C4 and prostaglandin I2 in the unanesthetized American bullfrog, Rana catesbeiana

The cardiovascular effects of leukotriene (LT) C4 and prostaglandin (PG) I2 were compared in the unanesthetized American bullfrog, Rana catesbeiana. Bullfrogs were instrumented to measure mean arterial pressure, peak ventricular pressure, its derivative (VP + dP/dt), and heart rate. Two hours after recovery from anesthesia, intravenous injections of LTC4 or PGI2 were tested over a dose range from 0.003 to 3 micrograms/kg body weight (bw). Both eicosanoids decreased mean arterial pressure, systolic ventricular pressure, and its derivative (VP + dP/dt). The effects of LTC4 and PGI2 on all parameters were similar at doses below 3 micrograms/kg bw. However, at 3 micrograms/kg bw, LTC4 had more potent negative inotropic effects than PGI2. Both compounds increased heart rate at 0.3 microgram/kg bw, but at 3 micrograms/kg bw PGI2 caused greater increases than LTC4. The hypotensive and negative inotropic effects of LTC4 were blunted in animals pretreated with indomethacin (4 mg/kg bw) to prevent endogenous prostaglandin and thromboxane synthesis, whereas the cardiovascular effects of PGI2 were unaffected by the blockade. The data show that both eicosanoids have similar qualitative effects on blood pressure and cardiac performance. However, the effects of LTC4 may be partially mediated by release of endogenous cyclooxygenase products, possibly PGI2. These results suggest that the bullfrog, an animal with no coronary arteries, is a useful model for comparative studies of cardiac actions of eicosanoids which are independent of effects mediated by changes in coronary vascular resistance.     

Effect of PGI2 on the response of the ovine placenta to norepinephrine

We have examined the effects of PGI2, 50 microgram/kg, on norepinephrine induced placental vasoconstriction in 6 chronically catheterized near-term sheep. Regional blood flows were measured with radioactive microspheres. Control flows were measured. Norepinephrine was than infused at 50 microgram/min throughout the experiment. After 15 min the blood flows were again measured and PGI2 was then added to the infusate at 50 microgram/min. In 15 min regional blood flows were again measured and the PGI2 infusion was stopped. Regional blood flows were measured for the last time 15 min later. The renal and nonplacental uterine vasculatures behaved in a predictable manner. There was constriction with norepinephrine but PGI2 opposed the effects of norepinephrine and decreased the resistance towards the normal levels. The placenta did not behave as did the other organs. Norepinephrine increased placental resistance but PGI2 did not decrease the resistance and severely depress the placental blood flows. PGI2 does not appear to oppose norepinephrine induced placental vasoconstriction.     

The effects of prostacyclin on glycemia and insulin release in man

Prostacyclin /PGI2/ administered intra-arterially or intravenously to patients with peripheral vascular disease exerted a hyperglycemic effect. In normoglycemic patients receiving PGI2 at a dose of 5 ng/kg/min these effects were barely detectable, but they became unmasked by a rapid glucose injection. In diabetic patients the same PGI1 dose led to distinct elevation in blood glucose. Prostacyclin at a dose of 10 ng/kg/min raised blood glucose levels both at rest and after stimulation with glucose, and opposed effectively hypoglycemic action of tolbutamide in non-diabetic patients. PGI2 repressed glucose-induced insulin release in some normoglycemic patients but in others it either increased it or did not affect it. While hyperglycemic effects are reversible when PGI2 infusion is stopped, and do not interfere with the usual therapeutic administration of prostacyclin for a few days they, nevertheless, might constitute a risk in a patient with poorly controlled diabetes.     

Efficacy of intravenous infusion of prostacyclin (PGI2) or prostaglandin E1 (PGE1) in augmentation of skin flap blood flow and viability in the pig

The dose-response effects of 6-h intravenous infusion of PGI2 (0, 5, 10, 25 or 75 ng/kg/min) or PGE1 (0, 25, 50, 100 or 300 ng/kg/min) on skin hemodynamics and viability were studied in 4 x 10 cm random pattern skin flaps (n = 24) raised on both flanks of the pig. Infusion of PGI2 or PGE1 was started immediately after intravenous injection of a loading dose 30 min before skin flap surgery. PGI2 infusion significantly (P less than 0.05) increased the total skin flap capillary blood flow at the dose of 10 ng/kg/min, compared with the control. However, the distance of blood flow along the skin flap from the pedicle to the distal end, i.e. perfusion distance, was not increased. Consequently, the length and area of skin flap viability was also not significantly increased. The effect of PGI2 infusion on skin blood flow was biphasic. Specifically, higher doses (greater than or equal to 25 ng/kg/min) of intravenous PGI2 infusion produced no beneficial effect on the skin flap capillary blood flow. PGI2 infusion at the dose of 10 or 75 ng/kg/min did not significantly increase plasma renin activities or plasma levels of norepinephrine compared with the control, therefore the biphasic effect of PGI2 on skin flap blood flow was not related to circulating levels of norepinephrine or angiotensin. Intravenous infusion of PGE1 did not produce any therapeutic effect on the skin capillary blood flow in the random pattern skin flaps at all doses tested. At the dose of 300 ng/kg/min, the mean arterial blood pressure was 17% lower (P less than 0.05) than the control, but the skin capillary flow still remained similar to the control. It was concluded that intravenous infusion of PGI2 or PGE1 was not effective in augmentation of distal perfusion or length of skin viability in the porcine random pattern skin flaps. Drug treatment modalities for prevention or treatment of skin flap ischemia is discussed.     

Inhibitory effects of beta adrenoceptor antagonist, atenolol, on the thromboxane system in the kidney of spontaneously hypertensive rats

We attempted to investigate the alterations in the vasoconstrictor thromboxane (TXA2) system in the kidney when spontaneously hypertensive rats (SHR) were treated subchronically with atenolol, a beta 1-adrenoceptor antagonist. Atenolol treatment (30 mg/kg body weight per day for 2 weeks) reduced systolic blood pressure by 11%, being accompanied by a decrease in heart rate. This treatment strikingly decreased thromboxane content in the renal cortex by 48% (p less than 0.05), whereas the tissue content was unaltered for prostaglandin E2 (PGE2) or slightly decreased for prostacyclin (PGI2). These alterations in the eicosanoid system led to an increase in the ratio of PGE2/TXA2 and of PGI2/TXA2. Similarly, thromboxane content in the renal papilla was lowered significantly with atenolol treatment, which raised the ratio of PGE2 to TXA2. Thromboxane reduction was not observed in the aortic walls and heart. However, in the vascular walls, PGI2 synthesis was markedly stimulated with atenolol treatment, resulting in an increase in the ratio of PGI2 to TXA2. Thus, these data indicate that subchronic atenolol-treatment inhibits the thromboxane system in the kidney, thereby shifting the eicosanoid system towards a vasodilator state. These alterations contribute, in part, to the anti-hypertensive properties of atenolol in genetic hypertension.     

Effect of metabolic acidosis on fetal renal haemodynamics

The effects of metabolic acidosis on renal haemodynamics and intrarenal blood flow distribution was studied in two groups of chronically-catheterized fetal sheep between 122 and 130 days of gestation. One group (experimental group) was studied before and during infusion of 1.1 M lactic acid, whereas the second group received on infusion of dextrose 5% (w/v) in water and served as a time-control group. Infusion of lactic acid for 2 h decreased fetal arterial pH from 7.37 +/- 0.01 to 6.95 +/- 0.02, did not change arterial blood pressure, but produced a significant decrease in renal blood flow (41 +/- 3 to 33 +/- 7 ml/min, P less than 0.05) and a significant increase in renal vascular resistance (1.42 +/- 0.13 to 1.86 +/- 0.18 mmHg/ml/min, P less than 0.05). Moreover, a significant decline in cortical blood flow was also observed in the outer portion of the renal cortex during lactic acidosis. Taken together, these results suggest that metabolic acidosis produces significant changes in fetal renal haemodynamics not associated with changes in arterial blood pressure.     

Modulation of prostaglandin of the renal vascular action of arginne vasopressin

To determine whether the renal vascular effect of arginine vasopressin (AVP) is modulated by renal prostaglandin E₂ (PGE₂) were determined during the infusion of AVP in dogs during control conditions and after the administration of the inhibitor of prostaglandin synthesis, indomethacin. During control conditions, intrarenal administration for 10 min of a dose of AVP calculated to increase arterial renal plasma AVP concentration by 75 pg/ml produced a slight renal vasodilation (p<0.01) and an increase in renal venous plasma concentration of PGE₂. Renal venous PGE₂ concentration during control and AVP infusion averaged 33 ± 7 and 52 ± 12 pg/ml (p<0.05), respectively. After administration of indomethacin, the same dose of AVP induced renal vasoconstriction (p<0.05) and failed to enhance renal venous PGE₂ concentration (9 ± 1 to 8 ± 1 pg/ml). Intrarenal administration of 20 ng/kg. min of AVP for 10 min induced a marked renal vasoconstriction (p<0.01) and increased renal venous plasma PGE₂. Renal venous PGE₂ during control and AVP infusion averaged 31 ± 10 and 121 ± 31 pg/ml (p<0.01), respectively. Administration of the same dose of AVP following indomethacin produced a significantly greater and longer lasting renal vasoconstriction (p<0.01) and failed to increase renal venous plasma PGE₂ (10 ± 1 to 9 ± 1 pg/ml). These results indicate that a concentration of AVP comparable to that observed in several pathophysiological conditions induces a slight renal vasodilation which is mediated by renal prostaglandins. The results also indicate that higher doses of AVP induce renal vasoconstriction and that prostaglandin synthesis induced by AVP attenautes the renal vasoconstriction produced by this peptide.     

Evidence for separate PGD2 and PGF2 alpha receptors in the canine mesenteric vascular bed.

Potential interactions between PGD2 and PGF2 alpha in the mesenteric and renal vascular beds were investigated in the anesthetized dog. Regional blood flows were measured with electromagnetic flow probes. PGD2, PGF2 alpha and Norepinephrine (NE) were injected as a bolus directly into the appropriate artery, and responses to these agents were obtained before, during and after infusion of either PGD2 or PGF2 alpha into the left ventricle. In each case, the infused prostaglandin caused vascular effects of its own. Left ventricular infusion of PGD2 reduced responses to local injections of PGD2 in the intestine, and a similar effect was observed for PGF2 alpha, suggesting significant receptor or receptor-like interactions for each of the prostanoids. However, systemic infusion of prostaglandin F2 alpha (20--100 ng/kg/min) had no effect on renal or mesenteric vascular responses to local injection of prostaglandin D2. Similarly, PGD2 administration (100 ng/kg/min) did not affect responses to PGF2 alpha in the intestine. The present results therefore suggest that these prostaglandins, i.e., D2 and F2 alpha, act through separate receptors in the mesenteric and renal vascular beds. In addition, increased prostaglandin F2 alpha levels produced by infusion of F2 alpha reduced mesenteric but not renal blood flow, suggesting that redistribution of cardiac output might participate in side effects often observed with clinical use of this prostaglandin, such as nausea and abdominal pain.     

Intrarenal infusion of bradykinin elicits a pressor response in conscious rats via a B2-receptor mechanism.

Bradykinin (BK) is a peptide known to activate afferent nerve fibers from the kidney and elicit reflex changes in the cardiovascular system. The present study was specifically designed to test the hypothesis that bradykinin B2 receptors mediated the pressor responses elicited during intrarenal bradykinin administration. Pulsed Doppler flow probes were positioned around the left renal artery to measure renal blood flow (RBF). A catheter, to permit selective intrarenal administration of BK, was advanced into the proximal left renal artery. The femoral artery was cannulated to measure mean arterial pressure (MAP). MAP, heart rate (HR), and RBF were recorded from conscious unrestrained rats while five-point cumulative dose-response curves during an intrarenal infusion of BK (5-80 microg x kg(-1) x min(-1)) were constructed. Intrarenal infusion of BK elicited dose-dependent increases in MAP (maximum pressor response, 26+/-3 mmHg), accompanied by a significant tachycardia (130+/-18 beats/min) and a 28% increase in RBF. Ganglionic blockade abolished the BK-induced increases in MAP (maximum response, -6+/-5 mmHg), HR (maximum response 31+/-14 beats/min), and RBF (maximum response, 7+/-2%). Selective intrarenal B2-receptor blockade with HOE-140 (50 microg/kg intrarenal bolus) abolished the increases in MAP and HR observed during intrarenal infusion of BK (maximum MAP response, -2+/-3 mmHg; maximum HR response, 15+/-11 beats/min). Similarly, the increases in RBF were prevented after HOE-140 treatment. In fact, after HOE-140, intrarenal BK produced a significant decrease in RBF (22%) at the highest dose of BK. Results from this study show that the cardiovascular responses elicited by intrarenal BK are mediated predominantly via a B2-receptor mechanism.     

The role of renal metabolism of PGE2 in determining its activity as a renal vasodilator in the dog

Since the mammalian renal cortex avidly metabolizes prostaglandin E₂ (PGE₂), we examined the importance of renal metabolism of PGE₂ in determining its renal vascular activity in the dog. We used 13, 14 dihydro PGE₂ (DHPGE₂) as a model compound to study this because DHPGE₂ retains similar activity to the parent prostaglandin, PGE₂, but is a poorer substrate than PGE₂ for both the metabolism and the cellular uptake of the prostaglandins. Using dog renal cortical slices, we found that under similar experimental conditions, PGE₂ was metabolized several-fold faster than DHPGE₂. Both prostaglandins were metabolized to the 15 keto 13, 14 dihydro PGE₂, which was positively identified using GC-MS. In vivo, we infused increasing concentrations of DHPGE₂ into the renal artery of dogs and measured renal hemodynamic changes using radioactive microspheres. DHPGE₂ was a potent renal vasodilator beginning at an infusion rate of 10⁻⁹g/kg/min. When compared to PGE₂, DHPGE₂ was about 10 times more potent in affecting renal vasodilation. The intrarenal redistribution of blood flow towards the inner cortex seen with DHPGE₂ was identical to that seen with PGE₂. We conclude that renal catabolism of PGE₂ is very important in limiting the in vivo biological activity of PGE₂, but regional differences in metabolism of PGE₂ within the cortex are an unlikely determinant of the pattern of redistribution of renal blood flow.     

Blockade of the systemic and renal vascular actions of angiotensisn II with the 1-sar, 8-ala analogue in the rat.

To assess the characteristics of blockade induced by 1-Sar, 8-Ala angiotensin II (P113) in the rat, dose-response relationships were established for angiotensin II and blood pressure, cardiac output and renal blood flow (measured with microspheres) and calculated total peripheral resistance. P113 infused at 1.0 μg/kg/min reduced renal and systemic vascular responses to angiotensin II, but did not modify the pressor response because of compensatory increase in cardiac output. Ganglionic blockade (pentolinium tartrate 2.5 mg) uncovered a significant influence of P113 at 1.0 μg/kg/ min on pressor responses to angiotensin II. P113 at 10 μg/kg/min totally prevented the pressor and renal vascular response to 1.0 μg/kg/min of angiotensin II. P113 at 10 and 100 μg/kg/min did not influence renal blood flow, cardiac output or total peripheral resistance, and had only a transient, small influence on blood pressure. P113 did not modify the renal or systemic vascular response to norepinephrine. The failure of P113 to influence renal blood flow in the rat and the relative insensitivity of the renal vasculature to angiotensin II suggest that the vascular receptor for angiotensin II in the rat differs from that in other species including the dog, rabbit and man.