Decrease In RBF Research Articles

HYPOTENSIVE EFFECTIVENESS OF THE INTRARENAL MEDULLARY ENDOTHELIN ETA RECEPTOR BLOCKADE IN THE TWO ANIMAL MODELS OF HYPERTENSION

Objective: Endothelin-1 (ET-1) is involved in the pathogenesis of arterial hypertension and chronic kidney disease, however, its mechanism of action is unclear. ET-1 is known to act via ETA and ETB receptors; their activation leads, respectively, to constriction or NO-mediated dilation of the systemic and renal vasculature. ET-1 levels are elevated in experimental and in human hypertension. Here we examined the effects of ETA receptor blockade with atrasentan, administered intravenously (i.v.) or directly to the renal medullary interstitium (i.med.) in two models of rat hypertension. Design and method: In anaesthetized rats with hypertension induced by uninephrectomy followed by high-salt (4% Na w/w) diet (HS/UNX) and in spontaneously hypertensive rats (SHR) we measured mean arterial pressure (MAP), total renal blood flow (RBF, renal artery probe), renal medullary blood flow (MBF, laser-Doppler flux), and renal medullary nitric oxide (NO) signal. Atrasentan doses were: 0.6 mg/kg/h i.v. or 0.12 mg/kg/h i.med. Results: In HS/UNX intravenous atrasentan reduced MAP (142 ± 7 to 117 ± 8 mmHg, p < 0.001) and increased NO signal by 12% (p < 0.05). RBF fell from 25.6 ± 1.7 to 22.3 ± 1.6 ml/min (p < 0.03). Intramedullary atrasentan decreased MAP (127 ± 6 to 115 ± 6, p < 0.04) and increased NO signal by 9.7% (p < 0.03). RBF and MBF did not change significantly. In SHR intravenous atrasentan decreased MAP (171 ± 3 to 152 ± 9 mmHg, p < 0.03) and RBF (6.4 ± 0.5 to 5.0 ± 0.4 ml/min, p < 0.02); NO signal increased by 9.1% (p < 0.01). Intramedullary atrasentan decreased MAP (176 ± 4 to 167 ± 7 mmHg, p < 0.001); NO increased by 10% and MBF by 26% (p < 0.02–0.05). Evidently, in both hypertension models atrasentan always decreased MAP and increased tissue NO. Conclusions: To summarise, in both hypertension models blockade of ETA receptors decreased MAP, reflecting systemic vasodilation. The pressure decrease was followed by a decrease in RBF, probably the result of reduced renal perfusion pressure and imperfect autoregulation. Remarkably, MAP decrease was also seen with intramedullary ETA blockade but then without impairment of renal circulation. Of particular interest was a regular increase in tissue NO: we propose that the blockade of ETA unmasked the action of unbound ET-1 via ETB receptors, leading to NO release.

P325 Features of intraoperative neurophysiological monitoring used in carotid endarterectomy

Objectives To determine the role of SSEP, TCDG in assessment of TIA and IS; to find the relationship between the decrease in the amplitude of the N20 and the duration period in the same patients. Methods: 15 patients with decrease of flow velocity in the (ICA) stenosis > 60% were examined. In all cases IOM was held with registration of SSEP (n.medianus) and TCDG of the ACM with an assessment of RBF. Results All patients underwent SSEP, RBF, TCDG. In 5 patients there were no significant changes in the parameters during the probe with compression of ICA. According to the results of the compression ICA, they did not need any shunt. In 6 patients the main parameters of tests were significantly lower in comparison with normal values, but the increase in SBP to 160/90 mmHg accompanied by an increase in N20 amplitude, of the RBF and decrease of flow velocity in the ICA the shunt assembly was not performed. The duration period of the decrease in the N20 amplitude did not exceed 10 min in all patients. In 4 patients the shunt was installed (the decrease in RBF was more than 1/3 of the baseline (TCDG 50%). Conclusions In patients with CEE the decrease of TCDG and SSEP parameters can be used as a predictors of ischemic changes. The role of the reduction of RBF, TCDG and SSEP parameters and the duration period of the temporary reduction should be checked in a bigger cohort of patients.

Hemodynamic basis for the limited renal injury in rats with angiotensin II-induced hypertension.

ANG II is thought to increase the susceptibility to hypertension-induced renal disease (HIRD) via blood pressure (BP)-dependent and BP-independent pathways; however, the quantitative relationships between BP and HIRD have not been examined in ANG II-infused hypertensive rats. We compared the relationship between radiotelemetrically measured BP and HIRD in Sprague-Dawley rats (Harlan) chronically administered ANG II (300-500 ng·kg(-1)·min(-1), n = 19) for 4 wk versus another commonly employed pharmacological model of hypertension induced by the chronic administration of N(ω)-nitro-l-arginine methyl ester (l-NAME, 50 mg·kg(-1)·day(-1), n = 23). [DOSAGE ERROR CORRECTED]. Despite the significantly higher average systolic BP associated with ANG II (191.1 ± 3.2 mmHg) versus l-NAME (179.9 ± 2.5 mmHg) administration, the level of HIRD was very modest in the ANG II versus l-NAME model as evidenced by significantly less glomerular injury (6.6 ± 1.3% vs. 11.3 ± 1.5%, respectively), tubulointerstitial injury (0.3 ± 0.1 vs. 0.7 ± 0.1 injury score, respectively), proteinuria (66.3 ± 10.0 vs. 117.5 ± 10.1 mg/day, respectively), and serum creatinine levels (0.5 ± 0.04 vs. 0.9 ± 0.07 mg/dl, respectively). Given that HIRD severity is expected to be a function of renal microvascular BP transmission, BP-renal blood flow (RBF) relationships were examined in additional conscious rats administered ANG II (n = 7) or l-NAME (n = 8). Greater renal vasoconstriction was observed during ANG II versus l-NAME administration (41% vs. 23% decrease in RBF from baseline). Moreover, administration of ANG II, but not l-NAME, led to a unique BP-RBF pattern in which the most substantial decreases in RBF were observed during spontaneous increases in BP. We conclude that the hemodynamic effects of ANG II may mediate the strikingly low susceptibility to HIRD in the ANG II-infused model of hypertension in rats.

Blood pressure-renal blood flow relationships in conscious angiotensin II- and phenylephrine-infused rats

Chronic ANG II infusion in rodents is widely used as an experimental model of hypertension, yet very limited data are available describing the resulting blood pressure-renal blood flow (BP-RBF) relationships in conscious rats. Accordingly, male Sprague-Dawley rats (n = 19) were instrumented for chronic measurements of BP (radiotelemetry) and RBF (Transonic Systems, Ithaca, NY). One week later, two or three separate 2-h recordings of BP and RBF were obtained in conscious rats at 24-h intervals, in addition to separate 24-h BP recordings. Rats were then administered either ANG II (n = 11, 125 ng·kg(-1)·min(-1)) or phenylephrine (PE; n = 8, 50 mg·kg(-1)·day(-1)) as a control, ANG II-independent, pressor agent. Three days later the BP-RBF and 24-h BP recordings were repeated over several days. Despite similar increases in BP, PE led to significantly greater BP lability at the heart beat and very low frequency bandwidths. Conversely, ANG II, but not PE, caused significant renal vasoconstriction (a 62% increase in renal vascular resistance and a 21% decrease in RBF) and increased variability in BP-RBF relationships. Transfer function analysis of BP (input) and RBF (output) were consistent with a significant potentiation of the renal myogenic mechanism during ANG II administration, likely contributing, in part, to the exaggerated reductions in RBF during periods of BP elevations. We conclude that relatively equipressor doses of ANG II and PE lead to greatly different ambient BP profiles and effects on the renal vasculature when assessed in conscious rats. These data may have important implications regarding the pathogenesis of hypertension-induced injury in these models of hypertension.

Role of adrenergic neurotransmission in the Median Preoptic Nucleus in experimental hypertension

The present study sought to determine the involvement of the adrenergic neurotransmission in the Median Preoptic Nucleus (MnPO) in arterial blood pressure (MAP) control in normotensive and spontaneously hypertensive rats (SH). Male Wistar normotensive (NT) and SH rats (250–320g) were anesthetized with urethane (1.2 g/kg, i.v.) and instrumented for recordings of MAP, aortic blood flow (ABF) and renal (RBF). The rats were fixed in a stereotaxic apparatus and made nanoinjections (100 nl) of saline (0. 15 M) and Fentolamina (6.3 mM; α‐adrenergic antagonist). Aortic vascular conductance (AVC) and renal (RVC) was calculated as the ratio ABF or RBF/MAP and expressed as percentage of baseline. The results demonstrated that adrenergic neurotransmission blocking in MnPO resulted in a decrease in MAP (−7.7 ± 1.1 mmHg, n=7), ABF (−7.3 ± 2.0% above baseline, n=5) and RBF (−7.2 ± 2.1% above baseline, n = 7) of NT rats. In SH also observed decrease in MAP (−14.3 ± 6 mmHg, n = 6) and increase in AVC (8.3 ± 3.0% above baseline, n=5) and RVC (9.6 ± 1.9% above baseline, n=6), indicating vasodilation. These results suggest the participation of MnPO in tonic regulation of blood pressure in NT and SH rats.

A cannabinoid receptor, sensitive to O‐1918, is involved in the delayed hypotension induced by anandamide in anaesthetized rats

Intravenous injection of the endocannabinoid anandamide induces complex cardiovascular changes via cannabinoid CB(1), CB(2) and vanilloid TRPV1 receptors. Recently, evidence has been accumulating that in vitro, but not in vivo, anandamide relaxes blood vessels, via an as yet unidentified, non-CB(1) vascular cannabinoid receptor, sensitive to O-1918 (1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene). We here examined whether the anandamide-induced hypotension in urethane-anaesthetized rats was also mediated via a non-CB(1) vascular cannabinoid receptor. Effects of two antagonists (O-1918 and cannabidiol) of the non-CB(1) vascular cannabinoid receptor on anandamide-induced changes in mean, systolic and diastolic blood pressure (MBP, SBP, DBP), mesenteric (MBF) and renal (RBF) blood flow and heart rate (HR) in urethane-anaesthetized rats was examined. In anaesthetized rats, anandamide (1.5-3 micromol.kg(-1)) and its stable analogue methanandamide (0.5 micromol.kg(-1)) caused a delayed and prolonged decrease in MBP, SBP, DBP, MBF and RBF by about 10-30% of the respective basal values without changing HR. In pithed rats, anandamide (3 micromol.kg(-1)) decreased blood pressure by about 15-20% of the basal value without affecting HR, MBF and RBF. All vascular changes were reduced by about 30-70% by cannabidiol and O-1918 (3 micromol.kg(-1), each). Non-CB(1) cannabinoid vascular receptors, sensitive to O-1918, contribute to the hypotensive effect of anandamide in anaesthetized rats. Activation of these receptors may be therapeutically important as the endocannabinoid system could be activated as a compensatory mechanism in various forms of hypertension.

CHRONIC BLOCKADE OF ENDOGENOUS FORMATION OF HYDROGEN SULFIDE CAUSED INCREASE IN SYSTEMIC BLOOD PRESSURE IN RATS

Hydrogen sulfide (H2S), an endogenous vasodilator, is produced by two enzymes; cystathionine γ‐lyase (CSE) and cystathionine β‐synthase (CBS). In this study, the effects of chronic inhibition of CSE by DL‐propargylglycine (37.5 mg/kg/day; ip) and CBS by aminoxyacetic acid (8.8 mg/kg/day; ip) given either alone or in combination for 4 weeks on systemic blood pressure (SBP) and renal function were examined in rats (n=6 in each group). Prior to the start and then every 7th day during treatment period, SBP was measured by tail‐cuff method and 24 hr urine collections were made using metabolic cages. Urinary excretion rate of sulfate (USV; marker for endogenous H2S level) was determined by a colorimetric assay. At the end of treatment period, rats were subjected to acute experiments under anesthesia for determination of renal blood flow (RBF; Transonic flow‐probe) and glomerular filtration rate (GFR; inulin clearance). Compared to vehicle treated group, only the combined therapy group showed a decrease in USV (553±71 vs 248±50 nmol/24hr) and an increase in mean SBP (107±3 vs 130±2 mmHg) with its consequent increase in sodium excretion (4±1 vs 13±3 mmol/24hr). This group with combined therapy also showed a decrease in RBF (7±0.4 vs 4±0.3 mL/min/g) but not appreciably in GFR (1.0±0.1 vs 0.9±0.03 mL/min/g). These data suggest that a decrease in endogenous H2S production exerts direct vascular effect leading to an increase in SBP.

A BRIEF COMMUNICATION

The mechanism of adenosine A1 receptor–induced intrarenal vasoconstriction is unclear; it depends on sodium intake and may be mediated by changing the intrarenal activity of the nitric oxide (NO) and/or cyclooxygenase (COX) pathway of arachidonic acid metabolism. The effects of 2-chloro-N6-cyclopentyl-adenosine (CCPA), a selective A1 receptor agonist, on renal hemodynamics were examined in anesthetized rats maintained on high sodium (HS) or low sodium (LS) diet. Total renal (i.e., cortical) blood flow (RBF) as well as superficial cortical (CBF), outer medullary (OMBF), and inner medullary (IMBF) flows were determined by laser-Doppler. In HS rats, suprarenal aortic infusions of 8–40 nmol/kg/hr CCPA decreased IMBF (15%) and other perfusion indices (22%–27%); in LS rats, IMBF increased 3% (insignificant) and other indices decreased 13%–24%. In LS rats, pretreatment with N-nitro-L-arginine methyl ester prevented the A1 receptor–mediated decrease in RBF and CBF but not OMBF; the response in IMBF was not altered. Pretreatment with indomethacin prevented the decreases in RBF, CBF, and OMBF and did not change the response of IMBF. Thus, within the cortex the vasoconstriction that follows A1 receptor activation results both from inhibition of NO synthesis and from stimulation of vasoconstrictor products of the COX pathway. In the outer medulla, the latter products seem exclusively responsible for CCPA-induced vasoconstriction. The observation that in LS rats IMBF was not affected by stimulation of adenosine A1 receptors suggests that limiting salt intake may help protect medullary perfusion against vasoconstrictor stimuli which have the potential to disturb long-term control of arterial pressure.

Effects of chemical stimulation of the rostral ventrolateral medulla on cerebral and renal microcirculation in spontaneously hypertensive rats

We investigated whether microcirculatory responses elicited by excitation of intrinsic neurons in the rostral ventrolateral medulla (RVLM) are altered in spontaneously hypertensive rats (SHR). SHR and Wistar–Kyoto rats (WKY) were anesthetized with chloralose, paralyzed with tubocurarine, and artificially ventilated. Cerebral and renal blood flows (CBF and RBF) were simultaneously measured using laser-Doppler flowmetry. Chemical stimulation of the RVLM neurons by microinjection of l-glutamate increased arterial pressure (AP) and heart rate in both SHR and WKY. Stimulation of the RVLM neurons also elicited stimulus-locked increase in CBF and decrease in RBF in both groups. The % changes in CBF and RBF were dose-dependent as stimulus intensity was increased and did not differ significantly between the SHR and WKY groups. Cerebral and renal vascular resistance (CVR and RVR) levels were calculated from changes in CBF or RBF and those in mean AP. The percent reduction in CVR and percent elevation in RVR were dose-dependent and did not differ significantly between the two groups. The data indicate that cerebral and systemic microcirculatory responses elicited by excitation of the RVLM neurons do not differ between SHR and WKY.

Effect of 14 years of antihypertensive treatment on renal function and urinary albumin excretion in primary hypertension

The effects on blood pressure (BP), renal function, and urinary albumin excretion (UAE) of 14 years of antihypertensive treatment were studied and compared to the changes seen with normal aging. The studied groups included randomly selected men with newly diagnosed primary hypertension at baseline (n = 23) and normotensive (NT) men of the same age (n = 11). The hypertensives (HT) were treated with β-blockers either as monotherapy or combined with diuretics or hydralazine. Glomerular filtration rate (GFR; inulin clearance), renal blood flow (RBF, para-aminohippurate clearance), renal vascular resistance (RVR), and 24-h UAE were determined. The two groups were investigated at baseline (before treatment) and after 7 and 14 years. At baseline, BP and RVR were significantly increased and RBF was significantly decreased in the HT over that in the NT. The BP in the HT was significantly reduced after 7 years of treatment and a further but nonsignificant reduction to 139 ± 14 88 ± 6 mm Hg (mean ± SD) was seen after 14 years. GFR in the HT was significantly reduced from 103 ± 15 mL/min to 84 ± 19 mL/min (mean ± SD) after 7 years, but no further reduction was seen after 14 years. During the 14 years RBF decreased and RVR increased in the HT but these changes were of the same magnitude as in the NT. The UAE did not change significantly during the study. In conclusion, good blood pressure control with conventional antihypertensive treatment in mild to moderate primary hypertension seems to protect the kidney from progressive decline in GFR and increase in UAE. The increase in RVR and the decrease in RBF seen during 14 years of antihypertensive treatment was of the same magnitude as that seen with normal aging.

Effects of the Cyclooxygenase Inhibitor Ibuprofen on Retinal and Choroidal Blood Flow during Hyperoxia in Newborn Piglets

The effect of the cyclooxygenase inhibitor ibuprofen (IB) on choroidal (ChBF) and retinal (RBF) blood flow during hyperoxia was examined in 21 spontaneously breathing newborn piglets. ChBF and RBF were measured using radiolabelled microspheres before and 30 min after either saline or IB (30 mg/kg, i.v.) infusion in room air and subsequently, after 90 min of hyperoxia (O2). The basal RBF and ChBF did not change after IB infusion. However, during hyperoxia a significant decrease in RBF was observed in the IB group (54 +/- 5 to 37 +/- 3 ml/min/100 g, p < 0.02) and in the control group (54 +/- 3 to 37 +/- 5 ml/min/100 g, p < 0.02). Also, ChBF decreased in the IB group (2,635 +/- 446 to 1,670 +/- 199 ml/min/100 g, p < 0.02) and in the control group, (2,997 +/- 346 to 2,014 +/- 246 ml/min/100 g,p < 0.02) during hyperoxia. Despite cyclooxygenase inhibition with IB, RBF and ChBF decreased to the same extent as in the control group following exposure to O2. These data suggest that hyperoxia decrease RBF and ChBF through mechanisms and/or mediators other than the cyclooxygenase by-products of arachidonic acid metabolism.

Effects of chemical stimulation of the rostral and caudal ventrolateral medulla on cerebral and renal microcirculation in rats

We investigated the effects of neurons in the rostral and caudal ventrolateral medulla (RVL and CVL) on cerebral and renal microcirculation in rats. Rats were anesthetized with chloralose, paralyzed with tubocurarine, and artificially ventilated. Cerebral and renal blood flows (CBF and RBF) were measured simultaneously using laser-Doppler flowmetry. Chemical stimulation of the RVL neurons by microinjection of the excitatory amino acid L-glutamate increased arterial pressure (AP), whereas that of the CVL neurons decreased AP. Stimulation of the RVL neurons also elicited a stimulus-locked increase in CBF and a decrease in RBF. The percent change in CBF and RBF was dose-dependent as stimulus intensity was increased. Cerebral and renal vascular resistance (CVR and RVR) levels were calculated from changes in CBF or RBF and changes in mean AP. The percent reduction in CVR and percent elevation in RVR were also dose-dependent. Chemical stimulation of the CVL neurons elicited a stimulus-locked decrease in CBF and an increase in RBF. The percent reduction in CBF and percent elevation in CVR were dose-dependent. The percent reduction in RVR was also dose-dependent, while the percent elevation in RBF was not significant. Blood withdrawal reduced AP by a similar degree to CVL stimulation, but did not significantly decrease CBF, The results suggest that RVL and CVL neurons integrate cerebral and systemic microcirculation.

Degree of renal artery stenosis alters nitric oxide regulation of renal hemodynamics.

Endothelium-derived nitric oxide (EDNO) maintains RBF in normal kidneys and to the nonclipped kidney of two-kidney, one-clip (2K, 1C) renovascular hypertensive rats. However, in clipped kidneys with severe renal stenosis, EDNO has been reported not to influence RBF, and it was suggested that low perfusion diminishes the stimulus of shear stress for EDNO synthesis. It was hypothesized that lesser degrees of renal artery stenosis would allow greater renal perfusion and, hence, a greater role for EDNO in maintaining RBF in the clipped kidney. The renal response to EDNO synthesis inhibition was studied with 10 mg/kg body wt N omega-nitro-L-arginine methyl ester (L-NAME). Four weeks after clipping, rats had different degrees of (functional) renal artery stenosis as determined by the ratio (R) of RBF (per gram kidney weight) in the nonclipped to clipped kidney. Stenosis was classified as either mild (R < or = 1.25) or moderate (R > or = 1.30). Both groups were similarly hypertensive (146 +/- 3 versus 148 +/- 6 mm Hg, respectively) and responded to L-NAME with a 42 mm Hg rise in blood pressure. In 2K,1C rats with mild renal artery stenosis, the renal response to L-NAME was similar in both nonclipped and clipped kidneys. RBF decreased by 17 to 19% (P < 0.005) and renal vascular resistance (RVR) increased by 59 to 63% (P < 0.005). When renal perfusion pressure was controlled, the decrease in RBF was exaggerated 3.6-fold in the nonclipped but only 2.3-fold in the clipped kidney, whereas the RVR increased proportionally.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasodilating effects of nicorandil and nitroglycerin in anaesthetized open-chest dogs.

Vasodilating effects of intravenous administrations of nicorandil (SG-75) and nitroglycerin were analyzed in anaesthetized open-chest dogs by measuring simultaneously, and continuously, coronary (CBF), vertebral (VBF), renal (RBF) and aortic blood flow (AoF). Nicorandil 10-300 micrograms/kg i.v. and nitroglycerin 1-30 micrograms/kg i.v. decreased aortic blood pressure and increased CBF in a dose-dependent fashion. The doses of nicorandil and nitroglycerin which reduced coronary vascular resistance to about 60% of the predrug value were 100 micrograms/kg and 10 micrograms/kg, respectively. Nicorandil 100 micrograms/kg i.v. significantly increased AoF and heart rate, significantly decreased left ventricular end-diastolic pressure and did not significantly change VBF, RBF and left ventricular dP/dt. Nitroglycerin 10 micrograms/kg i.v. significantly increased VBF and heart rate, significantly decreased left ventricular end-diastolic pressure and produced an initial increase followed by a decrease in AoF and RBF. When compared with these doses of both drugs, the ratio of percent decrease in coronary vascular resistance to that in total peripheral resistance was over 1.0 in both drugs and the value of this ratio in nicorandil was significantly larger than that in nitroglycerin. The duration of increase in CBF produced by nicorandil 10-300 micrograms/kg i.v. was dose-dependent, but was not changed by nitroglycerin 1-30 micrograms/kg i.v. The results indicate that nicorandil and nitroglycerin dilate coronary vasculature more markedly than other vascular beds and that the potency of selective coronary vasodilatation and the duration of action are more significant in nicorandil than in nitroglycerin.

Control of renal hemodynamics and glomerular filtration rate in chronic hypercalcemia. Role of prostaglandins, renin-angiotensin system, and calcium.

The role of prostaglandins (PG), renin-angiotensin system (RAS) and calcium (Ca) in the control of renal hemodynamics and glomerular filtration rate (GFR) in chronic hypercalcemia (serum Ca 12.8 mg%) was studied. Renal blood flow (RBF, 6.39 ml/min per gram kidney weight [gkw]) and GFR (0.52 ml/min per gkw) were significantly decreased in hypercalcemic rats when compared with normocalcemic rats (7.15, P < 0.001 and 0.74, P < 0.05, respectively). These changes in RBF and GFR occurred independent of any significant alterations in systemic hemodynamics, blood and plasma volume. Inhibition of the renal PG with indomethacin resulted in marked decrements in both RBF (6.39-4.12 ml/min per gkw, P < 0.01) and GFR (0.52-0.19 ml/min per gkw, P < 0.01) in hypercalcemic rats, whereas there was no significant alterations in normocalcemic rats. Inhibition of the RAS with captopril resulted in marked increments in both RBF (6.39-7.35 ml/min per gkw, P < 0.05) and GFR (0.52-0.74 ml/min per gkw, P < 0.05) in hypercalcemic rats. In fact, there was no significant difference from the RBF and GFR of similarly treated normocalcemic rats. Similar results were also obtained with the competitive angiotensin II (AII) antagonist (sarcosyl(1)-isoleucyl(5)-glycyl(8)) AII. Since both the renal PG and the RAS are involved in the control of RBF and GFR in hypercalcemia, the role of each is best revealed in the absence of the other. Hence, comparison of the RBF and GFR in the PG-inhibited hypercalcemic rats in the presence of AII (4.12 and 0.19 ml/min per gkw, respectively) and absence of AII (5.99 and 0.53 ml/min per gkw, P < 0.01 for both) reveals the vasoconstrictive role for AII in hypercalcemia. On the other hand, comparison of the RBF and GFR in the AII-inhibited hypercalcemic rats in the presence of PG (7.35 and 0.74 ml/min per gkw, respectively) and absence of PG (5.99 and 0.53 ml/min per gkw, P < 0.01 and P < 0.05, respectively) reveals the vasodilatory role for PG in hypercalcemia. Finally, comparison of the RBF and GFR in both PG- and AII-inhibited hypercalcemic rats (5.99 and 0.53 ml/min per gkw, respectively) with similarly treated normocalcemic rats (7.30 and 0.94 ml/min per gkw, P < 0.001 and P < 0.005, respectively) reveals the vasoconstrictive role for Ca in chronic hypercalcemia. Our study therefore demonstrates that in chronic hypercalcemia the RBF and GFR are controlled by an active interplay of the vasoconstrictive effect of AII, the vasodilatory effect of renal PG, and the direct vasoconstrictive effect of Ca, independent of either AII or PG. The sum total of these forces produces a modest but significant decrease in RBF and GFR.

Factors that alter the plasma renin activity of the marmot.

The effects of low doses of norepinephrine (NE) and furosemide and a volume load (nonhibernators only) on plasma renin activity (PRA), mean arterial pressure (MAP), heart rate (HR), left renal (RBF) and right iliac (IBF) blood flow, cardiac index (CI), and total peripheral resistance (TPR) were determined in euthermic and hibernating marmots. In nonhibernating marmots NE produced an increase in CI and TPR and a decrease in RBF. In hibernators this dose of NE caused an increase in MAP, HR, and renal resistance, whereas it decreased PRA and did not alter iliac resistance. Furosemide infusions led to an increase in PRA in both groups and an increase in TPR in nonhibernators. The volume load in nonhibernators produced only a decrease in PRA. A comparison of control data from the two groups indicated that the renal and iliac beds contribute only a small portion to the increase in TPR that occurs during hibernation.

Factors determining electrolyte excretion and renin secretion after closure of an arteriovenous fistula in the dog.

We studied 12 pentobarbital-anesthetized dogs 8 to 21 days after surgical placement of a femoral AV fistula in order to characterize the renal response to subsequent closure and reopening of the fistula. Closure of the fistula resulted in a significant reduction in cardiac output from 3.3 +/- 0.2 L/min to 2.2 +/- 0.1 (p less than 0.001) and heart rate from 163 +/- 7 beats/min to 150 +/- 7 (p less than 0.005), whereas blood pressure did not change significantly. These changes in systemic hemodynamics were associated with significant increases in GFR, renal vascular resistance, and filtration fraction and a significant decrease in RBF. UNaV (16.4 +/- 3.8 microEq/min to 31.3 +/- 6.5), UKV (27.9 +/- 1.6 microEq/min to 47.5 +/- 3.8), and UHCO3V (6.8 +/- 1.4 mumol/min to 25.0 +/- 2.4) increased significantly (p less than 0.005), whereas UCIV was unchanged. Renal denervation blunted the renal hemodynamic and natriuretic consequences of fistula closure, but other electrolyte excretory responses paralleled those in innervated kidneys. In innervated kidneys RSR fell significantly after fistula closure; RSR was low in denervated kidneys and did not change on fistula closure. Reopening the AV fistula restored systemic hemodynamics toward initial control values but produced no further changes in renal hemodynamics or electrolyte excretion. Overall, an inverse relationship between changes in cation excretion and changes in RSR was observed in innervated kidneys. These results demonstrate involvement of the renal nerves as well as an increase in GFR in the increased cation excretion that occurs after AV fistula closure. However, persistently elevated cation excretion after the reopening of the fistula may be due to other mechanisms.

PROSTAGLANDINS (PG) MODULATING RENAL BLOOD FLOW (RBF) AND PLASMA RENIN ACTIVITY (PRA) DURING FETAL LIFE

The effect of PG synthesis inhibition by indomethacin (I) (5.7 ±0.70 mg/kg fetal wt., i.v. bolus) on RBF and intracortical blood flow distribution was studied in 8 chronically catheterized fetal lambs (117-137 days gestation; term 145 days) using 15μ microspheres. Following I urinary PGE and PGF decreased significantly (p<0.01) from 0.72±0.12 to 0.27±0.04 ng/min and from 0.93±0.16 to 0.36±0.09 ng/min respectively. Fetal blood pressure increased significantly from 40±1 to 45±2 mmHg (p<0.01) and heart rate decreased significantly from 173±5 to 142±6 beats/min (p<0.05). Fetal arterial pH, blood gases, Na+, K+ and Cl− remained within normal limits. A significant decrease in RBF and increase in glomerular filtration rate (GFR), filtration fraction (FF) and renal vascular resistance (RVR) were observed following I.No change in intracortical blood flow distribution was seen following I. PRA decreased significantly from 6.3±1.2 to 3.1±0.7 ng/cc/hr following I (p<0.01). The present results suggest that during fetal life, renal PG's: a) have an important role in maintaining RBF by decreasing efferent arteriolar constriction and b) may modulate renin secretion.

Renal hemodynamics and renal O2 uptake during hypoxia in the anesthetized rabbit.

The effects of hypoxic hypoxia on renal hemodynamics and metabolism have been studied in anaesthetized mechanically ventilated rabbits. Acute hypoxa (FIO2 = 0.10, PaO2 = 35 torr) induces at constant mean arterial pressure a 45% decrease in RBF, GFR, TNa and RVO2 whereas free water clearance increases. These alterations were still apparent 50 min after resuming normal arterial oxygenation. In order to assess the role of the stimulation of catecholamine release in these observations, two other sets of experiments were performed: 1) the animals were ventilated with the same hypoxic gas mixture but after alpha adrenergic blockade (phentolamine: 0.2 mg - kg - min-1 i.v.), 2) hypoxia was induced by ventilating the animals with CO (FICO = 0.002) at constnat PaO2. Increase in renal vascular resistance and reduction of renal O2 uptake were still observed. This indicates that adrenergic stimulation cannot fully explain the renal vasoconstriction encountered in hypoxia. The role of a local vasoactive factor, especially that of the renin angiotensin system is discussed. The apparent O2 cost of Na reabsorption was not greatly modified by any type of hypoxia and the Na: O2 ratio remained close to the value observed in normoxic animals. This indicates that the kidney may adapt to hypoxia by reducing its O2 demand keeping unaltered its tubular function and basal O2 needs.

Relationship of sodium retention produced by catapres to changes in renal hemodynamics.

SummaryCatapres infused directly into a renal artery produces a dose related decrease in RBF and UNaV, along with a dose-related increase in RVR. A high degree of correlation existed between RBF and UNaV. These data indicate that the sodium retention caused by catapres is dependent upon the renal hemodynamic changes induced by this agent. Pre-treatment with phenoxybenzamine did not alter any of the actions of catapres.