Serum acute phase protein concentrations in dogs with autoimmune hemolytic anemia.

BACKGROUND: Serial monitoring of acute phase protein (APP) concentrations in canine autoimmune hemolytic anemia (AIHA) has not been reported. HYPOTHESES: Acute canine AIHA is accompanied by an acute phase response (APR) characterized by increased C-reactive protein (CRP) and alpha1-acid glycoprotein (AAG) concentrations and decreased albumin concentrations. ANIMALS: Twenty-seven dogs with AIHA and 11 control dogs. METHODS: Prospective, cohort study. CRP, AAG, and albumin concentrations, white blood cell (WBC) count, and packed cell volume (PCV) were determined at admission (day 1), every 48 hours until death or discharge, and on days 30, 90, 180, and 365. RESULTS: Compared with controls, CRP and AAG concentrations were increased and albumin concentration was decreased in dogs with AIHA (days 1-7; P < .002) and normalized with disease stabilization (days 9-365; P > .05). APP concentrations on day 1 were not predictive of survival, duration of hospitalization, or number of blood transfusions (P= .153-.940). PCV correlated with APP concentrations over time (CRP r=-.600, AAG r=-.665, albumin r= .533; P < .0001) as did WBC count (CRP r= .253, AAG r= .486, albumin r=-.246; P < .006). Day 1 CRP concentration was lower for dogs that received corticosteroids before referral (115.3 microg/mL) compared with dogs that did not (191.2 microg/mL; P= .02). CONCLUSIONS: An APR occurs in canine AIHA. Initial APP concentrations are not predictive of acute survival, correlate with hematologic markers of remission, and normalize rapidly with disease stabilization.

Modulation of tubuloglomerular feedback by angiotensin II type 1 receptors during the development of Goldblatt hypertension.

It has been suggested that the increased levels of angiotensin II (Ang II) in the contralateral kidney of two-kidney, one clip (2K1C) Goldblatt hypertensive rats act to enhance tubuloglomerular feedback responsiveness and proximal tubular reabsorption and thereby exert a substantial sodium-retaining influence on the nonclipped kidney. The current study investigated the Ang II dependency of tubuloglomerular feedback responsiveness in the nonclipped kidney during the early stages of development of 2K1C hypertension. Stop-flow pressure feedback responses were assessed in the nonclipped kidney of 2K1C rats during control conditions and after systemic administration of the Ang II type 1 receptor antagonist losartan (10 mg/kg). In 1-week clipped and sham-operated rats, losartan administration decreased mean arterial pressure (from 143 +/- 6 to 123 +/- 2 mm Hg, P < .01, and from 129 +/- 2 to 106 +/- 5 mm Hg, P < .01, respectively) and attenuated the magnitude of the maximal feedback responses (from -12.9 +/- 1.2 to -3.0 +/- 0.3 mm Hg, P < .01, and from -13.2 +/- 1.5 to -3.6 +/- 1.1 mm Hg, P < .01, respectively). The decreases in mean arterial pressure were not significantly different in sham-operated and 1-week clipped rats. In 3-week clipped rats, mean arterial pressure was further elevated (163 +/- 6 mm Hg) compared with sham-operated rats (134 +/- 4 mm Hg, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin and angiotensin converting enzyme tissue levels in two-kidney, one clip hypertensive rats.

Renal tissue angiotensin I (Ang I) and II (Ang II) content and angiotensin converting enzyme activity were assessed in both kidneys during initial (7 days) and maintenance (25 days) phases of two-kidney, one clip hypertension in rats. At 7 and 25 days, systolic arterial pressure was 146 +/- 2 and 170 +/- 7 mm Hg, respectively. After 7 days, Ang I content of clipped kidneys was 64% and 70% higher (p < 0.001) than in nonclipped and sham-operated kidneys, respectively, when compared with levels in kidneys from sham-operated rats. In kidneys harvested 25 days after clipping one renal artery, Ang I and Ang II contents in clipped kidneys were increased 102% and 24% (p < 0.01), respectively. Ang II content was also 32% higher in nonclipped kidneys. Angiotensin converting enzyme activity in nonclipped kidneys was greater (p < 0.05) than that in either clipped (46% higher) or sham-operated kidneys (57% higher). Plasma Ang I and Ang II levels were elevated at 7 days but were not different at 25 days in clipped rats. These results demonstrate a dissociation between intrarenal and circulating levels of Ang I and Ang II and suggest that qualitatively different mechanisms may be responsible for the elevated intrarenal Ang II levels during the initial and maintenance phases of renal hypertension.

Proximal tubular angiotensin II levels and renal functional responses to AT1 receptor blockade in nonclipped kidneys of Goldblatt hypertensive rats.

-Previous studies have shown that whereas the nonclipped kidney in two-kidney, one clip (2K1C) rats undergoes marked depletion of renin content and renin mRNA, intrarenal angiotensin II (Ang II) levels are not suppressed; however, the distribution and functional consequences of intrarenal Ang II remain unclear. The present study was performed to assess the plasma, kidney, and proximal tubular fluid levels of Ang II and the renal responses to intrarenal Ang II blockade in the nonclipped kidneys of rats clipped for 3 weeks. The Ang II concentrations in proximal tubular fluid averaged 9.19+/-1.06 pmol/mL, whereas plasma Ang II levels averaged 483+/-55 fmol/mL and kidney Ang II content averaged 650+/-66 fmol/g. Thus, as found in kidneys from normal rats with normal renin levels, proximal tubular fluid concentrations of Ang II are in the nanomolar range. To avoid the confounding effects of decreases in mean arterial pressure (MAP), we administered the nonsurmountable AT1 receptor antagonist candesartan directly into the renal artery of nonclipped kidneys (n=10). The dose of candesartan (0.5 microg) did not significantly decrease MAP in 2K1C rats (152+/-3 versus 148+/-3 mm Hg), but effectively prevented the renal vasoconstriction elicited by an intra-arterial bolus of Ang II (2 ng). Candesartan elicited significant increases in glomerular filtration rate (GFR) (0.65+/-0. 06 to 0.83+/-0.11 mL. min-1. g-1) and renal blood flow (6.3+/-0.7 to 7.3+/-0.9 mL. min-1. g-1), and proportionately greater increases in absolute sodium excretion (0.23+/-0.07 to 1.13+/-0.34 micromol. min-1. g-1) and fractional sodium excretion (0.38+/-0.1% to 1.22+/-0. 35%) in 2K1C hypertensive rats. These results show that proximal tubular fluid concentrations of Ang II are in the nanomolar range and are much higher than can be explained on the basis of plasma levels. Further, the data show that the intratubular levels of Ang II in the nonclipped kidneys of 2K1C rats remain at levels found in kidneys with normal renin content and could be exerting effects to suppress renal hemodynamic and glomerular function and to enhance tubular reabsorption rate.

Synergistic intrarenal actions of angiotensin on tubular reabsorption and renal hemodynamics.

There is a growing awareness that the direct intrarenal actions of angiotensin II (ANG II) on both tubular and vascular structures contribute to sodium conservation. Even very low concentrations of ANG II (10(-1)) mol/L) stimulate proximal reabsorption rate. Recent studies indicate that this stimulatory action is due to an enhanced activity of the sodium/hydrogen exchanger of the luminal membrane. Elevated ANG II levels in the renal interstitium, effected either through increased delivery of ANG II via the circulation or as a consequence of conversion of angiotensin I (ANG I) generated locally, can also enhance proximal reabsorption rate. One consequence of enhanced proximal reabsorption rate is reduced distal volume delivery, which would be expected to elicit arteriolar vasodilation mediated by the tubuloglomerular feedback (TGF) mechanism. It has been observed, however, that peritubular capillary infusions of either ANG I or ANG II, at doses sufficiently low to be without obvious direct effects on glomerular dynamics, can increase the sensitivity of the TGF mechanism. This enhanced TGF sensitivity serves to minimize or prevent TGF mediated increases in glomerular filtration rate in the face of reduced distal delivery. With greater increases in interstitial ANG II concentration, reductions in glomerular pressure have been observed, demonstrating a powerful action on preglomerular arterioles that predominates over the well known effects on efferent arterioles. At these higher doses, the direct hemodynamic actions of ANG II, plus the effects on the glomerular filtration coefficient, will directly reduce filtered sodium load. Through these synergistic effects on both tubular reabsorptive and hemodynamic function, ANG II can elicit sustained decreases in distal nephron sodium delivery which contribute greatly to its efficacy as a regulator of sodium excretion.

Renal responses to AT1 receptor blockade.

Because of the importance of the renin-angiotensin system in the pathophysiology of hypertension and in mediating associated alterations in renal function, angiotensin II (Ang II) AT1 receptor blockers provide a direct means of protecting against influences of excessive Ang II levels. The kidney is an important site of action of Ang II AT1 receptor blockers because intrarenal Ang II not only vasoconstricts the renal vasculature but also reduces sodium excretion and suppresses the pressure natriuresis relationship. Even in normal conditions, intrarenal Ang II content is greater than can be explained on the basis of circulating Ang II and is compartmentalized with proximal tubule concentrations of Ang I and Ang II being several times higher than plasma concentrations. The localization of angiotensinogen in proximal tubule cells further supports the concept that the proximal tubule secretes Ang II or precursors of Ang II into the tubular fluid to activate luminal Ang II receptors. Recent immunohistochemical studies have demonstrated an abundance of AT1 receptors on the luminal surface of proximal and distal tubule cells as well as on vascular smooth muscle cells of afferent and efferent arterioles and on glomerular mesangial cells. Activation of luminal AT1 receptors stimulates the sodium hydrogen exchanger and increases reabsorption rate. The prominence of AT1 receptors in vascular and epithelial tissues in the kidney provides the basis for the powerful effects of AT1 receptor blockers on renal function especially in hypertensive conditions. In the two-kidney, one-clip (2K1C) Goldblatt hypertensive rat model, the nonclipped kidney is renin depleted but the intrarenal Ang II levels are not suppressed and Ang II concentrations in proximal tubular fluid remain high (10(-8) mol/L). AT1 receptor blockers such as candesartan have been shown to cause significant increases in glomerular filtration rate, renal blood flow and proportionately much greater increases in sodium excretion and fractional sodium excretion. Ang II blockade also markedly increases the slope of the pressure natriuresis relationship. The collective actions of Ang II blockers on tubular transport and renal hemodynamics provide long-term effects to regulate sodium balance, which contributes to the long-term control of hypertension.

Effects of calcium antagonists on renal hemodynamics and glomerular function.

Cytosolic [Ca2+] can be increased by influx of the ion from the extracellular compartment, Ca2+ release from intracellular storage sites, and/or a reduced activity of active transport processes for Ca2+ extrusion or sequestration. Organic calcium antagonists block transmembrane calcium entry and, therefore, can be utilized to evaluate the importance of calcium influx in the regulation of renal hemodynamics. Recent studies indicate that calcium antagonists selectively vasodilate preglomerular arterioles, leading to increases in renal blood flow (RBF), glomerular filtration rate (GFR) and glomerular pressure. In contrast with angiotensin converting enzyme inhibitors and other vasodilator agents, calcium antagonists primarily influence the component of renal vascular resistance responsible for autoregulation, potently attenuating autoregulatory efficiency. Calcium antagonists also block the afferent arteriolar vasoconstriction elicited by angiotensin II, while not influencing the efferent arteriolar vasoconstriction evoked by this peptide. Tubuloglomerular feedback (TGF)-mediated vasoconstrictor responses are also abolished by calcium antagonists, indicating that the TGF effector mechanism may require transmembrane calcium influx into the smooth muscle cells of the afferent arterioles. These observations provide compelling evidence that calcium influx, through pathways which are influenced by organic calcium antagonists, is an integral component of the afferent arteriolar vasoconstriction elicited by a variety of stimuli, while efferent arteriolar vasoconstriction appears to depend on other calcium access pathways.

Heterogeneous activation mechanisms in the renal microvasculature.

Vascular smooth muscle cells in different renal microvascular segments utilize different activation mechanisms to respond to mechanical and vasoactive stimuli. L-type Ca2+ channel blockers vasodilate primarily the preglomerular vascular resistance component responsible for autoregulation. Local interstitial infiltration of Ca2+ channel blockers increases glomerular pressure and markedly reduces vascular responsiveness of the tubuloglomerular feedback mechanism. Ca2+ channel blockers selectively attenuate the afferent vasoconstrictor responses to increases in perfusion pressure. Although both afferent and efferent arterioles constrict in response to angiotensin II (Ang II), afferent but not efferent constriction requires Ca2+ influx through L-type Ca2+ channels. Sensitivity of the preglomerular arterioles to Ang II is also heterogeneous with the greatest sensitivity in glomerulus-near, terminal segments. Adenosine triphosphate (ATP) is a vasoconstrictor agonist that selectively activates Ca2+ entry pathways in afferent arterioles but has no effect on efferent arterioles. In isolated preglomerular smooth muscle cells, increasing extracellular [KCl] increases intracellular Ca2+ by stimulating voltage-dependent Ca2+ influx. Ang II, norepinephrine, and ATP also elicit similar increases in intracellular Ca2+. Mechanical and agonist-induced voltage-dependent Ca2+ influx is thus a primary pathway in the control of cytosolic Ca2+ in afferent arterioles. Efferent arterioles, however, rely primarily on intracellular Ca2+ mobilization and other Ca2+ influx pathways.

Role of nNOS in regulation of renal function in hypertensive Ren-2 transgenic rats.

The present study was performed to evaluate the role of neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) during the developmental phase of hypertension in transgenic rats harboring the mouse Ren-2 renin gene (TGR). The first aim of the present study was to examine nNOS mRNA expression in the renal cortex and to assess the renal functional responses to intrarenal nNOS inhibition by S-methyl-L-thiocitrulline (L-SMTC) in heterozygous TGR and in age-matched transgene-negative Hannover Sprague-Dawley rats (HanSD). The second aim was to evaluate the role of the renal sympathetic nerves in mediating the renal functional responses to intrarenal nNOS inhibition. Thus, we also evaluated the effects of intrarenal L-SMTC administration in acutely denervated TGR and HanSD. Expression of nNOS mRNA in the renal cortex was significantly increased in TGR compared with HanSD. Intrarenal administration of L-SMTC decreased the glomerular filtration rate (GFR), renal plasma flow (RPF) and sodium excretion and increased renal vascular resistance (RVR) in HanSD. In contrast, intrarenal inhibition of nNOS by L-SMTC did not alter GFR, RPF or RVR and elicited a marked increase in sodium excretion in TGR. This effect of intrarenal L-SMTC was not observed in acutely denervated TGR. These results suggest that during the developmental phase of hypertension TGR exhibit an impaired renal vascular responsiveness to nNOS derived NO or an impaired ability to release NO by nNOS despite enhanced expression of nNOS mRNA in the renal cortex. In addition, the data indicate that nNOS-derived NO increases tubular sodium reabsorption in TGR and that the renal nerves play an important modulatory role in this process.

Bait ingestion by free-ranging raccoons and nontarget species in an oral rabies vaccine field trial in Florida.

Oral rabies vaccine-laden baits, with a tetracycline biomarker, were distributed in Pinellas County (Florida, USA) by helicopter drop and from cars from January to April 1997. A total of 130,320 baits was distributed throughout the county, yielding an average bait density of 185 baits per km2. Bait ingestion was estimated by microscopic detection of tetracycline in tooth and bone samples from 244 raccoons (Procyon lotor), 33 opossums (Didelphis virginianus), 31 feral cats, and two gray foxes (Urocyon cinereoargenteus) that were trapped during February-April 1997. Active surveillance consisted of 17 trapping sites that were further categorized by six community descriptors. Passive surveillance consisted of animals that were collected as nuisance animals by Pinellas County Animal Services. The proportion of tetracycline positive raccoons was compared between collection techniques, among trapping sites, vegetation communities, and age and sex categories. Since there was no statistically significant difference in the frequency of tetracycline positive raccoons trapped during active surveillance (59%, 110/187) and passive surveillance (53%, 30/57), the data were pooled, resulting in a tetracycline positive frequency of 57% (140/244). The range in the positive tetracycline frequency established for raccoons from the 17 active surveillance sites was 9% (1/11) to 100% (3/3). The tetracycline positive frequency for raccoons ranged from 25% (3/12) at the dumpster sites to 78% (14/18) at the landfills. Juvenile male raccoons (71%, 34/48) were the most commonly marked age and sex class and adult females (42%, 21/50) were the least commonly marked age and sex class. Eighty-five percent (28/33) of the opossums, 3% (1/31) of the feral cats, and 50% (1/2) of the gray foxes were tetracycline positive.

[Distribution of viruses from the Californian encephalitis serogroup (Bunyaviridae, Bunyavirus) in the northern expanses of Russia]. / Rasprostranenie virusov serogruppy Kaliforniiskogo éntsefalita (Bunyaviridae, Bunyavirus) v severnykh shirotakh Rossii.

The study was carried out in 1983-1991 and covered a territory of about 10 x 10(6) km2 in various physico-geographic areas (East Fennoscandia, Northern Russian Plain, West Siberia, Central Siberia, North-Eastern Siberia, and Northern Pacific Region) in the Arctic, Subarctic, Northern-Central-Southern taiga, forest-steppe, and steppe in Northern Russia. A total of 251 strains were isolated from 1391,900 mosquitoes, identified as the California group snowshoe hare (83), Inkoo (44), and Tahyna (2) viruses; 122 strains were not completely identified. Some of the strains with uncommon antigenic composition can be natural reassortants. Fifty-two percent of strains were isolated from Aedes communis and the associate species of mosquitoes, other hosts were A. excrucians (8%), A. cantans (6.25%), A. flavescens (6.25%), A. ciprius (6.25%), A. punctor (4.5%), A. vexans (4.5%), A. cataphylla (3.6%), A. nigripes (3.6%), and A. hexodontus (2.6%). The infection rate of mosquitoes was 0.009% in the tundra, 0.012% in forest-tundra, 0.01% in Northern taiga, 0.02% in Central taiga, 0.017% in Southern taiga, 0.026% in forest-steppe, and 0.097% in steppe. The epidemic season is one month in the tundra (from the beginning of July till the beginning of August), two months in Northern taiga (July-August), and three months in Central taiga (from the second half of June till the beginning of September). The highest infection rate of mosquitoes was observed at the end of the epidemic season in all regions. SSH strains prevailed to the East from the Enisei river, whereas to the West and in the Subarctic regions INK virus predominated, SSH being rare; in the taiga the distribution was quite the opposite. TAH virus was virtually absent. Human morbidity was observed in all territories studied. The immune stratum of adult population is about 30% in the tundra and forest-tundra and about 50% in Northern and Central taiga.

Intrarenal renin-angiotensin system and counteracting protective mechanisms in angiotensin II-dependent hypertension.

It is now well accepted that alterations in kidney function, due either to primary renal disease or to inappropriate hormonal influences on the kidney, are a cardinal characteristic in all forms of hypertension, and lead to a reduced ability of the kidneys to excrete sodium and the consequent development of elevated arterial pressures. However, it is also apparent that many extrarenal factors are important contributors to altered kidney function and hypertension. Central to many hypertensinogenic processes is the inappropriate activation of the renin-angiotensin system (RAS) and its downstream consequences by various pathophysiologic mechanisms. There may also be derangements in arachidonic acid metabolites, endothelium derived factors such as nitric oxide and carbon monoxide, and various paracrine and neural systems that normally interact with or provide a counteracting balance to the actions of the RAS. Thus, when the capacity of the kidneys to maintain sodium balance and extracellular fluid volume within appropriate ranges is compromised, increases in arterial pressure become necessary to re-establish normal balance.

Modulation of tubuloglomerular feedback responsiveness by extracellular ATP.

Experiments were performed in pentobarbital sodium-anesthetized rats to determine the effects of activation of P2 purinoceptors sensitive to ATP on glomerular capillary pressure, as estimated from proximal tubule stop-flow pressure (SFP) measurements, and on the magnitude of maximal tubuloglomerular feedback-mediated reductions in SFP. To selectively expose nephrons in vivo to ATP without influencing arterial blood pressure, we infused ATP directly into the surrounding peritubular capillaries. Peritubular capillary infusion, at a rate of 20 nl/min, of an isotonic saline solution containing 10(-3) M ATP elicited a transient decrease in resting SFP. However, subsequent infusion of 10(-3) M ATP together with the adenosine receptor (P1 purinoceptor) antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (PSPX, 10(-3) M) into the same vascular sites elicited a sustained decrease in resting SFP. Peritubular infusion of the slowly metabolizable ATP analogue, beta,gamma-methylene-ATP (10(-3) M), at a rate of 20 nl/min, also elicited a transient decrease in SFP, but this was not converted to a sustained response by PSPX. The SFP feedback responses to a late proximal perfusion rate of 40 nl/min were markedly attenuated during peritubular infusion of either 10(-3) M ATP (8.7 +/- 1.2 vs. 1.8 +/- 0.9 mmHg; P < 0.01, n = 9) or 10(-3) M beta,gamma-methylene-ATP (8.2 +/- 1.3 vs. 2.2 +/- 1.2 mmHg; P < 0.01, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced tubuloglomerular feedback during peritubular infusions of angiotensins I and II.

Experiments were performed in pentobarbital sodium-anesthetized rats to determine whether increases in intrarenal generation of angiotensin II (ANG II) can enhance the sensitivity of the tubuloglomerular feedback mechanism. Stop-flow pressure (SFP) feedback responses to step increases in late proximal perfusion rate were obtained during control conditions and during simultaneous peritubular capillary infusion of either angiotensin I (ANG I) or ANG II. Infusion of either 10(-7) M ANG II or 10(-5) M ANG I, at rates (18.3 +/- 0.9 and 14.8 +/- 1.5 nl/min, respectively) that did not affect resting SFP, enhanced the magnitude of SFP feedback responses both at a low proximal perfusion rate of 10 nl/min (2.9 +/- 0.9 vs. 0.3 +/- 0.2 and 4.5 +/- 1.0 vs. 0.1 +/- 0.1 mmHg, respectively) and at proximal perfusion rates (greater than 30 nl/min) that elicited a maximal feedback response (13.1 +/- 1.0 vs. 10.1 +/- 0.7 and 13.5 +/- 1.6 vs. 9.8 +/- 0.8 mmHg, respectively). With a higher ANG I infusion rate (20 nl/min), control SFP measured in the absence of distal volume delivery decreased from 39.2 +/- 0.6 to 12.0 +/- 2.8 mmHg (n = 18). These effects were blocked when the ANG II receptor antagonist, saralasin (10(-5) M, Sar), was added to the infusate. In addition, the magnitude of the maximal SFP feedback response was not altered during infusion of Sar alone or ANG I + Sar. These findings indicate that ANG II, either added or formed de novo beyond the glomerular circulation, can enhance the sensitivity of the tubuloglomerular feedback mechanism.

ANG II dependence of tubuloglomerular feedback responsiveness in hypertensive ren-2 transgenic rats.

The present study was performed to determine the angiotensin II (ANG II) dependence of stop-flow pressure (SFP) tubuloglomerular feedback responses in hypertensive transgenic rats [strain name: TGR(mRen2)27] harboring the mouse ren-2 renin gene. SFP feedback responses to increases in late proximal perfusion rate were assessed in pentobarbital-anesthetized male ren-2 transgenic rats during control conditions and after administration of the AT1 receptor antagonist, L-158,809 (1 mg/kg iv). During control conditions, increases in late proximal perfusion rate elicited flow-dependent decreases in SFP. The magnitude of the maximal SFP feedback response to a late proximal perfusion rate of 40 nl/min averaged 16.1 +/- 1.4 mmHg (n = 7), a value higher than that normally observed in normotensive rats. Administration of L-158,809 decreased mean arterial blood pressure (174 +/- 6 vs. 117 +/- mmHg, P < 0.01, n = 10) and attenuated the magnitude of the maximal SFP feedback response by 84 +/- 4% (16.1 +/- 1.4 vs. 2.6 +/- 0.5 mmHg, P < 0.01, n = 7). In contrast, mechanical reduction of renal arterial pressure from 179 +/- 5 to 113 +/- 1 mmHg (P < 0.01, n = 7) attenuated the magnitude of the maximal SFP feedback response by only 43 +/- 5% (14.4 +/- 1.9 vs. 7.9 +/- 0.7 mmHg, P < 0.01, n = 7), indicating that approximately one-half of the attenuation of SFP feed-back responses elicited by AT1 receptor blockade was due to removal of the stimulatory effect of ANG II on the sensitivity of the tubuloglomerular feedback mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Superficial nephron responses to peritubular capillary infusions of angiotensins I and II.

Proximal tubular reabsorption, stop-flow pressure (SFP), and single nephron glomerular filtration rate (SNGFR) were measured in the absence of and during infusion of an isotonic saline solution containing either angiotensin I (ANG I; 10(-6) to 10(-5) M) or angiotensin II (ANG II; 10(-9) to 10(-7) M) into an adjacent peritubular capillary at a rate of 20 nl/min. Dilution of the infused ANG I and ANG II occurred in the peritubular capillary blood and as the peptides diffused into the interstitium. Infusion of either 10(-7) M ANG II or 10(-5) M ANG I increased proximal fractional fluid reabsorption (FRH2O) and decreased both SFP and SNGFR. There were no significant changes in FRH2O or SNGFR during infusion of 10(-5) M ANG I when the converting enzyme inhibitor enalaprilat (MK 422, 10(-3) M) was added to the infusate. Similarly, peritubular infusion at lower concentrations of either ANG II (10(-9) or 10(-8) M) or ANG I (10(-6) M) did not alter FRH2O, SFP, or SNGFR. These data indicate that conversion of ANG I to ANG II can occur in the peritubular capillary or interstitial environment and that increases above the normal endogenous levels in the postglomerular interstitial ANG II concentration can enhance proximal tubular reabsorption and increase preglomerular resistance and thereby reduce SNGFR.

Tubuloglomerular feedback responses during peritubular infusions of calcium channel blockers.

Experiments were performed in pentobarbital-anesthetized rats to evaluate the dependence of the effector limb of the tubuloglomerular feedback mechanism on transmembrane calcium flux through potential-operated calcium channels. Peritubular capillary infusions of the calcium channel blockers, verapamil and nifedipine, were used to achieve high intrarenal levels without influencing arterial blood pressure. Proximal tubule stop-flow pressure (SFP) and single-nephron glomerular filtration rate (SNGFR) tubuloglomerular feedback responses were obtained during control conditions and during simultaneous peritubular capillary infusion with an isotonic saline solution containing either verapamil or nifedipine. Infusion of either 10(-3) M verapamil or 10(-3) M nifedipine, at a rate of 20 nl/min, increased resting SFP (measured during conditions of zero distal volume delivery) and markedly attenuated both the SFP and SNGFR feedback responses to a late proximal perfusion rate of 30 nl/min. Infusion of verapamil (10(-3) M) also increased the slope of the relationship between SFP and renal arterial perfusion pressure between 80 and 120 mmHg (0.43 +/- 0.03 vs 0.24 +/- 0.02, P less than 0.001, n = 10). These findings support the hypothesis that the preglomerular contractile elements responsive to signals from the macula densa cells are activated by calcium influx through potential-operated calcium channels. Furthermore, the preglomerular contractile elements sensitive to calcium channel blockers can dilate further even when orthograde flow to a single macula densa segment is interrupted.