(Hypertension. 1995;25:803-808.)
© 1995 American Heart Association, Inc.
Articles |
Endothelium-Derived Constricting Factor in Renovascular Hypertension
From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.
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Abstract |
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Abstract We have reported that in two-kidney, one clip hypertensive rats, renal perfusion is maintained by a balance between the vasodilator endothelium-derived nitric oxide and the vasoconstrictor angiotensin II. Others have suggested that endothelium-derived constricting factor, reported to be thromboxane A2 and/or endoperoxide, contributes to increased blood pressure in angiotensin II–dependent hypertension. We hypothesized that in angiotensin II–dependent two-kidney, one clip hypertension, endothelium-derived constricting factor contributes to vasoconstriction of the clipped kidney following nitric oxide synthesis inhibition. Using radioactive microspheres, we studied renal blood flow to the stenotic kidney of two-kidney, one clip hypertensive rats 4 weeks after clipping. The influence of nitric oxide on systemic and renal hemodynamics was evaluated by determining the response to nitric oxide synthesis inhibition using 10 mg/kg N
-nitro-L-arginine methyl ester
in these rats, which were either not treated (n=8) or treated (n=8)
with 4 mg/kg of the constricting factor receptor antagonist BMS
180,291. Mean basal blood pressure in rats was 167±9 mm Hg
(mean±SEM). N-Nitro-L-arginine
methyl ester increased blood pressure by 35±7 mm Hg
(P<.001). In the clipped kidney,
N-nitro-L-arginine methyl ester
decreased renal blood flow by 40% (from 4.5±0.9 to 2.7±0.6
mL · min-1 · g kidney-1;
P<.01) and increased renal vascular resistance by 100%
(from 51.9±9.6 to 105.0±19.2
mm Hg · mL-1 · min-1 · g
kidney-1; P<.005). Pretreatment with BMS
180,291 had no effect on basal blood pressure (167±7 mm Hg) or blood
flow to the clipped kidney. However, constricting factor blockade
diminished the pressor response to
N-nitro-L-arginine methyl ester
by 63%, decreasing the response to only 13±4 mm Hg
(P<.02). In rats treated with BMS 180,291,
N-nitro-L-arginine methyl ester
decreased blood flow to the clipped kidney by only 12% (from 5.4±0.6
to 4.7±0.5 mL · min-1 · g kidney-1;
P<.05), while renal vascular resistance increased by only
17% (from 36.7±7.1 to 43.0±7.2
mm Hg · mL-1 · min-1 · g
kidney-1; P<.005). In conclusion, although
blocking endothelium-derived constricting factor in
hypertensive rats affected neither basal blood pressure nor renal blood
flow, it dramatically blunted both the systemic pressor and renal
constrictor responses to inhibition of
endothelium-derived nitric oxide synthesis. These data
suggest a significant regulatory interaction between
endothelium-derived constricting factor and
endothelium-derived nitric oxide in renovascular
hypertension.
Key Words: nitric oxide • hypertension, renovascular • thromboxanes • angiotensin II • renal circulation
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Introduction |
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Two cyclooxygenase products—the intermediate endoperoxide, or prostaglandin H2 (PGH2), and one of its metabolites, thromboxane A2 (TxA2) — have been shown to be vasoconstrictors in the kidney and systemic circulation.1 2 3 4 These vasoconstrictor metabolites of arachidonic acid are produced by both platelets and blood vessels and stimulate vascular contraction by interacting with a common receptor.2 Evidence from different laboratories has implicated both vascular PGH21 and TxA24 as the endothelium-derived constricting factor (EDCF). Vascular generation of this vasoconstricting factor is linked to increases in circulating angiotensin II (Ang II). Infusion of exogenous Ang II results in elevated vascular tissue levels and renal excretion of thromboxane.3 4 5 Mistry and Nasjletti6 demonstrated that the increase in blood pressure (BP) produced by chronic infusion of Ang II in rats was attenuated by administration of an EDCF receptor antagonist, and others have shown that the pressor response to short-term infusion of Ang II was attenuated by pretreatment with either an EDCF receptor antagonist or an inhibitor of thromboxane synthase.7 8 9 Additionally, blocking the EDCF receptor lowered BP in rats with established Ang II–dependent hypertension.3 10 11 In contrast, blocking EDCF had no effect on BP in either normotensive rats or hypertensive rats with normal or depressed plasma renin activity.3 8 9 These findings suggest that the contribution of EDCF to peripheral or renal resistance is correlated with plasma Ang II levels.
The endothelium also produces the potent vasodilator
endothelium-derived nitric oxide (EDNO). Continuous
production of EDNO is regulated by flow-induced shear
stress12 13 and can be stimulated by certain vasoactive
factors such as acetylcholine, bradykinin, and
histamine.14 15 Vasodilator tone imparted by EDNO has been
shown to modulate BP as well as renal vascular resistance
(RVR).16 17 18 19 Inhibition of EDNO synthesis with substrate
analogue antagonists such as
N-nitro-L-arginine methyl ester
(L-NAME) or
NG-monomethyl-L-arginine
has been shown to increase BP, decrease renal blood flow (RBF), and
increase RVR.16 17 18 19 20 21 In addition, it has been demonstrated
that the renal vasoconstriction resulting from inhibition of EDNO
synthesis is mediated by the constrictor influence of Ang II under
various acute or chronic conditions in which Ang II is
elevated.20 21 We have reported that when the
vasoconstrictor influence of Ang II was first inhibited with losartan
(DuP 753, Du Pont), an Ang II subtype 1 (AT1) receptor
antagonist, or by converting-enzyme inhibition, the renal response to
L-NAME was greatly attenuated.20 21 22 Interestingly, in
these studies, which suggest an important regulatory interaction
between EDNO and Ang II in controlling renal perfusion, the systemic
pressor response to EDNO synthesis inhibition was not affected by
blocking of the renin-angiotensin system.
Overall, the literature suggests that EDNO is an important buffer of the vasoconstriction resulting from elevated Ang II. However, the dissociation of renal and systemic pressor responses to inhibition of EDNO synthesis after Ang II blockade suggests that some constricting factor other than Ang II may be influencing these responses. Because elevation of Ang II has been linked to generation of EDCF, we hypothesized that in an Ang II–dependent model of hypertension—two-kidney, one clip (2K1C) renovascular hypertension—EDCF plays an important role in mediating both systemic and renal vasoconstriction and that this constriction is buffered by EDNO synthesis.
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Methods |
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2K1C hypertension was induced as described previously.23 In brief, male Sprague-Dawley rats weighing 180 to 200 g were anesthetized with sodium pentobarbital (Abbott). Under antiseptic conditions, the left renal artery was exposed through a retroperitoneal flank incision and partially occluded by a silver clip with an internal diameter of 0.23 mm. The wound was closed and the rat was allowed to recover for 4 weeks before the experiment.
The day before the experiment, a catheter made from PE-50 tubing with a PE-10 tip (Fisher Scientific) was passed through the right common carotid artery into the left ventricle for infusion of microspheres. Ethyl ether anesthesia and antiseptic technique were used. The position of the catheter tip in the left ventricle was adjusted until the pulse pressure could be read without artifacts. In addition, the right femoral vein was catheterized with PE-50 tubing for drug infusion and blood replacement, while the right femoral artery was catheterized for monitoring BP and obtaining reference blood samples. All catheters were tunneled subcutaneously and brought out at the nape of the neck. After being fasted overnight, rats were isolated in restraining cages for 1 hour, during which time BP was monitored with a Statham pressure transducer (Viggo-Spectramed) connected to a Gould chart recorder.
The effect of EDNO synthesis inhibition on RBF, RVR, cardiac output (CO), and total peripheral resistance (TPR) was measured with the use of radioactive microspheres (Du Pont–New England Nuclear) with a diameter of 15±1.5 µm, labeled with either Ce141 or Sr85 and suspended in 3.5 mol/L glucose with 0.01% Tween-80 as an antiaggregant. Changes in response to inhibition of EDNO synthesis were evaluated by intravenous administration of a 10 mg/kg dose of L-NAME (Sigma Chemical Co). Hemodynamic responses to L-NAME were used to reflect the contribution of EDNO in maintaining these parameters. We have previously documented that this dose inhibits both systemic and renal EDNO synthesis.17
Microspheres at a concentration of 400 000/mL were ultrasonically agitated for approximately 15 minutes. A volume of 0.2 mL of the suspension, containing about 80 000 microspheres, was drawn into a syringe, counted to obtain the preinjection dose, and infused into the left ventricle with 0.2 mL saline over 20 seconds, and a reference arterial blood sample was withdrawn simultaneously at a rate of 0.48 mL/min for 75 seconds. The withdrawn blood was replaced with heparinized blood from a donor rat nephrectomized 16 to 24 hours earlier. The empty injection syringe was counted to obtain the postinjection activity, and the injection dose was calculated by subtracting preinjection from postinjection counts. To determine the effect of inhibition of EDNO synthesis on renal hemodynamics, microspheres were injected again 15 minutes after EDNO synthesis was inhibited with L-NAME. Five minutes after injection of the microspheres, the animals were killed with an intravenous overdose of sodium pentobarbital (150 mg/kg), and the kidneys were removed, weighed, and counted in a Packard gamma counter with a dual window setting of 10 to 250 and 400 to 700 MeV at a sample level of 0.5 cm.
RBF (in mL/min, corrected by kidney weight), RVR (in mm Hg · mL-1 · min-1 · g kidney-1 [hereafter referred to as resistance units, or RURVR]), CO (in mL · min-1 · 100 g-1), and TPR (in mm Hg · mL-1 · min-1 · 100 g-1 [RUTPR]) were determined as follows: (1) RBF=(cpm organxpump speed)/(cpm bloodxg kidney); (2) RVR=mean BP/RBF; (3) CO=(cpm injectedxpump speed)/(cpm blood per 100 g body weight); and (4) TPR=mean BP/CO. All results are expressed as mean±SEM for each group of rats.
Data were evaluated by two analytical methods. To assess the influence of inhibition of EDNO synthesis, Student's paired t test was run on the changes induced by L-NAME. Comparisons among the three experimental groups were analyzed by ANOVA, with the P value adjusted for multiple comparisons by the Bonferroni method. A P (or adjusted P) value of <.05 was considered significant. All protocols were approved by our institutional animal care review committee. The three experiments are described below.
Effect of EDNO Synthesis Inhibition on Systemic and Renal
Hemodynamics in 2K1C Hypertensive Rats
Four weeks after clipping, eight 2K1C hypertensive rats were
prepared as described above. Conscious restrained rats were allowed a
60-minute equilibration period, during which BP was recorded. Baseline
values were then obtained by injection of the first set of
microspheres. To determine the influence of EDNO synthesis inhibition
on systemic and renal hemodynamics, rats were treated with L-NAME.
Fifteen minutes later, after BP had stabilized at its new level, the
second set of microspheres was administered.
Effect of EDNO Synthesis Inhibition on Systemic and Renal
Hemodynamics in 2K1C Hypertensive Rats After Ang II Blockade
Four weeks after clipping, seven 2K1C hypertensive rats
were prepared as described above. Conscious restrained rats were
allowed a 30-minute equilibration period, during which BP stabilized
and was recorded. The rats received 10 mg/kg of the nonagonistic Ang II
receptor antagonist losartan,24 and BP was again
stabilized and recorded over 30 minutes. Baseline values were obtained
by injection of the first set of microspheres. Rats were then
administered L-NAME, which was followed 15 minutes later by the second
set of microspheres for determination of the effect of EDNO synthesis
inhibition on systemic and renal hemodynamics after losartan
administration.
Effect of EDNO Synthesis Inhibition on Systemic and Renal
Hemodynamics in 2K1C Hypertensive Rats After Blocking of the
TxA2/PGH2 Receptor
Four weeks after clipping, eight 2K1C hypertensive rats were
prepared as described above. Conscious restrained rats were allowed a
30-minute equilibration period, during which BP was recorded. The rats
then received 4 mg/kg BMS 180,291 (Bristol-Myers Squibb), a selective
blocker of the TxA2/PGH2
receptor,25 and BP was again recorded over 30 minutes.
Baseline values were obtained by injection of the first set of
microspheres. The effect of EDNO synthesis inhibition on systemic and
renal hemodynamics after BMS 180,291 administration was determined by
treating the rats with L-NAME and injecting the second set of
microspheres 15 minutes later.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effect of EDNO Synthesis Inhibition on Systemic and Renal Hemodynamics in 2K1C Hypertensive Rats
Basal BP of the 2K1C hypertensive rats was 167±9 mm Hg; CO was 30.7±2.6 mL · min-1 · 100 g-1; and TPR was 5.8±0.6 RUTPR. The changes in BP, CO, and TPR are shown in Fig 1. L-NAME significantly increased BP by 35±3 mm Hg (P<.001), decreased CO by 54% (to 14.2±0.9 mL · min-1 · 100 g-1; P<.001) and increased TPR by 155% (to 14.8±1.2 RUTPR; P<.001).
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Nonclipped kidneys weighed 1.95±0.12 g. Corrected basal RBF was 4.15±0.56 mL · min-1 · g kidney-1 and RVR was 46.9±7.4 RURVR. The weight of the clipped kidneys was 1.23±0.10 g; RBF was 4.45±0.87 mL · min-1 · g kidney-1; and RVR was 51.9±9.6 RURVR. Changes in RBF and RVR in response to L-NAME are shown in Fig 2. In the nonclipped kidney, L-NAME decreased RBF by 40% (P<.001) and increased RVR by 112% (P<.005). Similarly, in the clipped kidney, L-NAME decreased RBF by 39% (P<.01) and increased RVR by 102% (P<.005).
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Effect of EDNO Synthesis Inhibition on Systemic and Renal
Hemodynamics in 2K1C Hypertensive Rats After Ang II Blockade
Basal BP of the 2K1C hypertensive rats was 154±4 mm Hg.
Treatment with losartan decreased BP to 119±6 mm Hg
(P<.005). After losartan, CO was 32.3±1.5
mL · min-1 · 100 g-1 and TPR was
3.8±0.2 RUTPR. The systemic changes induced by L-NAME in
losartan-treated rats are shown in Fig 1. L-NAME significantly
increased BP by 43±5 mm Hg (P<.001), decreased CO by 28%
(to 23.2±1.2 mL · min-1 · 100 g-1;
P<.001) and increased TPR by 89% (to 7.2±0.4
RUTPR; P<.001). Although the pressor response
to L-NAME was no different from that in the untreated rats, changes in
CO and TPR with L-NAME were significantly less than in the absence of
losartan (P<.05).
The nonclipped kidneys weighed 2.18±0.09 g. After losartan treatment, corrected basal RBF was 5.55±0.27 mL · min-1 · g kidney-1, which was no different from that in untreated 2K1C rats. Losartan decreased RVR in the nonclipped kidney by 50% (to 20.0±0.9 RURVR, P<.01). The clipped kidneys weighed 1.50±0.04 g. Losartan tended to decrease basal RBF (3.42±0.45 mL · min-1 · g kidney-1), but this was not significant compared with untreated controls. Basal RVR was not significantly different from that in untreated rats (42.8±8.4 RURVR).
Changes in RBF and RVR induced by L-NAME in losartan-treated rats are shown in Fig 2. In the nonclipped kidney, L-NAME decreased RBF by only 10% (P<.001) and increased RVR by only 55% (P<.005). Both of these changes were significantly attenuated compared with the changes induced by L-NAME in untreated rats (P<.05). In the clipped kidney, L-NAME caused a paradoxical 58% increase in RBF (P<.005) with no change in RVR. Each of these responses to L-NAME was significantly different from that in untreated rats (P<.05).
Effect of EDNO Synthesis Inhibition on Systemic and Renal
Hemodynamics in 2K1C Hypertensive Rats After Blocking of the
TxA2/PGH2 Receptor
Basal BP of the 2K1C hypertensive rats was 167±7 mm Hg.
Treatment with BMS 180,291 had no effect on BP. After administration of
BMS 180,291, CO was 36.7±3.9 mL · min-1 · 100
g-1 and TPR was 5.1±0.7 RUTPR. The systemic
changes induced by L-NAME in BMS 180,291–treated rats are shown in Fig 3. L-NAME increased BP by only 13±4 mm Hg
(P<.02), only one third of the pressor response seen in
untreated or losartan-treated 2K1C rats. L-NAME decreased CO by 49%
(to 18.6±1.9 mL · min-1 · 100 g-1;
P<.001) and increased TPR by 107% (to 10.6±1.2
RUTPR; P<.005).
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Nonclipped kidneys weighed 2.40±0.16 g; corrected basal RBF after BMS 180,291 administration was 4.75±0.49 mL · min-1 · g kidney-1 and RVR was 38.2±4.2 RURVR, similar to values in untreated controls. Clipped kidneys weighed 1.52±0.04 g, RBF was 5.36±0.62 mL · min-1 · g kidney-1, and RVR was 36.7±7.1 RURVR; the latter two values were not different from those in clipped kidneys of untreated rats.
Changes in RBF and RVR induced by L-NAME in BMS 180,291–treated rats are shown in Fig 4. In the nonclipped kidney, L-NAME decreased RBF by only 24% (P<.001) and increased RVR by only 54% (P<.005), less than half the changes seen in untreated rats (P<.05). In the clipped kidney, L-NAME decreased RBF by only 11% (P<.001) and increased RVR by only 17% (P<.005), changes only a fraction of the corresponding ones in clipped kidneys of untreated rats (P<.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Acute or chronic elevation of circulating Ang II has been linked to generation of EDCF, proposed to be PGH21 and/or TxA2,4 from the vascular endothelium. Induction of EDCF results in peripheral and renal vasoconstriction supplemental to the specific effect of Ang II.6 7 8 9 It has been shown that nitric oxide, also of endothelial origin, is an important buffer to the renal vasoconstriction resulting from elevated Ang II.20 26 Because Ang II–induced vasoconstriction is buffered by EDNO, and increased Ang II also provokes EDCF synthesis, we hypothesized that in Ang II–dependent 2K1C renovascular hypertension, EDCF should play a significant role in mediating both systemic and renal vasoconstriction and that this constriction would be buffered by the dilator action of EDNO.
We observed a dissimilarity in the depressor effect of Ang II blockade compared with EDCF blockade. Ang II blockade with losartan resulted in an immediate 40 mm Hg hypotensive response, whereas EDCF blockade with BMS 180,291 did not alter BP. Previous reports have suggested that blocking EDCF lowers BP in models of established Ang II–dependent hypertension,3 10 11 but not in normotensive rats or rats with Ang II–independent hypertension.8 9 10 However, the antihypertensive effect of EDCF blockade is reported to be much slower (often hours) than the immediate response seen with Ang II blockade. Our study lasted only some 30 minutes after drug administration, which may account for the disparity with previous reports. However, the observation that losartan immediately and dramatically lowers BP supports the predominant role of Ang II in its synergistic constrictor relationship with EDCF in maintaining this form of hypertension.
Despite the reduction in basal BP after losartan, the systemic pressor response to L-NAME was similar to that seen in untreated hypertensive rats. However, losartan greatly diminished L-NAME–induced renal vasoconstriction. This divergence of systemic and renal responses to EDNO synthesis inhibition after Ang II blockade has previously been reported in normotensive21 26 and hypertensive rats.22 These data contrast with our results in BMS 180,291–treated rats, in which the systemic pressor response to L-NAME was attenuated to merely a third of that observed in untreated or losartan-treated rats. This disparity in systemic pressor responses suggests that the increase in BP observed after L-NAME treatment reflects a dominance in the balance between EDNO and EDCF rather than between EDNO and Ang II in maintaining BP. This is particularly interesting because basal BP was not reduced by EDCF blockade. In each treatment group, the rise in TPR was blunted; moreover, losartan attenuated the fall in CO whereas BMS 180,291 did not. On the basis of how Ang II, EDNO, and EDCF influence peripheral resistance beds, there is a possibility, although it is not directly addressed in these studies, that an Ang II–EDNO interaction predominates over EDCF in influencing cardiac function in these hypertensive rats, whereas the EDCF-EDNO interaction may be more important in maintaining BP.
It has been reported that the renal circulation is more responsive to EDCF than is the systemic circulation.3 4 We found that renal hemodynamic responses to L-NAME after either Ang II or EDCF blockade were essentially the same in the nonclipped contralateral kidneys. The increase in RVR was reduced by 50% with either treatment. It has been reported that EDCF blockade blunts the renal vasoconstriction and decrease in glomerular filtration rate produced by intrarenal infusion of Ang II.5 7 Infusion of Ang II also increases vascular and excreted thromboxane.3 4 5 In the contralateral kidney, in which circulating but not renal Ang II is presumably elevated,27 our results seem to mirror the response of normal kidneys to Ang II infusion.5 Additionally, our data suggest that EDNO counteracts the constrictor influence of both Ang II and EDCF. In the clipped kidney, in which both circulating and intrarenal Ang II would be expected to be high,27 blockade of either Ang II or EDCF almost completely eliminated the hemodynamic responses to L-NAME. The difference between the renal hemodynamic responses to L-NAME in losartan-treated compared with BMS 180,291–treated rats is due to the different systemic pressor responses and consequently to the different changes in renal perfusion pressure. This would suggest that the vasoconstriction balanced by EDNO is Ang II induced but largely EDCF mediated, as has been proposed and studied using models of artificially increased Ang II.3 4
In summary, we observed different systemic pressor responses in Ang II–dependent 2K1C hypertensive rats when Ang II and EDCF blockade were compared. Although elevated Ang II has been targeted as the predisposing signal for the systemic influence of EDCF, both vasoconstrictors seem to contribute synergistically to the increase in resistance. Furthermore, both are buffered by the counteracting vasodilator influence of EDNO. In both nonclipped and stenotic kidneys, renal perfusion is maintained by a balance between these constrictor influences and EDNO, and these effects are somewhat exaggerated in clipped kidneys, in which Ang II should be more abundant.27 Importantly, our studies suggest that there is no predisposing deficiency in EDNO in this model of hypertension, but rather that EDNO serves as an important counterregulatory buffer, retarding hypertension and maintaining renal perfusion in the presence of elevated Ang II and the subsequent additional constrictor influence of EDCF.
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Acknowledgments |
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These studies were supported in part by a Grant-in-Aid from the American Heart Association, Michigan Affiliate, and in part by grant HL-28982-11 from the National Institutes of Health. We would like to thank Du Pont for supplying us with the Ang II receptor blocker losartan (DuP 753), produced by Du Pont Pharm/Merck Sharp & Dohme. We would also like to thank Dr Martin L. Ogletree of Bristol-Myers Squibb for his suggestions and for supplying us with BMS 180,291.
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Footnotes |
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Reprint requests to Dr David H. Sigmon, Hypertension and Vascular Research Div, 7121 E & R Blvd, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202.
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