(Hypertension. 1997;30:672.)
© 1997 American Heart Association, Inc.
Articles |
Abnormal Endothelium-Dependent Responses in Early Radiation Nephropathy
From Instituto Privado de Especialidades Médicas, Córdoba, Argentina (L.I.J., J.C.C., J.G., S.B.), and the Department of Nephrology, Mayo Clinic, Rochester, Minn (L.A.J.).
Correspondence to Luis I. Juncos, MD, Instituto Privado de Especialidades Médicas, Colón 4154, Córdoba, Argentina 5003.
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Abstract |
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Abstract While arterial hypertension and renal dysfunction are well recognized complications of renal irradiation, the mechanisms that trigger the development of these complications are unknown. Recently, it was reported that the endothelium is a major target in radiation injury. Because dysfunction of the endothelial cells may lead or contribute to the development of hypertension and renal dysfunction in radiation nephropathy, we tested the hypothesis that endothelium-dependent vasodilation is impaired in radiated kidneys prior to the onset of hypertension. To test this hypothesis, we used Long-Evans rats that had undergone left nephrectomy (3 weeks earlier) and irradiation (3000 r’s) to the right kidney 8 days earlier (mean blood pressures in the irradiated rats were not different than in the controls). We then measured the changes in renal blood flow (RBF) induced by endothelium-dependent (acetylcholine and bradykinin) and -independent (nitroprusside, norepinephrine, and angiotensin II) vasoactive agents. We found that the increases in RBF induced by the endothelium-dependent but not independent vasodilators were markedly impaired in the irradiated kidneys. Blocking nitric oxide synthesis with nitro L-arginine methyl ester in sham rats mimicked the blunted responsiveness of the irradiated rats, whereas indomethacin (an inhibitor of prostaglandin synthesis) had no effect on either sham or irradiated rats. Finally, the RBF responses to the endothelium-independent vasoconstrictors, norepinephrine and angiotensin II, were not altered in the irradiated kidneys. These results suggest that renal irradiation causes endothelial dysfunction (prior to the onset of hypertension) but spares the vascular smooth muscle cells.
Key Words: nitric oxide • radiation nephritis • renal blood flow • endothelium • endothelium-dependent relaxation
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Introduction |
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Total-body irradiation for bone marrow transplantation has spawned a renewed interest in radiation nephropathy.1 2 3 4 This condition is characterized by azotemia and high blood pressure. For years, investigators have assumed that the radiation to the kidneys caused renal dysfunction that in turn would lead to hypertension. However, hypertension may precede the fall in glomerular filtration rate by weeks or months,5 6 making it unlikely for renal failure to be the sole cause of the hypertension. Despite this discrepancy, most studies have focused almost exclusively on renal failure. Consequently, little is known about other potential mechanisms that may lead to hypertension in this model. Furthermore, previous investigations have studied the established phase of hypertension7 8 that is weeks or months after the radiation injury; thus, the early events bringing about the rise in blood pressure remain poorly understood.
The search for these early mechanisms is made difficult by the undiscriminating nature of the actinic injury. Indeed, every renal structure is affected9 10 and thus could contribute to the development of hypertension. More recently, there have been several reports suggesting both morphological11 12 and functional13 14 alterations in the endothelium following renal irradiation. Thus, it is possible that radiation damage to the endothelium could shift the normal balance between endothelial vasoconstrictors (which also stimulate proliferation) and vasodilators (which inhibit proliferation) to favor the vasoconstrictors. If so, this could lead to increased peripheral vascular resistance (and hypertension) and proliferative lesions of the affected areas. Interestingly, radiation nephropathy is characterized by increased peripheral vascular resistance (with hypertension) and marked proliferation of vascular and glomerular mesangial cells. Hence, it is tempting to speculate that endothelial damage may be a primary event in radiation nephropathy subsequently leading to alterations in glomerular hemodynamics, hypertension, and progressive nephron loss. Thus, we felt it important to investigate whether endothelial dysfunction is present in early radiation nephropathy.
In the present study, we tested the hypothesis that radiation to the kidney impairs endothelium-dependent vasodilatation of the renal vessels in vivo. Because hypertension by itself can cause endothelial responses, we studied renal vascular responses to endothelium-dependent vasodilators early in the course of radiation nephropathy (prior to the onset of hypertension). The results show that radiation injury to the kidney causes impaired endothelium- dependent vasodilation but spares the direct vascular smooth muscle (VSM) responses to nitroprusside, angiotensin II, and norepinephrine.
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Methods |
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Animal Preparation
The protocol for exposure to radiation was identical to that previously described.15 The procedures followed were in accordance with our institutional guidelines. Briefly, a total of 98 Long-Evans rats underwent right nephrectomy. Three weeks later, we weighed the rats and measured their systolic blood pressure by the tail-cuff method (Narco BioSystem). In addition, we collected 24-hour urine specimens and obtained blood samples from the severed tails of the rats for measurements of serum creatinine, sodium and potassium excretion rates, and creatinine clearance. Then, the rats were anesthetized with sodium pentobarbital (50 mg/kg IP); the left kidney was drawn through a flank incision, the capsule stripped, and the corresponding adrenal gland dissected apart. In 47 rats, the remnant kidney was irradiated utilizing an x-ray generator (style 592-SN113, Pickers x-ray Corp) at approximately 200 rads/min at the TSD of 15 cm. The total dose was 3000 rads. The remaining 51 rats underwent a sham procedure instead of radiation. Throughout the experiment the rats ate a standard laboratory chow containing 0.46% sodium and 0.72% potassium and tap water ad libitum.
On the 8th day after the radiation or sham procedure, we measured the systolic blood pressure. Then, under pentobarbital anesthesia, we placed a catheter in the femoral artery for continuous assessment of mean blood pressure (MBP; Narco BioSystem). Through a midabdominal incision an electromagnetic flowmeter probe was positioned around the renal artery to measure renal blood flow (RBF; model T106, Transsonic Systems). Both RBF and MBP were measured constantly throughout the experiments. In a retrograde fashion, we placed a perfusion needle through the abdominal aorta up into the renal artery, being careful not to disturb RBF according to previous readings. We then allowed the rats to stabilize until their RBF and MBP measurements had been stable for at least 30 minutes before any infusions were made. Once the stabilization period was complete we used the perfusion needle to inject increasing doses (10-8 through 10-5 mol/L) of acetylcholine, bradykinin, sodium nitroprusside, angiotensin II, or norepinephrine into the renal artery as we continued to measure both RBF and MBP. Each dose of each drug was injected 3 times, allowing 20 minutes between doses. The changes observed were averaged and the results presented as percentage in dose-response curves.
Because we observed altered endothelium-dependent renal vascular responses in the radiated rats (see "Results"), we ran separate experiments in which we evaluated the role of nitric oxide and prostaglandins in the altered responses of radiation nephropathy. For this, we pretreated rats with either L-NAME (an inhibitor of nitric oxide synthase) or indomethacin (a cyclooxygenase inhibitor) and then obtained dose-response curves to intrarenal acetylcholine infusions in the same manner as described above. L-NAME (1 µg · 100 g body weight-1 · min-1) was given as an intravenous infusion started 1 hour prior to the onset of the experiments and continued throughout the entire experiment. Indomethacin was given IP at a dose of 5 mg/100 g body weight, 24 hours ahead of the procedure. These doses of L-NAME and indomethacin have been shown to inhibit endothelium-dependent vasodilation and renal synthesis of prostaglandins, respectively.
Acetylcholine, bradykinin, sodium nitroprusside, angiotensin II, norepinephrine, L-NAME, and indomethacin were all obtained from Sigma Chemical Co and prepared immediately prior to being used. The changes observed were averaged and the results are presented as percentage in dose-response curves.
Data Analysis
The drug-induced changes in RBF and MBP are expressed as percent
changes. Data are reported as mean±SE. In each set of experiments, n
equals the number of rats studied.
Statistical Analysis
When comparing differences between means within groups, we
assumed that the SDs could be different. Thus, we performed a
Kruskal-Wallis nonparametric ANOVA test followed by Dunn’s
multiple comparisons test if the calculated value of P was
<.05. To compare pairs of experiments, again we did not assume equal
SDs and used the more conservative alternate (Welch) t test.
Systolic blood pressure before and after radiation were
analyzed by Student’s paired t test. Means were
considered significantly different in all cases at a value of
P<.05.
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Results |
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Baseline Data
Mean body weight, baseline renal blood flow, and creatinine clearance (Table), as well as urinary excretion of sodium and potassium (data not shown), were not different in any of the groups. Systolic blood pressure was normal in all groups before the study (82.7±0.7 mm Hg) and remained unchanged throughout the entire span of the study (82.5±0.8 mm Hg).
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Endothelium-Dependent Responses
To assess endothelium-dependent relaxation, we
studied the RBF changes induced by intrarenal infusion of 2 distinct
endothelium-dependent vasodilators, acetylcholine and
bradykinin, in radiated and sham-radiated rats. Acetylcholine evoked
dose-dependent increments in RBF in both radiated (P<.0001,
n=8) and sham control rats (P<.0001, n=8). However, these
increments were markedly reduced in the radiated kidneys by 89%
(P<.0005), 80% (P<.0001), 75%
(P<.0001), and 49% (P<.05) for the
10-8, 10-7,
10-6, and 105 mol/L doses,
respectively (Fig 1, left). Likewise,
bradykinin also evoked dose-dependent increases in RBF in sham control
rats (P<.005, n=6) that were completely inhibited in
radiated rats (n=6). Compared with controls, the increments in RBF in
radiated rats were reduced by 88% (P<.005), 90%
(P<.05), 93% (P<.01), and 94%
(P<.01) for the 10-8,
10-7, 10-6, and
105 mol/L doses, respectively (Fig 1, right).
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Mean blood pressure was unchanged by 10-8 to 10-6 mol/L of either acetylcholine or bradykinin. At 10-5 mol/L, acetylcholine decreased MBP by 9% in controls (P=.05) and by 12% in radiated rats (P<.05). Bradykinin, at the same 10-5 mol/L dose, decreased MBP by 9% (P<.05) in control rats and by 3% (P<.05) in radiated rats. The MBP changes took place long after the changes in RBF had occurred (65±1.8 seconds for acetylcholine-control, 48±1.3 seconds for acetylcholine-radiated, 76±4.0 seconds for bradykinin-control, and 75±1.5 seconds for bradykinin-radiated, all after the infusion). Thus, the RBF responses to acetylcholine and bradykinin are not secondary to the changes in MBP.
Endothelium-Independent Responses
Because radiation-induced injury to the VSM could possibly also
account for the altered responses seen above, we assessed whether
responses to sodium nitroprusside (an
endothelium-independent vasodilator) as well as
angiotensin II and norepinephrine
(endothelium-independent vasoconstrictors) were
preserved. As seen in Fig 2, sodium
nitroprusside caused dose-dependent rises in RBF that were very similar
in both the radiated (n=8) and sham control rats (n=7). Again, MBP
remained stable in both groups at all doses of sodium nitroprusside
except at 10-5 mol/L, which caused MBP
to fall by 23% in control rats (P<.01) and by 25% in
radiated rats (P<.05). Again, however, the changes occurred
82±2.5 seconds and 74±4.8 seconds postinfusion, respectively, over 60
seconds after the effect on RBF had taken place.
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Fig 3 shows the responses to angiotensin II (left) and norepinephrine (right). Both angiotensin II and norepinephrine evoked dose-dependent reductions in RBF that were essentially the same in the radiated (n=6 and n=11, respectively) and the sham control rats (n=6 and n=8, respectively). As with the other vasoactive agents, MBP changed at the highest 10-5 dose of angiotensin II, rising by 15% in control rats (P<.05) and 23% in radiated rats (P<.001). On the other hand, norepinephrine at 10-5 mol/L tended to increase MBP in control rats (6%, P=NS) and increased MBP by 21% in radiated rats (P<.05), thus confirming that RBF responses to angiotensin II and norepinephrine are not due to changes in MBP.
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Effect of L-NAME on Acetylcholine-Induced Vasodilation
We next tested whether (1) L-NAME treatment mimics radiation with
regards to acetylcholine-induced responses and (2) whether there is an
additive effect between L-NAME and radiation in blunting
acetylcholine-induced responses. As expected, L-NAME markedly blunted
acetylcholine-induced vasodilation in the sham rats (n=6; Fig 4, left), so that it resembled that of the
untreated radiated rats. However, L-NAME seemed to enhance the negative
effects of radiation (n=6) on the acetylcholine response (although the
differences did not reach statistical significance). Of note, L-NAME
caused similar drops in renal blood flow in both radiated
(P<.05) and in sham control rats (P<.05),
despite similar significant rises in MBP (P<.05).
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Effect of Indomethacin on
Acetylcholine-Induced Vasodilatation
Finally, since it is also possible that the abnormal
endothelial responses might result from either
diminished effects of vasodilating prostaglandins or an
increase in vasoconstricting prostaglandins, we tested
whether inhibiting prostaglandin production with
indomethacin blunts (or restores) acetylcholine-induced
increases in RBF in the sham and radiated rats, respectively. The right
panel of Fig 4 shows the dose-response curves to acetylcholine in
indomethacin-treated rats. Contrasting the
inhibitory effects of L-NAME, indomethacin
did not affect the RBF response to acetylcholine in either the radiated
(n=6) or the sham controls (n=6).
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Discussion |
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Radiation nephropathy is characterized by hypertension, progressive renal dysfunction, and proliferative lesions of the affected vasculature and glomerular mesangium. The presence of these lesions has been well established, but the mechanisms leading or contributing to their progression are not known. One such mechanism may be endothelial dysfunction. Thus, in the present study we investigated whether endothelium-dependent vasodilation is altered very early in the course of the disease. We found that radiation to the kidneys impaired endothelium-dependent vasodilation while sparing VSM function. The diminished endothelium-dependent responses resemble that observed with inhibitors of nitric oxide and were independent of cyclooxygenase products.
Our studies show that radiated kidneys respond poorly to the endothelium-dependent vasodilators acetylcholine and bradykinin, but respond normally to the endothelium-independent vasodilator nitroprusside. These findings strongly suggest that early in the course of radiation nephropathy, endothelial function is selectively impaired. This early vasomotor dysfunction has not been reported. However, earlier histologic studies have shown radiation-induced endothelial cell damage11 and abnormal endothelium-leukocyte interactions in irradiated kidneys,16 albeit in a much later stage.
This endothelial dysfunction, as suggested by the poor response to acetylcholine and bradykinin, could be explained through a receptor defect or decreased nitric oxide activity (eg, decreased synthesis or increased metabolism). Indeed, the response in the radiated kidneys closely resembled the response of L-NAME-treated-sham-radiated rats. While our study does not present direct evidence for a nitric oxide defect, it is intriguing to note that L-NAME treatment tended to mimic radiation injury with regards to its effect on acetylcholine- and bradykinin-induced changes in RBF. On the other hand, L-NAME significantly decreased the basal RBF, whereas radiation did not. Despite this apparent discrepancy between L-NAME and radiation, these findings are consistent with other reports showing L-NAME caused vasoconstriction, whereas various deendothelialization maneuvers did not.17 18 The reason why L-NAME decreases endothelium-dependent relaxation and increases basal tone, while early radiation nephropathy (or the other methods that cause endothelial damage) only alter endothelium-dependent relaxation is unclear. However, it may be that endothelial damage eliminates both dilating and constricting factors derived from the endothelium, whereas L-NAME only eliminates nitric oxide. Alternatively, L-NAME-induced vasoconstriction may be due to inhibition of nitric oxide synthesis by vascular smooth muscle cells and/or some actions other than inhibition of nitric oxide.19 20
In addition to nitric oxide–dependent relaxation, acetylcholine and bradykinin may stimulate prostaglandin release.21 In this respect, Salom et al22 reported that during nitric oxide inhibition by L-NMMA the kidney retains its ability to respond to acetylcholine. This response was inhibited by the cyclooxygenase inhibitor meclofenamate. Hence, the authors concluded that acetylcholine could exert vasodilating effects through the endothelial release of prostaglandin I2. Renal radiation could have impaired endothelial release of prostaglandin I2.23 24 If so, the poor response to acetylcholine could have resulted from inadequate prostaglandin I2 release rather than deficient nitric oxide. Although prostaglandins have been shown to be deficient late in the course of radiation nephropathy,25 26 a possible role early in the course has not been reported. Alternatively, release of vasoconstrictor prostaglandins such as prostaglandin H2 and thromboxane may be enhanced, which in turn could also impair endothelium-dependent relaxation. In the present study, the administration of indomethacin had no effect on the renal vascular response to acetylcholine in radiated or control rats. The lack of effect of indomethacin suggests that prostaglandin I2 deficiency and/or enhanced prostaglandin H2/thromboxane play a limited or no role at all in the abnormal response to acetylcholine in early radiation nephropathy.
We further established VSM functional integrity by showing unaltered dose-response curves to the endothelium-independent constrictors angiotensin II and norepinephrine. These findings are somewhat complex to interpret, however, because angiotensin II and norepinephrine are modulated by endothelium-derived factors such as nitric oxide and prostaglandins.18 27 28 29 30 If so, the response to angiotensin II and norepinephrine in radiated rats should have been enhanced. In this respect our findings differ with other studies showing that animals treated with nitric oxide inhibitors respond more to angiotensin II.31 Why we did not find hyperreactivity to angiotensin II and norepinephrine is unclear, although we could speculate that prostaglandin I2 was still available to modulate the vascular action of these vasoconstrictors. On the other hand, imported systemic nitric oxide could have moderated the angiotensin effects. Finally we cannot completely exclude a possible minimal damage in radiated VSM that render them less reactive than expected.
This study has several implications. First, our data suggest a possible link between endothelial dysfunction and the ensuing radiation nephropathy and arterial hypertension, as shown in animals undergoing long-term blockade of nitric oxide synthesis.32 33 Second, the endothelial dysfunction could be responsible at least in part for the striking vascular structural abnormalities of radiation nephropathy.6 8 Indeed, chronic L-NAME administration causes marked vascular proliferation and sclerosis in the kidney and other organ vessels.34 35
We conclude that renal radiation causes endothelium dysfunction before the onset of hypertension. In contrast, the vascular smooth muscle is spared in these early stages. The mechanisms whereby this endothelial dysfunction can lead to hypertension need to be investigated.
Received March 17, 1997; first decision April 22, 1997; accepted May 13, 1997.
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