VASCULAR ACTIONS OF ENDOTHELIN IN THE RABBIT KIDNEY

1. The effect of two doses of endothelin, 10 and 50 ng/kg per min, i.v., on glomerular filtration rate (GFR), tubular stop flow pressure and pre- and post-glomerular vascular resistance have been studied in anaesthetized rabbits. 2. Blood pressure did not change significantly in response to 10 ng/kg per min endothelin or vehicle infusion, but rose steadily during infusion of 50 ng/kg per min endothelin, increasing 11.8 +/- 2.7 mmHg by 90 min of infusion. 3. Glomerular filtration fraction (3H-inulin extraction ratio) rose and remained elevated throughout the endothelin infusion at 50 ng/kg per min. GFR did not change significantly until 70-90 min of the infusion (50 ng/kg per min) when it decreased by about 35%. No significant changes were seen at 10 ng/kg per min endothelin. 4. Sodium excretion rate rose in response to the lower dose, due to an increase in fractional sodium excretion. No changes in sodium excretion were seen at the higher dose of endothelin. 5. Glomerular capillary pressure rose significantly in response to endothelin infusion (50 ng/kg per min). 6. Renal blood flow fell progressively in response to endothelin (50 ng/kg per min), to about one-third of the pre-infusion value. 7. Renal vascular resistance increased progressively with both doses of endothelin, by about 35% at 10 ng/kg per min and about 400% at 50 ng/kg per min after 70-90 min. Preglomerular resistance increased from 1.0 +/- 0.1 to 5.0 +/- 1.9 mmHg/mL per min in response to endothelin 50 ng/kg per min. Postglomerular resistance rose from 1.0 +/- 0.1 to 5.6 +/- 2.17 mmHg/mL per min. 8. Thus endothelin infusion caused progressive renal vasoconstriction with similar magnitude increases in both pre- and postglomerular vessels. The vasoconstriction of the kidney caused by endothelin occurred at a dose which did not effect systemic blood pressure.     

STRUCTURAL INFLUENCES ON RESISTANCE IN THE HINDLIMB VASCULAR BED OF THE RENAL HYPERTENSIVE RABBIT

1. The contribution of arteriolar structural change to hindlimb vascular resistance was examined in the renal wrap hypertensive rabbit. 2. Haemodynamic variables were recorded at rest and after maximal vascular dilation using sodium nitroprusside and peripheral autonomic effector blockade. In the same animals at the end of experiments, morphometric measurements of hindlimb muscle arterioles were made. 3. Mean arterial pressure (MAP) and hindlimb vascular resistance were elevated in hypertensive animals compared with normotensive animals at rest and after maximal dilation. 4. Lumen area and lumen diameter were reduced whereas wall area and wall area to lumen area ratio were increased in hypertensive animals compared with normotensive animals. 5. In the renal wrap model of hypertension, the reduction in lumen area of arterioles, < 200 pm in diameter, is sufficient to explain the increase in haemodynamic resistance.     

SODIUM INTAKE MODULATES RENAL VASCULAR REACTIVITY TO ENDOTHELIN-1 IN DAHL RATS

1. The systemic and renal haemodynamic responses to endothelin-1 (ET1) were evaluated and compared to Angiotensin II (AII) in anaesthetized Dahl salt-sensitive (DS) and salt-resistant (DR) rats on either low (0.1% NaCl in diet) or high (8% NaCl in diet) salt intake. 2. Baseline mean arterial pressure on low salt diet was similar in both strains, while on high salt diet it was 73 +/- 4 mmHg in DR rats and 119 +/- 8 mmHg in DS rats (P less than 0.05). Baseline renal blood flow (RBF) and renal vascular resistance (RVR) were similar in all groups. 3. AII in bolus injection induced a short, dose-dependent increase in blood pressure and renal vascular resistance and a fall in renal blood flow. The maximal pressure increase was significantly greater in DS rats on high salt diet than that in each of the other groups (P less than 0.05). The fall in renal blood flow and the increase in renal vascular resistance were attenuated in both strains on low salt diet. 4. ET1 induced an initial decrease followed by a prolonged increase in blood pressure; both phases were similar in all groups. However, renal vascular reactivity to ET1 was markedly modulated by salt intake. On low salt diet, following a bolus injection of ET1 (1 nmol/kg), RBF decreased by 34% in DR and by 20% in DS rats, while on high salt diet RBF decreased by 76% in DR and by 80% in DS rats (P less than 0.05 high vs low salt).(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECT OF RENAL AND ADRENAL DENERVATION ON THE RENIN RESPONSE TO SLOW HAEMORRHAGE IN DOGS

SUMMARY 1. The effect on plasma renin activity of moderate slow haemorrhage (7.5 ml. kg⁻¹. h⁻¹ for 2 h) was studied in intact dogs and in dogs whose adrenals and kidneys had been denervated surgically.
2. In dogs with intact renal and adrenal nerves, plasma renin activity rose during haemorrhage without any accompanying change in systemic blood pressure, but with marked decreases in renal function, an increased filtration fraction and an increased haematocrit. The latter effects can be attributed to sympathetic stimulation evoked by haemorrhage.
3. In dogs with denervated kidneys and adrenals, haemorrhage did not result in a significant elevation of plasma renin activity until the 2 h collection period, at which time mean systemic blood pressure had fallen 32 mmHg. Renal function changes were less marked and neither filtration fraction nor haematocrit rose, suggesting the absence of sympathetic stimulation.
4. It concluded that the sympathetic nervous system plays an important role in the renin response to slow haemorrhage until such time as blood pressure falls sufficiently to activate a second stimulatory mechanism, perhaps a renal baro-receptor.     

RENAL RESPONSES TO SLIGHT ELEVATIONS OF RENAL ARTERIAL PLASMA ANGIOTENSIN II CONCENTRATION IN DOGS

1. Angiotensin II was infused into the renal artery of intact kidneys of slightly volume expanded anaesthetized dogs at rates of 125, 250, 500, and 1000 pg/kg body weight per min, resulting in elevations of the calculated renal arterial plasma angiotensin II concentration of 16·9 (s.e.m. = 2·1), 35·0 (s.e.m. = 4·3), 73·3 (s.e.m. = 8·8), and 159·8 (s.e.m. = 20·4) pg/ml. 2. Angiotensin II caused significant dose-dependent decreases of renal blood flow and of renal plasma flow of -4·1% (s.e.m. = 1·5, P(0·05) at the lowest and of -19·6% (s.e.m. = 1·4, P(0·001) at the highest rate of infusion. Glomerular filtration rate remained essentially unchanged at the two lower infusion levels and decreased by -6·7% (s.e.m. = 2·2, P(0·05) and -8·3% (s.e.m. = 2·5, P(0·05) at the higher rates of infusion. Filtration fraction thus increased by +6·3% (s.e.m. = 2·4, P(0·05) at the lowest and by +14·2% (s.e.m. = 3·6, P(0·01) at the highest rate of infusion. 3. Urine volume decreased by -7·7% (s.e.m. = 0·8, P(0·001) at the lowest and by -35·2% (s.e.m. = 4·8, P(0·001) at the highest rate of infusion, while the study showed similar dose-dependent decreases for urinary sodium and potassium excretion and for the fraction of filtered sodium excreted.     

RENIN SECRETION AND RENAL VASCULAR RESISTANCE FOLLOWING PROLONGED ADMINISTRATION OF DESOXYCORTICOSTERONE (DOC) IN RATS DRINKING NORMAL SALINE

1. The effect of long-term administration of desoxycorticosterone (DOC)-saline on arterial blood pressure, renal vascular resistance and renin secretion rate was studied in the rat. 2. Renin secretion rate and peripheral plasma renin activity was markedly reduced in the DOC-saline treated rats. Renal vascular resistance was comparable to that found in a corresponding control group. Responsiveness to isoprenaline suggested that the β-adrenoceptor mediating renin release was grossly intact. 3. A significant rise in blood pressure occurred in only 50% of the treated animals: However, no differences in weight gain, renal vascular resistance or renin levels were apparent when compared with animals which remained normotensive. 4. These findings indicate that suppression of renin secretion during prolonged DOC-saline administration cannot be directly attributed to changes in arterial pressure, renal vascular resistance or β-adrenoceptor sensitivity.     

CORONARY AND PERIPHERAL VASCULAR RESISTANCE IN THE ANAESTHETIZED DIABETIC SHEEP

To determine whether vascular resistance was altered in diabetes, the vascular resistance in both the peripheral arterial bed and the circumflex coronary artery was compared in six normal and five diabetic adult sheep, under pentobarbitone anaesthesia. Diabetes induced by alloxan significantly increased blood glucose (15.6 mmol/l, s.e.m. = 2.8, vs 5.5 mmol/l, s.e.m. = 0.6; P greater than 0.001) compared with controls. Systolic blood pressure was lower in diabetics (92 mmHg, s.e.m. = 12, vs 123 mmHg, s.e.m. = 5; P less than 0.025) as was diastolic blood pressure (73 mmHg, s.e.m. = 15, vs 104 mmHg, s.e.m. = 4; P greater than 0.05). Basal peripheral resistance was lower in diabetics than controls (36.0 mmHg.min/l, s.e.m. = 7.9, vs 42.3 mmHg.min/l, s.e.m. = 2.8), but not significantly so. Methoxamine markedly increased peripheral vascular resistance in both groups, but did not change coronary vascular resistance, due to autoregulation. The dose-response curves of peripheral or coronary arteries to methoxamine showed no significant difference between diabetic and control sheep. Dose-response curves for isoprenaline and noradrenaline infusion suggested there may be altered beta-receptor sensitivity in diabetes. In conclusion, there are marked differences in the vascular beds of diabetic and normal sheep under basal conditions. In contrast to previous studies, alpha-adrenoceptors are not different in diabetics, but further studies in unanaesthetized animals are indicated, as beta-receptor sensitivity may be altered in diabetes.     

HYPERTENSION AND COMPONENTS OF VASCULAR RESISTANCE

1. In renal wrap hypertension in the rabbit and in essential hypertension in humans, non-autonomic components of resistance are the major factors contributing to elevated blood pressure. 2. The central nervous system plays an important role in moment to moment blood pressure control but is not responsible for maintenance of elevated pressure in essential hypertension. 3. Specific regions of the brain-stem maintain vascular tone through the effects of bulbospinal neurones which are organized both topographically and by chemical content. 4. Structural wall thickening in resistance vessels in hypertension is a manifestation of an abnormality of a growth controlling process. 5. Although several structural muscle growth factors have been identified, it is likely that only a few regulatory processes are critical. 6. Future studies in hypertension should examine associations between genetic markers of medial thickening and environmental influences.     

PRESERVATION OF RENAL FUNCTION IN THE RAT REMNANT KIDNEY MODEL OF CHRONIC RENAL FAILURE BY BLOOD PRESSURE REDUCTION

The remnant kidney model of chronic renal failure was established in female Sprague-Dawley rats subjected to surgical removal of the right kidney and segmental infarction of seven-eighths of the left kidney. Plasma creatinine (mumol/l) rose from 65 (s.e.m. = 16, n = 18) to 153 (s.e.m. = 27, t-test, P less than 0.001, d.f. = 17) over 6 weeks. Histological glomerulosclerotic lesions were present from 2 weeks and prominent by 6 weeks post-surgery. Rats were treated with enalapril (5 mg/kg per day, n = 11) or felodipine (30 mg/kg per day, n = 13) from 1 week post-surgery, and their course compared to untreated rats (n = 18). Blood pressure (mmHg) was lowered by both treatments. Six weeks post-nephrectomy, systolic blood pressure in the untreated group was 176 (s.e.m. = 7, n = 18), enalapril group 122 (s.e.m. = 5, t-test, P less than 0.001, d.f. = 27), and felodipine group 128 (s.e.m. = 3, t-test, P less than 0.001, d.f. = 29). Plasma creatinine (mumol/l) was lower in the enalapril group (110, s.e.m. = 8, t-test, P less than 0.05, d.f. = 27) but not the felodipine group (173, s.e.m. = 19, t-test, n.s.) 6 weeks after subtotal nephrectomy compared to the untreated group (153, s.e.m. = 27). Glomerulosclerosis (blinded histological score) was reduced with enalapril treatment (1.93, s.e.m. = 0.03, t-test, P less than 0.05, d.f. = 27) but not felodipine treatment (2.15, s.e.m. = 0.04, c.f. untreated 2.36, s.e.m. = 0.12, t-test, n.s.). Urinary protein excretion (mg/24 h) was 84 (s.e.m. = 22, n = 13) in untreated rats, 15 (s.e.m. = 3, t-test, P less than 0.001, d.f. = 22) in enalapril-treated rats and 221 (s.e.m. = 35, n = 10) with felodipine treatment. Functional and structural damage in the rat remnant kidney model of chronic renal failure was ameliorated by treatment with enalapril but not by treatment with felodipine.     

EFFECTS OF FIVE NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ON THE RENAL AND SYSTEMIC RESPONSES TO ARACHIDONATE IN CONSCIOUS DOGS

1. The effects of five different non-steroidal anti-inflammatory drugs (NSAID) on the renal blood flow responses to arachidonate were compared. 2. Arachidonate (5-200 micrograms/kg) injected into the renal arteries of conscious dogs caused dose-related renal vasodilatation with no systemic effects. 3. Aspirin (35 mg/kg), phenylbutazone (12 mg/kg) and ibuprofen (25 mg/kg) all markedly reduced arachidonate-induced renal vasodilatation. 4. In contrast, neither indomethacin (3 mg/kg) or its related drug sulindac sulphide (6 mg/kg) significantly reduced arachidonate-induced renal vasodilatation. 5. All NSAID abolished the hypotensive response to intravenous injection of arachidonate (10 mg). 6. Thus, indomethacin and sulindac did not block the effects of renal artery injections of arachidonate but did abolish the systemic effects. Aspirin, phenylbutazone and ibuprofen greatly reduced responses to both renal artery and intravenous arachidonate. 7. Indomethacin and aspirin both reduced the production of prostaglandin E2 and 6-keto-PGF1 alpha by dog renal cortical microsomes in vitro. 8. Thus, indomethacin and sulindac had different effects to other NSAID on arachidonate-induced renal vasodilatation. The results are compatible with the hypothesis that some sites of prostaglandin production in the kidneys of conscious dogs may be relatively resistant to inhibition by indomethacin and sulindac.     

PATHWAYS LINKING RENAL EXCRETION AND ARTERIAL PRESSURE WITH VASCULAR STRUCTURE AND FUNCTION

1. A brief review is presented which summarizes the role of the kidney in the long-term regulation of arterial pressure and the mechanism whereby changes in body fluid volume can influence the function and structure of the systemic vasculature. 2. Studies indicate that the kidney detects changes of arterial pressure via changes of medullary blood flow which in the volume expanded state is poorly autoregulated. Elevations of renal arterial pressure raise vasa recta capillary pressure and renal interstitial fluid pressure, which in turn reduces tubular reabsorption of sodium and water. 3. The sensitivity of the pressure-diuresis relationship is controlled by renal sympathetic nerve activity and a variety of hormone and autocrine systems. 4. Evidence is also reviewed which shows that small changes of blood volume (5%) resulting from reduced renal excretion can acutely and chronically result in 25% increases of total peripheral resistance and arterial pressure. 5. Short-term increases of vascular resistance are predicted by regional autoregulatory responses while long-term elevations of vascular resistance appear to result from the structural changes of large vessel hypertrophy and microvascular rarefaction within skeletal muscle.     

ASSESSING VASCULAR REACTIVITY OF ARTERIES IN THE SMALL VESSEL MYOGRAPH

1. Using a small vessel myograph, experiments were performed on rat small mesenteric arteries (and in some cases dog small coronary arteries) to assess the dependence of vasoconstrictor potency (EC50) and maximum response (Emax) on the initial passive conditions and on the mode of recording (i.e. isometric, isobaric or isotonic). 2. Maximum active isometric tension development to methoxamine occurred at different points on the passive diameter--tension curve depending on the origin of the vessel. The point of maximum sensitivity of methoxamine did not coincide with the point of maximum tension development on the passive diameter-tension curve. 3. Vascular reactivity to methoxamine was assessed under isobaric, isotonic and isometric conditions using a new computerized myograph. Methoxamine was significantly more potent, but only by a factor of twofold, when assessed under isometric conditions. In addition, the maximum response to methoxamine, in terms of diameter change, was always greater under isobaric than under isotonic conditions. 4. The results show that, in studies comparing vascular reactivity of vasoactive drugs, the results depend, to some extent, on the initial passive conditions selected. In terms of assessing the pharmacological activity of drugs on isolated blood vessels, the use of common isometric recording procedures are adequate. However, the use of isobaric, isotonic and isometric recording procedures have shown the complexities of vascular reactivity which depend on the passive and active properties of the blood vessel. These factors may need to be taken into account when comparing the reactivity of isolated blood vessels.     

RENAL RESPONSES TO ANGIOTENSIN II IN CONSCIOUS DOGS: EFFECTS OF ASPIRIN AND INDOMETHACIN

1. Angiotensin II was infused into the renal artery of unanaesthetized dogs at 0.4 and 2.0 ng/kg per min for 40 min each. 2. Indomethacin (3 mg/kg, and 1 mg/kg per h infusion i.v.) accentuated the angiotensin II-induced falls in glomerular filtration rate, renal blood flow and urine flow rate. Indomethacin did not alter the effects of angiotensin II on Na+ or K+ excretions. 3. Aspirin (35 mg/kg p.o. 2.5 h and 0.5 h prior to experiment) did not significantly change the renal effects of angiotensin II. 4. Both aspirin and indomethacin accentuated renal vasoconstriction during briefer (5 min) angiotensin II infusion. 5. Thus indomethacin and aspirin had markedly different effects on the actions of angiotensin II in the kidney. This suggests that at least one of these drugs has actions which affect angiotensin II-mediated vasoconstriction other than via cyclooxygenase inhibition.     

ACUTE HAEMODYNAMIC RESPONSES TO UNILATERAL RENAL ARTERY STENOSIS IN CONSCIOUS DOGS

The acute responses to renal artery stenosis were studied in chronically instrumented, unanaesthetized dogs. Stenosis of one renal artery produced a rise in arterial pressure and a fall in total peripheral conductance, but no change in cardiac output. The resistance to blood flow of the stenotic kidney 1 h after stenosis was 25% greater than before stenosis. This rise in resistance was due to the resistance of the renal artery stenosis itself. Blood flow to the contralateral kidney fell by 13% (s.e.m. = 3) at 1 h and resistance rose by 39% (s.e.m. = 5). Plasma renin activity was elevated approximately 10 fold. Calculations of changes in peripheral conductances following stenosis showed that the stenotic kidney was responsible for 14% of the fall in total peripheral conductance at 1 h, and the contralateral kidney for 18%. Thus acute renal artery stenosis produced a prompt rise in arterial pressure due to reduced peripheral conductance, of which the two kidneys (stenotic and contralateral) were responsible for one-third.     

EFFECT OF CATIONIC DRUGS ON THE RENAL SECRETION OF RANITIDINE IN THE RAT ISOLATED PERFUSED KIDNEY

1. The rat isolated perfused kidney (IPK) was used to determine whether the renal tubular secretion of ranitidine is influenced by clinically relevant concentrations of other organic cationic drugs (amantadine, pseudoephedrine, triamterene and trimethoprim) that also undergo tubular secretion. 2. Ranitidine and [³H]-ranitidine were administered to the recirculating perfusion medium as a loading dose followed by a constant infusion to maintain clinically relevant perfusate ranitidine concentrations in the range 400–700 ng/mL. The renal clearance of ranitidine (CL_R) was calculated, as was glomerular filtration rate (GFR), from the renal clearance of [¹⁴C]-inulin. 3. A total of 20 perfusions were performed and, in each case, ranitidine was administered for 80 min. In four control IPK, no drug other than ranitidine was administered. In the remaining IPK, amantadine, pseudoephedrine, triamterene or trimethoprim (n= 4 in each case) were administered to achieve low, medium and high concentrations during the 20–40, 40–60 and 60–80 min periods, respectively. 4. The mean (± SD) unbound fraction of ranitidine in the perfusion medium was 0.889±0.046 and was not altered (P>0.05) by the presence of the other drugs. 5. The CL_R/GFR ratio for ranitidine in all kidneys was substantially greater than unity and had a mean value of 10.65 or greater in control kidneys, indicating extensive net tubular secretion. 6. The CL_R/GFR was not affected (P>0.05) by amantadine, pseudoephedrine or triamterene at any concentration or by trimethoprim at the low concentration. However, medium (2000 ng/mL) and high (5000 ng/mL) concentrations of trimethoprim caused significant reductions in CL_R/GFR of 20 and 28%, respectively (P<0.05). 7. The results indicate that at clinically relevant concentrations the renal tubular secretion of ranitidine is inhibited by trimethoprim, but not by amantadine, pseudoephedrine or triamterene.     

前胡丙素对高血压大鼠血压及犬血管阻力的影响

目的　观察前胡丙素(pra C)的降压及对外周血管阻力的影响。方法　在肾型高血压大鼠模型与正常血压大鼠用尾容积法测血压。用RDB III型输液泵连接于麻醉杂种犬,以控制血流量与压力法直接测定锥动脉、冠脉左旋支、股动脉的阻力。结果　pra-C 20 mg·kg^-1·d^-1 ig给药3 0d对肾性高血压大鼠(RHR)降压峰值时间为6h ,从(213±10 )mmHg降至(144.0±1.5)mmHg,降低原水平30% ,持续至20h。pra-C分别以100 μg·kg^-1 及20 μg·kg^-1与pra-E 20 μg·kg^-1iv可降低上述血管的阻力,减慢心率,降低阻力呈剂量相关。结论　pra-C有降压作用,降低犬外周动脉阻力,增加小鼠耐缺氧时间。     

EFFECTS OF CLONIDINE ON VASCULAR RESPONSES IN KIDNEY AND HINDLIMBS OF CATS

1. Cardiovascular reflexes to intravenous adrenaline and histamine and to carotid occlusion were studied in the renal vasculature, and direct effects of nor-adrenaline and clonidine were compared in renal and hindlimb vascular beds in anaesthetized cats. 2. Unlike its reported effects on cardiovascular reflexes in the hindlimbs, clonidine depressed all three reflexes in the kidneys. 3. Noradrenaline caused vasoconstriction when given directly into both renal and hindlimb circulations, but clonidine produced vasoconstriction only in the hindlimb vascular bed. 4. These results suggest that α-adrenoceptors in the renal vasculature may be different from those in the hindlimbs, and that the cardiovascular reflexes in these two areas are under different control.     

ROLE OF THE KALLIKREIN-KININ SYSTEM IN THE RENAL EFFECTS OF ANGIOTENSIN-CONVERTING ENZYME INHIBITION IN ANAESTHETIZED DOGS

1. Administration of captopril (1.5mg/kg i.v.) to anaesthetized dogs was associated with an increase in renal blood flow of 56 ml min^-1 (s.e.m. = 13, n= 9) despite a significant fall of 17 mmHg (s.e.m. = 5, n= 9) in mean arterial pressure. 2. Treatment of dogs with the angiotensin receptor antagonist, Sar'lle⁸-angiotensin II (2.5 fxgjkg per min i.v.), or the cyclo-oxygenase inhibitor indo-methacin (10 mg/kg i.v.) did not prevent the renal vasodilation and hypotension following angiotensin-converting enzyme inhibition. This suggests that these effects are neither solely due to inhibition of the renin-angiotensin system nor mediated by prostaglandins. 3. Increased urinary kinin excretion, possibly reflecting increased renal concentrations of kinins, accompanied the renal vasodilation after both captopril and renal artery occlusion. 4. The kallikrein-kinin system may play a role in the regulation of the renal vasculature in anaesthetized dogs.