Angiotensin II-induced renal vasoconstriction in genetic hypertension.

Previous studies demonstrate that renovascular responses to angiotensin II (Ang II) are enhanced in spontaneously hypertensive rats (SHRs); however, it is possible that this hyperresponsiveness is mediated by Ang II-induced release of substances from the adrenal gland. Previous studies also show that pertussis toxin normalizes renovascular responses to Ang II in SHRs; however, it is possible that this response is mediated by effects of pertussis toxin on endogenous Ang II levels and/or the sympathoadrenal axis. The purpose of this study was 2-fold: 1) to determine whether the renovascular response to Ang II in SHRs is enhanced even in adrenalectomized SHRs and 2) to determine whether pertussis toxin normalizes enhanced renovascular responses to Ang II when pertussis toxin-induced changes in the renin-angiotensin system and the sympathoadrenal axis are prevented. SHRs and Wistar Kyoto (WKY) rats were anesthetized and administered 20 ml/kg 0.9% saline, and an infusion of aldosterone and hydrocortisone was initiated. After bilateral adrenalectomy, left renal denervation, and pretreatment with captopril, animals received an intrarenal artery infusion of Ang II at 10 ng/kg/min for 5 min. Ang II-induced changes in renal vascular resistance were greater in SHRs compared with WKY rats (p =. 010, n = 19/group). Pertussis toxin (10 microgram/kg i.v. 3 days before the experiment) attenuated Ang II-induced changes in renal vascular resistance in SHR (p <.05), but not in WKY rats (strain x treatment interaction: p =.046). These results suggest that the enhanced renovascular response to Ang II in SHRs is mediated by a G(i)-dependent pathway within the renal vasculature.     

Protective effects of the angiotensin II type 1 (AT1) receptor blockade in low-renin deoxycorticosterone acetate (DOCA)-treated spontaneously hypertensive rats

The present study evaluates the participation of oxidative stress, tissue angiotensin II (Ang II) and endothelin (ET) in the effects of losartan on blood pressure (BP), ventricular hypertrophy and renal injury in spontaneously hypertensive rats (SHRs), and explores how these effects are modified when spontaneous hypertension is transformed in a low-renin model by the administration of deoxycorticosterone acetate (DOCA). The following groups were used: SHR-control, SHR+DOCA, SHR+losartan and SHR+DOCA+losartan. Tail systolic BP was measured once a week. After 9 weeks of treatment, direct BP and metabolic, morphological, biochemical and renal variables were measured. DOCA administration to SHRs produced an increase in BP, ventricular hypertrophy, renal weight, proteinuria, renal histopathological lesions, urinary excretion of isoprostane F2alpha and ET levels in the renal cortex. Losartan reduced BP, plasma malondialdehyde levels, urinary excretion of isoprostane F2alpha, renal Ang II and renal and urinary levels of ET in the SHR and DOCA-treated SHR groups. Losartan increased plasma nitrite/nitrate in SHRs, but not in low-renin DOCA-treated SHRs. Losartan reduced ventricular hypertrophy and ventricular Ang II in SHRs, but not in DOCA-treated SHRs. Losartan significantly decreased proteinuria and renal injury in DOCA-treated SHRs. We conclude that (i) the DOCA-induced aggravation of hypertension, ventricular hypertrophy and renal injury in SHRs is accompanied by augmented oxidative stress and increased levels of ET in the renal cortex, which could contribute to their development; and (ii) losartan reduced oxidative stress and renal Ang II and ET in SHRs and DOCA-treated SHRs, which might contribute to its antihypertensive and renoprotective effects, regardless of renin status.     

alpha 2-Adrenoceptors potentiate angiotensin II- and vasopressin-induced renal vasoconstriction in spontaneously hypertensive rats

Hypertension in spontaneously hypertensive rats (SHRs) is due in part to enhanced effects of vasoactive peptides on the renal vasculature. We hypothesize that the G(i) signal transduction pathway enhances renovascular responses to vasoactive peptides in SHRs more so than in normotensive Wistar-Kyoto (WKY) rats. To test this hypothesis, we examined in isolated perfused kidneys from SHRs and WKY rats the renovascular responses (assessed as changes in renal perfusion pressure in mm Hg) to angiotensin II (10 nM) and vasopressin (3 nM) in the presence and absence of UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; an agonist that selectively activates the G(i) pathway by stimulating alpha(2)-adrenoceptors]. In SHR, but not WKY, kidneys, UK-14,304 (10 nM) enhanced (P < 0.05) renovascular responses to angiotensin II (control WKY, 43 +/- 6; UK-14,304-treated WKY, 52 +/- 19; control SHR, 66 +/- 17; UK-14,304-treated SHR, 125 +/- 16) and vasopressin (control WKY, 42 +/- 17; UK-14,304-treated WKY, 36 +/- 11; control SHR, 16 +/- 8; UK-14,304-treated SHR, 83 +/- 17). Pretreatment of SHRs with pertussis toxin (30 microg/kg, intravenously, 3-4 days before study) to inactivate G(i) blocked the effects of UK-14,304. Western blot analysis of receptor expression in whole kidney and preglomerular microvessels revealed similar levels of expression of AT(1), V(1a), and alpha(2A) receptors in SHRs compared with WKY rats. We conclude that activation of alpha(2)-adrenoceptors selectively enhances renovascular responses to angiotensin II and vasopressin in SHRs via an enhanced cross talk between the G(i) signal transduction pathway and signal transduction pathways activated by angiotensin II and vasopressin.     

自发性高血压大鼠心脏和肾脏血管紧张素转换酶2和血管紧张素转换酶的表达

目的 观察不同月龄的自发性高血压大鼠(SHR)的心脏和肾脏血管紧张素转换酶2(ACE2)和血管紧张素转换酶(ACE)的Mrna和蛋白质表达水平,探讨ACE2/ACE与血压状态的内在联系.方法 12周龄雄性自发性高血压大鼠(spontaneously hypertensive rat,SHR)18只和12周龄WKY大鼠(Wistar-Kyoto rats,WKY)18只.随机分为SHR组和WKY组,每组抽取各9只,处死进行与喂养12周后处死的24周龄大鼠相同的研究内容.采用实时定量RT-PCR法(Real-time Quantitative RT-PCR)检测ACE2、ACE Mrna(messenger ribonucleic acid,Mrna)的表达,免疫组织化学榆测ACE2、ACE等蛋白的表达.结果 (1)与同周龄WKY组比较,SHR组的血压显著增加(P均＜0.01),心脏和肾脏的ACE2 Mrna表达显著降低(P均＜0.01),ACEmRNA表达显著升高(P＜0.05,P＜0.01);与12周龄SHR组比较,24周龄SHR的血压亦显著增加(P＜0.01),ACE2 Mrna表达显著降低(P均＜0.01),ACE Mrna表达显著升高(P均＜0.01).(2)与同周龄的WKY组比较,SHR组心脏和肾脏的ACE2免疫染色表达显著减少,ACE免疫染色表达显著增多.结论 心脏和肾脏的ACE2/ACE Mrna表达与血压升高相关.     

ACE Inhibitors and Renal Vascular Responses in the Spontaneously Hypertensive Rat

BACKGROUND: Substantial evidence has accumulated for the intrarenal generation of functionally important quantities of angiotensin II (Ang II). To assess the possibility that Ang II generation occurs beyond a barrier to diffusion from the vascular compartment, six angiotensin-converting enzyme (ACE) inhibitors varying widely in their lipid solubility were employed in the spontaneously hypertensive rat (SHR) and their normotensive controls (WKY). The biological end points were renal blood flow and its response to Ang II. RESULTS: Two ACE inhibitors, ramipril and captopril, induced a larger increase in renal blood flow and enhanced the renal vascular response to Ang II substantially more than did enalapril and lisinopril. The two prodrugs, enalapril and ramipril, which are substantially more lipophilic than the respective active drugs, enalaprilat and ramiprilat, showed equivalent responses. The partial agonist saralasin virtually abolished the renal vasodilator response to ramipril. The pattern of response was similar in WKY, but the responses were substantially smaller. CONCLUSIONS: The results support the concept that a functionally important compartment for intrarenal Ang II formation exists in the healthy rat and that this process is amplified in the SHR.     

Radiotelemetric evaluation of hemodynamic effects of long-term ethanol in spontaneously hypertensive and Wistar-Kyoto rats

This study determined the hemodynamic effects of chronic ethanol in telemetered freely moving age-matched spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Changes in blood pressure (BP), heart rate (HR), and plasma norepinephrine (as index of sympathetic activity) were evaluated in pair-fed rats receiving liquid diet with or without ethanol (5%, w/v) for 12 weeks. The SHRs exhibited higher baseline BP and lower HR compared with WKY rats. When normalized for body weight, daily ethanol intake was higher in SHRs compared with WKY rats. However, blood ethanol concentration was similar except for a higher level in SHRs at weeks 7 through 9. Ethanol had no effect on BP in WKY rats but caused decreases in BP in SHRs that reached a maximum (approximately 30 mm Hg) at week 5 and remained thereafter. Ethanol also caused reductions in the BP variability and the circadian fluctuations in BP in SHRs but not in WKY rats. Plasma norepinephrine levels were elevated by ethanol in WKY rats, but not in SHRs. The HR was not affected by ethanol in SHRs and showed increases in WKY rats. These findings suggest that chronic ethanol feeding differentially affects BP in SHRs (hypotension) and WKY rats (no effect). The lack of a hypotensive response to ethanol in WKY rats may relate, at least partly, to the associated sympathoexcitation. The present study used the telemetry technique for BP measurement, which eliminates the confounding and stressful effects of other conventional techniques.     

Renal extraction of angiotensin II

Angiotensin II regulates many aspects of renal function and thereby influences long-term blood pressure. The effects of angiotensin II on the kidney have been exhaustively studied; however, the converse (i.e., effects of the kidney on angiotensin II) has received little attention. Accordingly, the focus of this study was to determine whether renal degradation of angiotensin II is regulated by chronic levels of angiotensin II or long-term levels of blood pressure. Twenty hypertensive rats and 22 normotensive rats were treated for 1 week with either vehicle, angiotensin II (50 ng/kg/min, subcutaneously) or captopril (100 mg/kg/day, orally). Right kidney vascular resistance was measured during infusions of angiotensin II into the left renal artery or vena cava at the level of left renal vein. Dose-response data were curve-fitted, and the extraction of angiotensin II by the left kidney was calculated by comparing the doses of angiotensin II required to elicit equal increases in right renal vascular resistance during intravenous versus left intrarenal artery infusions. Renal extraction of angiotensin II was high (mean, 81%) and demonstrated little animal-to-animal variation (coefficient of variation, 23%; standard deviation, 19%). Renal extraction of angiotensin II was independent of hypertension (P = 0.257) or previous chronic exposure to angiotensin II or captopril (P = 0.270), and there was no interaction between hypertension and chronic exposure to angiotensin II or captopril (P = 0.950). We conclude that renal degradation of angiotensin II is constitutively high, is unaffected by chronic levels of arterial blood pressure, and is independent of long-term changes in levels of angiotensin II.     

Enhanced slow-pressor response to angiotensin II in spontaneously hypertensive rats

Rapid-pressor and slow-pressor responses to angiotensin (ANG) II and norepinephrine (NE) in spontaneously hypertensive rats (SHR) and Wistar Kyoto control rats (WKY) were examined. All animals were treated from 4 wk of age with captopril (100 mg/kg/day in drinking water) to prevent development of hypertension so that changes in responsiveness could not be attributed to disparate base-line blood pressures or to hypertension-induced injury of the cardiovascular system. In 11-wk, conscious, unrestrained, captopril-treated rats, ANG II and NE induced rapid-pressor responses (i.e., a rapid increase in arterial blood pressure that reached a maximum within 10 min) that were of similar magnitude in SHR and WKY. In an additional group of 9-wk captopril-treated rats, both ANG II and NE caused slow-pressor responses (i.e., a slow increase in arterial blood pressure over 2 wk). Although the slow-pressor response to NE was similar in SHR versus WKY, the slow-pressor response to ANG II was much greater in SHR compared with WKY. Further studies were conducted in captopril-treated (from 4 wk of age) SHR and WKY to investigate whether the increased slow-pressor response to ANG II in SHR was mediated by an enhanced ability of ANG II to potentiate peripheral sympathetic neurotransmission, contract vascular smooth muscle, increase sympathetic tone to nonadrenal sites, release aldosterone, and/or reduce renal function. No evidence was found that supported a role for the aforementioned nonrenal actions of ANG II. However, 11-wk captopril-treated SHR were 10-fold more sensitive to the antidiuretic, antinatriuretic, and renal vascular effects of intrarenal infusions of ANG II compared with captopril-treated WKY. Also, chronic (1 wk) intrarenal infusions of a very low dose of ANG II (1 ng/min) caused a marked slow-pressor response in 11-wk captopril-treated SHR but did not alter arterial blood pressure in WKY. We conclude that 1) the slow-pressor response to ANG II is greatly enhanced in SHR, 2) this enhancement is specific with respect to type of response (slow not rapid) and pressor agent (ANG II not NE), 3) a genetic defect underlies the increased slow-pressor response to ANG II in SHR, and 4) the enhanced slow-pressor response to ANG II contributes significantly to the pathophysiology of hypertension in SHR. Finally, the current studies are consistent with our working hypothesis that the kidneys mediate the enhanced slow-pressor response to ANG II in SHR.     

Sympatho-inhibitory actions of irbesartan in pithed spontaneously hypertensive and Wistar-Kyoto rats

Angiotensin II (Ang II) can enhance sympathetic neurotransmission by acting on (AT1) receptors that are located on sympathetic nerve terminals. We investigated presynaptic blockade by the selective AT1-receptor antagonist irbesartan in pithed spontaneously hypertensive rats and normotensive Wistar-Kyoto rats (WKY). We compared the presynaptic inhibitory dose with that required for the blockade of AT1-receptors on vascular smooth muscle in both strains. To investigate blockade of presynaptic AT1-receptors, we studied the effect of irbesartan on the sequelae of electric stimulation of the thoraco-lumbar sympathetic outflow (0.25-8 Hz). To study the interaction between postsynaptic AT1-blockers and alpha-adrenoceptors, the effects of irbesartan on pressor responses to exogenous noradrenaline (NA) were established. Additionally, we studied the effect of irbesartan on dose-response curves for the vasoconstriction induced by exogenous Ang II. Pressor responses to electrical stimulation of thoracolumbar sympathetic neurones, to exogenous Ang II, as well as to (NA) were enhanced in spontaneously hypertensive rats (SHR) compared with WKY. The stimulation-induced rise in DBP could be dose-dependently reduced by irbesartan (0.3-10 mg/kg) in both SHR and WKY. The pIC50 values (doses which suppress the rise in DBP by 50% compared with control) were 5.60 +/- 0.09 and 5.72 +/- 0.08 for SHR and WKY, respectively (P > 0.05). In SHR, no effect of irbesartan (3 mg/kg) on pressor responses to exogenous NA was observed. In contrast, in WKY, irbesartan (3 mg/kg) caused a rightward shift of the dose-response curve to exogenous NA. Irbesartan (0.3-3 mg/kg) caused a depression of E(max) values and a rightward shift of the dose-response curves to exogenous Ang II in a similar fashion in both SHR and WKY. From these results we conclude that both in SHR and in WKY, Ang II exerts a facilitatory effect on sympathetic neurotransmission, which is mediated by prejunctional AT1-receptors in both strains. Irbesartan displays comparable sympatho-inhibitory potency in the normotensive and hypertensive pithed rat preparations. A facilitatory effect via postsynaptically located AT1-receptors on alpha-adrenoceptor-mediated responses exists in WKY, but not in SHR. In both strains the required dose to inhibit presynaptic effects is somewhat higher than the dose required to inhibit postsynaptic effects. No differences, therefore, seem to exist between the two strains regarding the affinity of irbesartan for pre- and postjunctional AT1-receptors, respectively.     

Sustained antihypertensive effects of chronic administration of two kappa-opioid agonists in spontaneously hypertensive rats.

The ability of two nonpeptide kappa-opioid receptor agonists, U-50, 488H and U-62,O66E (spiradoline), to lower arterial pressure on chronic administration to 12-week-old male spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar Kyoto (WKY) rats was assessed. Each drug was infused subcutaneously at approximately 9.6 mg/kg/d, over a 14-day period with Alzet osmotic pumps in each strain of rat. Arterial pressures were determined daily in each rat by photoelectric tail-cuff plethysmography. Control rats received similar infusions of 0.9% NaCl. Body weights and water consumption were also recorded daily. Both drugs effected a 10% to 20% sustained lowering of arterial pressure beginning on the second day of infusion, until explantation of the pumps on day 14. Heart rates similarly were decreased by 10% to 15% in SHRs. By contrast, neither drug caused significant decrements in arterial pressure or heart rate in the normotensive WKY group. Control infusions of 0.9% NaCl had no significant effects on arterial pressure or heart rate in either SHRs or WKY rats. U-62,066E, but not U-50,488H, caused sustained increased water consumption in both SHRs and WKY rats, with a greater effect in the SHR strain. This likely was accompanied by a water diuresis. Body weight gains over the 14-day period were similar for both strains of rats treated with U-50,488H, compared with saline-treated controls, but rats of both strains infused with U-62,066E gained significantly less weight than saline controls over the 14-day period. The results are supportive of further experimental evaluations of the potential antihypertensive use of nonpeptide kappa-opioid agonist drugs.     

Enhanced in vivo responsiveness of presynaptic angiotensin II receptor-mediated facilitation of vascular adrenergic neurotransmission in spontaneously hypertensive rats

Presynaptic angiotensin II (AII) receptor-mediated facilitation of vascular adrenergic neurotransmission was studied in the in situ, blood-perfused mesentery of 13- to 16-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY). Mesenteric arterial perfusion pressure frequency-response curves to periarterial adrenergic nerve stimulation (PNS) and dose-response curves to exogenous norepinephrine (NE) were obtained in SHR and WKY. The effects of the following treatments on the mesenteric vascular perfusion pressure responses (PPR) to PNS and NE were studied: All alone infused i.a. at 1 and 5 ng/min; All infused at 5 ng/min after [Sar1-lle8]All infused at 20 ng/min; [Sar1-lle8]All infused at 20 ng/min alone; captopril alone at 0.1 mg/kg i.v.; All infused i.a. at 0.3 and 1 ng/min after captopril at 0.1 mg/kg and angiotensin I injected at 3 dose levels after captopril at 0.1 mg/kg. Control PPR to PNS and NE were greater in SHR than in WKY. Comparisons of PPR in SHR to those in WKY were made, therefore, at the predetermined PPR levels of 15, 20, 30, 40, 50, 60 and 70 mm Hg. All alone shifted the PNS frequency-response curve to the left to a greater extent in the SHR than in the WKY when infused at 5 ng/min but not when infused at 1 ng/min. Both infusion rates of All had significantly different effects on the dose-response curves to NE in WKY and SHR. The effects of All infusion (5 ng/min) on both the response to PNS and to NE were antagonized completely by the concurrent infusion of [Sar1-lle8] All at 20 ng/min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary 6-ketoprostaglandin F1 alpha in genetically hypertensive rats of the Lyon strain

In order to assess the pathophysiological role of renal prostacyclin in genetic hypertension, the urinary excretion of its main stable metabolite, 6-ketoprostaglandin F1 alpha, was followed in 12 hypertensive, normotensive and low blood pressure female rats of the Lyon strains at the ages of 5, 9, 21, 32 and 45 weeks. The urinary excretion of 6-ketoprostaglandin F1 alpha, which progressively decreased in the three strains between 5 and 21 weeks of age, was found to be increased in 5- and 9-week-old hypertensive rats and it was reduced in 5-week-old low blood pressure rats, compared with age-matched normotensive controls. The urinary 6-ketoprostaglandin F1 alpha was found to be significantly related to the systolic blood pressure in 5- and 9-week-old rats of the three strains (r = 0.42; n = 71; P less than 0.001). These results exclude a primary role in the development of hypertension for a genetically determined defect in the renal biosynthesis of prostacyclin in the spontaneous hypertensive rat of the Lyon strain.     

Effects of the beta 3-adrenergic receptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on bladder micturition reflex in spontaneously hypertensive rats

The present study investigated whether beta3-adrenoceptor activation acts on the bladder afferent pathway by examination of the visceromotor reflex (VMR) and pressor responses to urinary bladder distension (UBD) and whether beta3-adrenoceptor activation produces urinary bladder relaxation in hyperactive spontaneously hypertensive rats (SHRs) in comparison with their normotensive control rats [Wistar-Kyoto (WKY)]. Using the VMR responses to noxious UBD as a measure of bladder afferent signal transmission, SHRs did not present a sensitized bladder phenotype. However, reduced bladder compliance accompanied by a reduced void threshold was detected in the SHR detrusor. Furthermore, the selective beta3-adrenoceptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) (i.v.) failed to attenuate VMR or pressor responses to UBD in either SHRs or WKY rats, but it dose-dependently inhibited rhythmic contraction (RC) in SHRs. The minimal effective dose was 0.001 mg/kg. Using the same model in WKY rats, CL-316243 did not elicit significant inhibition of contractions in the bladder RC assay. These results suggest that SHRs represent abnormal efferent/detrusor function (detrusor overactivity) without mechanosensory afferent hypersensitivity. The beta3-adrenoceptor agonist CL-316243 acts on the detrusor muscle to increase urine storage in SHRs.     

Failure of angiotensin II to suppress plasma renin activity in normotensive subjects with a positive family history of hypertension

The renin-angiotensin system is implicated in the pathophysiology of hypertension. Renin release is regulated by a number of factors, including circulating Ang II (angiotensin II), the so-called short feedback loop. The aim of the present study was to investigate the responsiveness of circulating Ang II on PRA (plasma renin activity) in normotensive subjects with a PFH or NFH (positive or negative family history of hypertension respectively). PRA, renal haemodynamics and urinary sodium excretion were measured during infusion of Ang II without and with pretreatment with the AT1 (Ang II type 1) receptor blocker irbesartan. Normotensive men with a PFH (n=13) and NFH (n=10), with a mean age of 38 years, were given on different occasions intravenous Ang II infusions of 0.1, 0.5 and 1.0 ng.kg-1 of body weight.min-1 before and after pretreatment with 150 mg of irbesartan once a day for 5 consecutive days. RPF (renal plasma flow) and GFR (glomerular filtration rate) were also measured. Before Ang II infusion, the PFH and NFH groups did not differ with respect to BP (blood pressure), body mass index, PRA, RBF (renal blood flow) or urinary sodium. There was no difference in BP or renal haemodynamic response to the highest Ang II dose between the groups. PRA declined with the highest Ang II dose (P<0.01) in subjects with a NFH, but not in subjects with a PFH. After treatment with irbesartan when Ang II had no effect on BP in either group, Ang II also suppressed PRA in subjects with a PFH (P<0.01), and the difference between the groups at baseline was thus eliminated. In conclusion, these findings indicate that subjects with a PFH have a defective Ang II suppression of PRA, which is corrected by AT1 receptor blockade.     

Direct, simplified, and sensitive assay of angiotensin II in plasma extracts performed with a high-affinity monoclonal antibody.

A very simple, fast, and sensitive RIA of angiotensin (Ang) II has been developed, based on a monoclonal antibody with high affinity and specificity, making possible the direct measurement of circulating Ang II in human plasma after solid-phase extraction. The purified monoclonal antibody 4D8 has an association constant of 1.3 x 10(11) L/mol with Ang II and a cross-reactivity of < 1% for Ang I. The assay can detect as little as 0.8 fmol of Ang II in 2 mL of plasma and is not influenced by the presence of Ang I. Analytical recoveries between 112% and 116% were obtained for Ang II added to human plasma at physiological concentrations. Comparison of the RIA with a reversed-phase, high-performance liquid chromatographic method followed by RIA to measure Ang II in human plasma samples from normal and hypertensive subjects--and from normotensive subjects before and after an acute inhibition of angiotensin-converting enzyme with captopril (50 mg)--showed a high degree of correlation (r2 = 0.93) between the two methods.     

The antiproteinuric action of enalapril in stroke-prone spontaneously hypertensive rats is unrelated to alterations in urinary prostaglandins.

We examined whether the renal protective effect of the angiotensin I converting enzyme inhibitor enalapril in stroke-prone spontaneously hypertensive rats (SHRSP) is dose-related and associated with alterations in the urinary excretion of prostaglandin (PG) E2 and 6-keto-PGF1 alpha, a stable breakdown product of prostacyclin. Enalapril maleate at 1.5, 5 and 15 mg/kg/day or vehicle was chronically administered to saline-drinking SHRSP (six per group) starting at 8.1 weeks of age. Vehicle-treated SHRSP developed severe hypertension, proteinuria and strokes (age at death, 14 +/- 1 weeks; mean +/- S.E.). Enalapril prolonged survival dose-dependently and reduced proteinuria; all SHRSP given 15 mg/kg/day lived beyond 23 weeks of age without evidence of stroke or proteinuria. There was no effect of enalapril at any dose on systolic arterial blood pressure in spite of variable levels of urinary protein excretion and onset of stroke in the different groups. Likewise, urinary 6-keto-PGF1 alpha and PGE2 excretion did not differ among the groups except for an increase in 6-keto-PGF1 alpha in the 15 mg/kg/day group at one week after initiation of enalapril therapy. These results are consistent with a dose-related renal protective action of enalapril in saline-drinking SHRSP that is not closely associated with sustained alterations in urinary excretion of renal vasodilatory PGs.     

Captopril and ANP: changes in renal hemodynamics, glomerular-ANP receptors and guanylate cyclase activity in rats with heart failure.

To define the renal effects of atrial natriuretic peptide (ANP) in heart failure, we studied rats with heart failure after coronary artery ligation. The rats received either captopril (2 milligrams drinking water) or placebo for 4 weeks. Glomerular filtration rate, renal plasma flow, filtration fraction, urine volume, urinary sodium excretion and the percent fractional excretion of sodium were measured before and after an infusion of ANP (0.3 microgram/kg/min). To determine whether changes in ANP receptor binding and responsiveness occur in heart failure and after captopril treatment, we performed radioreceptor binding studies and measured guanylate cyclase activity. Atrial natriuretic peptide in sham-operated rats decreased mean arterial pressure from 118 +/- 5 to 95 +/- 5 mm Hg (P less than .001), increased urine volume from 0.06 +/- 0.02 to 0.16 +/- 0.05 ml/min/kg (P less than .05), urinary sodium excretion, 14.2 +/- 3.1 to 41.4 +/- 8.9 mu eq/min/kg (P less than .02), filtration fraction from 0.30 +/- 0.03 to 0.40 +/- 0.4 (P less than .05), and the percent fractional excretion of sodium from 0.84 +/- 0.19 to 2.85 +/- 0.61 (P less than .02). Atrial natriuretic peptide in untreated rats with heart failure produced no significant systemic or renal hemodynamic effects. In rats with heart failure treated with captopril, ANP decreased mean arterial pressure from 93 +/- 4 to 86 +/- 4 mm Hg (P less than .05) and increased hematocrit from 50 +/- 2 to 52 +/- 1 (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal kallikrein activity in rats developing spontaneous hypertension

1. Spontaneously hypertensive rats (SHR) excrete less kallikrein in urine than Wistar-Kyoto rats (WKY) during the developmental phase of hypertension. The present study was designed to examine whether the urinary defect is related to abnormalities in the renal kallikrein content in this hypertensive model. 2. Active and total kallikrein were measured (amidolytic assay) in the renal cortex of newborn and 4-, 8- and 12-week-old SHR and age-matched WKY. Active and total kallikrein were also measured in urine at the same ages, except at birth. 3. Tissue active kallikrein was significantly lower in SHR at birth, representing on average 53% of the values in WKY expressed as content per total cortex weight. Tissue total kallikrein did not differ between newborn SHR and WKY. 4. SHR at 4, 8 and 12 weeks of age had lower urinary active and total kallikrein excretion. Tissue active akllikrein, but not total kallikrein, was higher than in age-matched WKY per g of cortex weight or per mg of protein, whereas both tissue active and total kallikrein were lower in SHR when expressed as content per total cortex weight. At these three ages, active kallikrein represented, on average 86%, while total kallikrein represented 77%, of the values in age-matched WKY. 5. Our results indicate a defect in prokallikrein activation rather than in kallikrein synthesis in the renal cortex of SHR at birth. The reduction in urinary kallikrein excretion during the developmental phase of hypertension in young SHR is similar to the reduction observed in the renal tissue.     

Effect of acute and chronic treatment of tin on blood pressure in spontaneously hypertensive rats.

Cytochrome P450-dependent metabolites of arachidonic acid (AA) are increased in the kidneys of spontaneously hypertensive rats (SHR) as compared to control rats (WKY) in the period of rapid elevation of blood pressure (BP) from 5 to 13 weeks. We treated rats with stannous chloride (SnCl2) (10 mg/100 g body weight/day for 4 days) to decrease selectively renal cytochrome P450 content through increasing renal heme oxygenase activity. A decrease in renal cytochrome P450-dependent AA metabolites was associated with decreased BP and increased urinary Na+ excretion in 7- but not in 20-week-old SHR rats. Chronic treatment with SnCl2 (10 mg/100 g body weight twice a week) from 5 to 20 weeks prevented the elevation of BP in SHR rats. Further, the antihypertensive effects of tin persisted for 7 weeks beyond its discontinuation. BP in WKY rats was unaffected by tin. Both the acute and chronic treatment with tin are the first studies to demonstrate amelioration of hypertension in SHR by an intervention which is targeted at a single enzyme system.