Captopril-treated Spontaneously Hypertensive Rats Research Articles

Interaction between Angiotensinase Activities in Pituitary and Adrenal Glands of Wistar-Kyoto and Spontaneously Hypertensive Rats under Hypotensive or Hypertensive Treatments.

In the present study, we analyzed the activity of several aminopeptidases (angiotensinases) involved in the metabolism of various angiotensin peptides, in pituitary and adrenal glands of untreated Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHR) or treated with the antihypertensive drugs captopril and propranolol or with the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). Intra- and inter-gland correlations between angiotensinase activities were also calculated. Membrane-bound alanyl-, cystinyl-, and glutamyl-aminopeptidase activities were determined fluorometrically using aminoacyl-β-naphthylamide as substrates. Depending on the type of angiotensinase analyzed, the results reflect a complex picture showing substantial differences between glands, strains, and treatments. Alanyl-aminopeptidase responsible for the metabolism of Ang III to Ang IV appears to be the most active angiotensinase in both pituitary and adrenals of WKY and particularly in SHR. Independently of treatment, most positive correlations are observed in the pituitary gland of WKY whereas such positive correlations are predominant in adrenals of SHR. Negative inter-gland correlations were observed in control SHR and L-NAME treated WKY. Positive inter-gland correlations were observed in captopril-treated SHR and propranolol-treated WKY. These results may reflect additional mechanisms for increasing or decreasing systolic blood pressure in WKY or SHR.

Adverse cardiac remodelling in spontaneously hypertensive rats: acceleration by high aerobic exercise intensity

In the present study it was hypothesized that voluntary aerobic exercise favours a pro-fibrotic phenotype and promotes adverse remodelling in hearts from spontaneously hypertensive rats (SHRs) in an angiotensin II-dependent manner. To test this, female SHRs at the age of 1 year were started to perform free running wheel exercise. Captopril was used to inhibit the renin-angiotensin system (RAS). Normotensive rats and SHRs kept in regular cages were used as sedentary controls. Training intensity, expressed as mean running velocity, was positively correlated with the left ventricular mRNA expression of TGF-β(1), collagen-III and biglycan but negatively correlated with the ratio of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA)2a to Na(+)-Ca(2+) exchanger (NCX). A pro-fibrotic phenotype was verified by Picrosirius red staining. Sixty-seven per cent of SHRs performing free running wheel exercise died either spontaneously or had to be killed during a 6 month follow-up. In the presence of captopril, aerobic exercise did not show a similar positive correlation between training intensity and the expression of fibrotic markers. Moreover, in SHRs receiving captopril and performing free running wheel exercise, a training intensity-dependent reverse remodelling of the SERCA2a-to-NCX ratio was observed. None of these rats died spontaneously or had to be killed. In captopril-treated SHRs performing exercise, expression of mRNA for decorin, a natural inhibitor of TGF-β(1), was up-regulated. Despite these differences between SHR-training groups with and without captopril, positive training effects (lower resting heart rate and no progression of hypertension) were found in both groups. In conclusion, high aerobic exercise induces an angiotensin II-dependent adverse remodelling in chronic pressure overloaded hearts. However, high physical activity can potentially induce reverse remodelling in the presence of RAS inhibition.

Altered Expression of BK Channel β 1 Subunit in Vascular Tissues from Spontaneously Hypertensive Rats

Correlation of blood pressure (BP) with expression levels of large-conductance, voltage- and Ca2+-activated K+ (BK) channel beta1 subunit in vascular tissues from spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) at different ages was investigated. Systolic BP and BK beta1 expression in mesenteric arteries at either mRNA or protein levels were not different among 4-week-old SHR, WKY, and SD. With hypertension developed at 7 weeks and reached plateau at 12 weeks, expression levels of BK beta1 mRNA in mesenteric arteries and aortae from SHR during this period of time were significantly higher than in age-matched normotensive WKY. The BK beta1 protein expression was significantly higher in mesenteric arteries from 12-week-old but not 7-week-old SHR when compared with age-matched WKY and SD. The BK beta1 protein levels in aortae were not different among 7-week-old SHR, WKY, and SD but were significantly lower in 12-week-old WKY than in age-matched SHR and SD. Captopril treatment normalized BP of 12-week-old SHR. This treatment downregulated BK beta1 protein in mesenteric arteries but upregulated it in aortae. No significant difference in BK alpha subunit expression was detected in mesenteric arteries from three strains of rats as well as the captopril-treated SHR. It appears that expression patterns of BK beta1 in vascular tissues vary depending on tissue types, animal age, and animal strains. Expression of BK beta1 in mesenteric arteries is closely correlated with BP in SHR. Increased BK beta1 expression in mesenteric arteries may represent a compensatory reaction to limit the development of hypertension.

Role of eNOS and DDAH1 in the impairment of collateral growth in Spontaneously Hypertensive Rats (SHR) and its reversal by captopril.

Introduction Preliminary microarray studies indicated that eNOS and DDAH1 mRNA were upregulated in collaterals of normotensive (WKY) rats but not SHR collaterals which do not enlarge. Captopril and anti-oxidant therapy restores collateral growth in SHR. The objective of this study was to confirm these microarray results and to determine if upregulation of these genes occurs in captopril-treated SHR (TrSHR). Methods Ileal arteries were sequentially ligated to produce a collateral pathway. Collateral and same animal control arteries were harvested one day after ligation. mRNA levels were determined by RT-PCR. Results The average ratio of collaterals to same animal controls is shown in the table for all groups. eNOS upregulation occurred in collaterals of WKY and TrSHR, but not SHR. DDAH1 was upregulated in collaterals of all groups Conclusions Two novel findings are apparent. 1.) shear-related eNOS upregulation is suppressed in the SHR and this state is reversed with captopril therapy. 2.) In all cases, DDAH1 was increased in the collaterals vs. the controls. The significance of this finding is that DDAH1 inactivates ADMA, the endogenous inhibitor of eNOS. Thus, NO levels may be increased in collaterals which successfully enlarge by these 2 independent mechanisms. These observations are consistent with an essential role for the NO system in collateral growth and indicate that therapy to enhance the NO system may be effective in promoting collateral growth. Support: HL42898

Effect of captopril in the presence of kinin B2-receptor antagonist on duration of survival after prolonged coronary artery ligation in hypertensive rats

In the present investigation, we evaluated the potential effects of captopril, an angiotensin-converting enzyme inhibitor, in the absence and presence of kinin B(2) receptor antagonist (D-Arg-[Hyp3-D-Phe7]-BK) on the duration of survival after prolonged coronary artery ligation in spontaneously hypertensive rats (SHR). The captopril treatment (16 and 32 microg/kg; i.v.) resulted in a significant (p < 0.05) increase in survival time of SHR when compared with that of saline-treated control SHR. Kinin B(2) receptor antagonist (4 microg/kg; i.v.) pretreatment abolished (p > 0.05) the beneficial effect of captopril on the survival time when compared with that in saline-treated control SHR. Both the ligation of coronary artery and captopril treatment resulted in a significant (p < 0.001) fall in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) of SHR when compared with those of the saline-treated control SHR. In addition, captopril administration caused a significant (p < 0.05) fall in SBP, DBP, and HR of SHR before ligation of the coronary artery (preligation). However, there was no significant change (p > 0.05) in SBP, DBP, and HR between saline- and kinin B(2) receptor antagonist plus captopril-treated SHR during preligation. These finding might indicate that captopril possesses a cardioprotective property as demonstrated by an increase in the survival time of SHR. This beneficial effect of captopril is mediated via the kinin B(2) receptor pathway because kinin B(2) receptor antagonist pretreatment blocked the captopril-induced increase in the survival time of SHR.

A bradykinin antagonist abolishes beneficial effect of captopril on duration of survival after acute coronary artery ligation in hypertensive rats

It has been recently suggested that bradykinin (BK) may act as a cardioprotectve agent. In the present investigation, we evaluated the effects of captopril, an angiotensin-converting enzyme inhibitor (ACEI), and kinin B 2 receptor antagonist, d-Arg-[Hyp3- d-Phe7]-BK, on the duration of survival after acute coronary artery ligation for 15 min in spontaneously hypertensive rats (SHR). The captopril treatment (16 and 32 ug/kg, i.v.) resulted in a significant ( p < 0.05) increase in survival time of SHR as compared with saline-treated control SHR. Kinin B 2 receptors antagonist (4 ug/kg, i.v.) pretreatment abolished ( p > 0.05) the beneficial effect of captopril on survival time as compared to saline-treated control SHR. Both the ligation of coronary artery and captopril treatment resulted in a significant ( p < 0.001) fall in systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) of SHR as compared to the saline-treated control SHR. In addition, captopril administration caused a significant ( p < 0.05) fall in the SBP, DBP and HR of SHR before ligation of the coronary artery (preligation). However, there was no significance ( p > 0.05) in SBP, DBP and HR between saline- and kinin B 2 receptor antagonist plus captopril-treated SHR during preligation. These finding might indicate that captopril possesses a cardioprotective property as demonstrated by increased in survival time of SHR. This beneficial effect of captopril is mediated via the kinin B 2 receptor pathway because kinin B 2 receptor antagonist pretreatment blocked the captopril-induced increase in survival time of SHR.

Diminished β-adrenoceptor-mediated relaxation of femoral arteries from young spontaneously hypertensive rats

A β-adrenoceptor agonist, norepinephrine (NE)-induced relaxation in the presence of an α-adrenoceptor antagonist and indomethacin was investigated in isolated femoral arteries from 5-week-old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). NE elicited endothelium-dependent and -independent relaxation in WKY. In endothelium-intact WKY artery, the NE-induced relaxation was reduced by nitro l-arginine ( l-NA) and methylene blue. The residual response to NE in the presence of l-NA was further reduced by tetraethylammonium (TEA). Glibenclamide attenuated the NE-induced, endothelium-independent relaxation in WKY. In SHR, on the other hand, the relaxation to NE was solely endothelium-independent, unaffected by a combination of l-NA and TEA and inhibited by glibenclamide. The relaxation in response to NE in SHR was less than that in WKY, regardless of the presence and absence of endothelial cells. When WKY and SHR were treated for 10 days with captopril, the response to NE was increased not only in WKY but also in SHR. The relaxation in captopril-treated SHR consisted of endothelium-dependent and -independent components. The former was attenuated by l-NA and to a greater extent by TEA with l-NA. Sodium nitroprusside- and forskolin-induced, endothelium-independent relaxations in SHR were not significantly different from those in WKY. Captopril did not affect the response to these drugs. The present results indicate that the relaxation to NE is in part mediated by NO and a vasorelaxing factor distinct from NO in WKY but not in SHR. It is suggested that NE-induced, endothelium-independent relaxation in both groups is in part mediated by ATP-sensitive K + channels. It is also suggested that in SHR, captopril increases the response to NE through increases in endothelial production of NO and the non-NO vasorelaxing factor.

The Relationship Between Angiotensin II (ANG II) and Oxidative Stress in the Maintenance of Mean Arterial Pressure (MAP) of Spontaneously Hypertensive Rats.

48 Spontaneously hypertensive rats (SHR) reportedly have inappropriately high levels of Ang II despite normal plasma renin activity (PRA). Because Ang II stimulates oxidative stress, which in turn quenches nitric oxide, it is possible that Ang II-induced increases in oxidative stress contribute to the increase in blood pressure. Indeed, administering either a converting enzyme inhibitor (to decrease Ang II) or Tempol (a potent antioxidant) reduces blood pressure in SHR. We tested whether decreasing Ang II with a converting enzyme inhibitor reduces oxidative stress as well as MAP in SHR. For this, we divided 12 weeks old SHR into two groups (n=5 each). One group was treated with captopril (100 mg/kg/day added to the drinking water) and the other served as our untreated time controls. After 16 days of treatment, the rats were anesthetised and we measured MAP and collected blood samples to determine PRA, and the plasma levels of Ang II and thiobarbituric acid-reactive substances (TBARS). The captopril-treated rats had a lower MAP than the untreated rats (92±4 vs. 160±5 mmHg, respectively) and an increased PRA (42±1 vs. 26±6 ng/ml/h; captopril-treated vs. untreated rats, respectively). The decreased MAP in the captopril-treated SHR was accompanied by reduced plasma levels of Ang II (630±47 vs. 836±205 pg/ml) and TBARS (5.4±1.0 vs. 3.0±0.2 nmol/ml). Despite the significant decrease in Ang II levels in the captopril-treated SHR, they are still 20-fold higher rhan in normotensive Sprague-Dawley rats (34.0±8.8 pg/ml). In summary, captopril-induced decreases of MAP in SHR are accompanied not only by reduced levels of Ang II, but also by reduced oxidative stress. Because antioxidants also lower MAP in SHR, it suggests that oxidative stress induced by Ang II may play a role in the pathogenesis of the increased blood pressure in SHR.

PERSISTENT IMPROVEMENT OF CARDIOVASCULAR RISK FACTORS IN SPONTANEOUSLY HYPERTENSIVE RATS FOLLOWING EARLY SHORT-TERM CAPTOPRIL TREATMENT

This study was designed to determine whether an improvement in cardiovascular risk factors persists in spontaneously hypertensive rats (SHR) following withdrawal of angiotensin converting enzyme inhibitor (ACE-I) treatment. SHR were given deionized drinking water or captopril solution from four to sixteen weeks of age. At twelve weeks of age, rats from each group were instrumented with radiotelemetry devices for continuous monitoring of blood pressure. Mean arterial blood pressure was significantly lower in captopril-treated SHR during treatment (92±2 vs 147±1 mm Hg), and at twelve weeks after treatment withdrawal (131±2 vs 158±2 mm Hg). In addition, proteinuria, renal vascular resistance, plasma triglyceride levels, fasting glucose levels, postprandial insulin levels, and heart weights were significantly reduced in the treated SHR compared to control SHR, at time-points between three to seven months after captopril withdrawal. Our findings indicate that short-term administration of an ACE-I during the developmental phase of hypertension in the SHR results in a long-term overall improvement of cardiovascular risk factors.

Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) demonstrate elevated blood pressure, cardiac hypertrophy, glucose intolerance, and insulin resistance compared with age-matched Wistar-Kyoto rats (WKY). We investigated concurrent effects of captopril on blood pressure, cardiac mass, myocardial enzyme activities, glucose tolerance, and insulin action in young male SHR. At 10 weeks of age, SHR were randomized into two groups, one receiving distilled water, the other a captopril solution (50 mg/kg body weight/day). We also examined age-matched WKY receiving distilled water. Blood pressure was measured by tail-cuff during the 4-week treatment period and oral glucose tolerance was tested at the end of treatment. Hearts were weighed and ventricular tissue was assayed for activities of 3-hydroxyacyl-CoA dehydrogenase, citrate synthase, and hexokinase. Growth rates were similar between captopril-treated and control SHR, but less than those of WKY. Captopril reduced blood pressure (134 ± 8 v 177 ± 8 mm Hg, P < .05) and left ventricular mass ( −18%, P < .05) in SHR. Cardiac enzyme activities also changed with captopril treatment, reflecting an increased capacity for β-oxidation of fatty acids and reduced potential for glucose phosphorylation in the left ventricle of SHR. Serum concentrations of glucose, insulin, and free fatty acids after a brief fast and in response to oral glucose were not different after captopril treatment, suggesting no improvement in insulin action or glucose tolerance. In summary, treatment of young male SHR with captopril reduces blood pressure and cardiac mass, and promotes a small but significant increase in cardiac capacity for oxidation of fatty acids and reduction of glucose phosphorylation. In contrast, metabolic effects of captopril on oral glucose tolerance and insulin action were not evident.

Lifetime Treatment with Captopril Improves Renal Function in Spontaneously Hypertensive Rats

Lifetime treatment with captopril prevents the development of hypertension in spontaneously hypertensive rats (SHR). This study tests the hypothesis that compared to untreated hypertensive SHR, captopril-treated SHR display similar diuretic and natriuretic responses to an isotonic saline infusion despite significantly lower arterial pressure. Eight-week-old, male SHR were instrumented with femoral arterial, venous, and bladder catheters. Forty-eight hours later, each rat was infused intravenously with an isotonic saline load (5% of body weight; 0. 5 ml/min). Lifetime captopril-treated SHR and untreated control SHR displayed nearly identical natriuretic and diuretic responses to the saline infusion. Thus, although lifetime captopril treatment significantly reduces mean arterial pressure in SHR, renal excretory responses appear to be unaltered. Moreover, histological examination of the kidneys of the lifetime captopril-treated SHR did not reveal significant structural damage in the kidneys at either 8 weeks of age or at 12 months of age. Together, the data suggest that lifetime captopril treatment does not adversely affect renal function and structure in SHR.

Long-Term Treatment With Angiotensin Converting Enzyme Inhibitor Restores Reduced Calcitonin Gene-Related Peptide-Containing Vasodilator Nerve Function in Mesenteric Artery of Spontaneously Hypertensive Rats

Effects of long-term treatment with angiotensin converting enzyme (ACE) inhibitor on decreased function of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRP nerves) in mesenteric resistance artery were investigated in spontaneously hypertensive rats (SHR). Eight-week-old SHR were treated for 7 weeks with 0.1% captopril, 0.01% temocapril, 0.05% pindolol or 0.005% hydralazine in drinking water. Long-term treatment with each drug significantly lowered mean blood pressure of SHR. In isolated and perfused mesenteric vascular beds with active tone, periarterial nerve stimulation (PNS) (0.5 to 8 Hz) produced frequency-dependent vasodilations, which were abolished by CGRP(8-37) (CGRP-receptor antagonist) and significantly smaller in SHR than in normotensive Wistar Kyoto rats. Treatment of SHR with captopril and temocapril but not with pindolol and hydralazine resulted in significantly greater PNS-induced vasodilation than in non-treated SHR, but ACE-inhibitor treatment did not affect vasodilation induced by exogenous CGRP. In captopril-treated SHR preparations, PNS evoked significantly larger CGRP-like immunoreactive release than in non-treated SHR. In non-treated 15-week-old SHR preparations, direct perfusion of captopril or temocapril (0.1 μM and 1 μM) did not modify frequency-dependent vasodilation in response to PNS. These results suggest that long-term ACE inhibitor treatment prevents or restores CGRP nerve function reduction in SHR.

Early captopril treatment prevents hypertrophydependent gene expression in hearts of SHR.

Treatment of spontaneously hypertensive rats (SHR) with captopril (100 mg . kg-1 . day-1) throughout development and during the first 16 wk of life leads to a reduction in blood pressure and left ventricular hypertrophy. Blood pressures and hypertrophy are reduced in these animals (vs. untreated SHR) for up to 24 wk after discontinuation of the drug. We used conventional blot hybridization and Western analysis to examine hypertrophy-dependent gene expression during this period. Ventricular expression of the atrial natriuretic peptide gene was reduced by >90% at 16 wk of age in the captopril-treated SHR. Expression increased in the 24 wk after discontinuation of treatment, but remained well below that of the untreated SHR. A similar reduction in ventricular c-myc gene expression was seen with captopril treatment. Neither renal expression of the atrial natriuretic peptide gene nor ventricular expression of the c-fos gene was affected by captopril. This study demonstrates that captopril treatment during a critical period of development in the SHR leads to a sustained reduction in hypertrophy-dependent myocardial gene expression, which does not revert to levels seen in the untreated SHR after discontinuation of the drug.

Contribution of the sympathetic nervous system to salt-sensitivity in lifetime captopril-treated spontaneously hypertensive rats.

To test the hypothesis that, in lifetime captopril-treated spontaneously hypertensive rats (SHR), the sympathetic nervous system contributes importantly to the hypertensive effect of dietary sodium chloride supplementation. Male SHR (aged 6 weeks) that had been treated from conception onward with either captopril or vehicle remained on a basal sodium chloride diet or were fed a high sodium chloride diet. After 2 weeks, the rats were subjected to ganglionic blockade and 2 days later, an infusion of clonidine. Lifetime captopril treatment significantly lowered mean arterial pressure in both groups. Intravenous infusion of the ganglionic blocker hexamethonium resulted in a rapid decline in MAP that eliminated the dietary sodium chloride-induced increase in MAP in both groups. Infusion of the central nervous system alpha2-adrenergic receptor agonist clonidine also resulted in a greater reduction in MAP in both groups of SHR that were fed the high (compared with the basal) sodium chloride diet. In both lifetime captopril-treated and control SHR, the sympathetic nervous system contributes to the pressor effects of a high sodium chloride diet.

Spinal nociceptive transmission in the spontaneously hypertensive and Wistar-Kyoto normotensive rat

Background and noxious heat-evoked responses of wide-dynamic-range (WDR) and high-threshold (HT) lumbosacral spinal dorsal horn neurons were recorded in spontaneously hypertensive rats (SHRs), Wistar-Kyoto normotensive rats (WKYs), lifetime captopril-treated SHRs, SHRs with bilateral cervical vagotomy, SHRs with bilateral sino-aortic deafferentation (SAD), and SHRs with either a single or repeated administration of naloxone methobromide (NMB). Stimulus-response functions (SRFs) were generated for neurons using 15 sec of heating of the foot at temperatures ranging from 38 to 52°C. Comparisons were made of neuronal response thresholds, slopes of the SRFs, mean discharge frequency during heat stimulation, arterial blood pressure (ABP), and heart rate (HR). The primary finding was that group mean SRFs for both WDR and HT neurons were shifted in a parallel, rightward fashion in SHRs compared to WKYs. Heat-evoked response thresholds were increased and asymptotic discharge frequencies were decreased in WDR and HT neurons of SHRs compared to WKYs. Analyses of group mean SRFs for WDR and HT neurons of SHRs receiving lifetime captopril treatment indicated they were normalized to the SRFs of WKYs, but detailed comparisons using discharge frequency during heat stimulation revealed that this was due to a statistical averaging effect. Specifically, lifetime captopril-treated SHRs not only showed enhanced neuronal responses to the onset of noxious heat but also enhanced adaptation of neuronal responses with continued heating compared to WKYs. Bilateral SAD in SHRs significantly increased the total discharge frequency of WDR neurons to heat stimuli between 44 and 52°C, but produced no change in the response threshold for heat-evoked activation of these neurons. A similar effect of SAD was observed in HT neurons of SHRs, but the greater response thresholds of HT neurons precluded detection of any significant effect. Bilateral cervical vagotomy did not affect response thresholds, slopes, or total discharge frequencies of SHRs, although only WDR neurons were studied. SRFs of WDR and HT neurons in SHRs obtained pre- and post-administration of a single dose of NMB did not differ. However, repeated administration of NMB in SHRs resulted in a parallel, leftward shift in SRFs of both WDR and HT neurons. In all strains and treatments studied, there were no significant differences in background activities of these neurons that might contribute to the observed outcomes. In conclusion, the hypoalgesia reported in human essential hypertensives and animals with chronic hypertension may be due to a significant attenuation in spinal nociceptive transmission. Our data are not definitive on whether increased ABP produced the attenuation of spinal nociceptive transmission in SHRs because the use of the lifetime captopril treatment to lower systemic ABP of SHRs to levels of WKYs may also have affected endogenous facilitatory and inhibitory opioid systems. However, it was possible to demonstrate an inhibitory influence of both sino-aortic afferents and endogenous central opioids on spinal nociceptive transmission in the SHR.

Changes in renal angiotensin II receptors in spontaneously hypertensive rats by early treatment with the angiotensin-converting enzyme inhibitor captopril.

We tested the hypothesis that in utero treatment with the angiotensin-converting enzyme inhibitor captopril could change the affinity, density, and/or subtypes of angiotensin II (Ang II) receptors in the kidneys of spontaneously hypertensive rats (SHR). Newborn, 7-day-old, and 4-month-old SHR and Wistar-Kyoto (WKY) rats were used. SHR and WKY rat breeders were treated with captopril (0.4 mg/mL, 100 mg/kg per day) in drinking water, and their pups were maintained on captopril treatment until experimentation. Control groups were untreated, age-matched SHR and WKY rats. The density, affinity, and subtypes of renal Ang II receptors were determined using radioligand binding techniques and receptor antagonists specific for Ang II receptor subtypes 1 and 2 (losartan, an AT1-specific antagonist, and CGP 42112B, an AT2-specific antagonist). AT1 receptor density in kidneys was higher than AT2 receptor density in both neonatal and adult rats. AT1 receptor density in kidneys increased approximately twofold from birth to 7 days of age in all groups. Newborn and 7-day-old SHR showed significantly greater Ang II receptor densities in kidneys than other rat groups because of significantly greater densities of both AT1 and AT2 receptors. At 4 months of age, there were no significant differences in Ang II receptor densities in kidneys between captopril-treated and control SHR. Our data indicate that the expression of AT1 and AT2 receptors in kidneys is differentially regulated during development. Enhanced activity of the renal renin-Ang II system in newborn and probably fetal SHR may be involved in the pathogenesis of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Salt-induced hypertension in normotensive spontaneously hypertensive rats.

Lifetime treatment with oral captopril prevents the development of hypertension in spontaneously hypertensive rats (SHR). We tested the hypothesis that this treatment also prevents the hypertensive response that occurs when untreated NaCl-sensitive SHR are placed on a high NaCl diet. Female SHR were continuously treated with oral captopril before conception and throughout lactation, and the offspring were similarly treated with oral captopril throughout life. At 6 weeks of age, treated male SHR were placed on an 8% (or remained on a 1%) NaCl diet, and systolic arterial pressure, heart rate, and body weight were monitored for 2 weeks. The 8% NaCl diet caused a rapid increase in arterial pressure in the lifetime captopril-treated rats, and 18 days after the initiation of the diet, the mean arterial pressure of this group was 136 +/- 7 mm Hg compared with 100 +/- 2 mm Hg in the 1% NaCl diet rats. The results of a second experiment confirmed the hypertensive effect of the high NaCl diet in lifetime captopril-treated SHR and demonstrated that after 18 days on the diet the dietary NaCl-induced hypertensive response was greater in magnitude in lifetime captopril-treated compared with untreated SHR. The results also demonstrated that lifetime captopril-treated Wistar-Kyoto rats, which are normotensive irrespective of captopril treatment, display no significant increase in arterial pressure when given a high NaCl diet. A third experiment demonstrated that rapidly progressing NaCl sensitivity is also present in female lifetime captopril-treated SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

ANGIOTENSIN CONVERTING ENZYME INHIBITOR, CAPTOPRIL, INHIBITS CARDIAC HYPERTROPHY WITHOUT CHANGING COLLAGEN TYPES AND CONCENTRATION IN SPONTANEOUSLY HYPERTENSIVE RATS

1. The effects of the ACE inhibitor, captopril, on collagen metabolism in spontaneously hypertensive rats (SHR) with cardiac hypertrophy was examined. Captopril (100 mg/kg per day) was administered in drinking water to 20 week old male SHR for 12 weeks. Collagen concentration was calculated from hydroxyproline content, and relative proportions of types I, III and V collagen were determined by non-interrupted SDS-polyacrylamide gel electrophoresis (SDS-PAGE). These parameters were examined in age and sex matched Wistar-Kyoto (WKY) rats, as well as in non-treated SHR, and compared with those of captopril-treated SHR. 2. Captopril significantly reduced both blood pressure (191 +/- 12.1 vs 146 +/- 11.2 mmHg, P < 0.01), and the ratio of left ventricular (LV) weight to bodyweight (BW; 2.38 +/- 0.17 vs 2.05 +/- 0.12 mg/g, P < 0.01). There were no significant differences in collagen concentration among WKY rats, captopril-treated SHR and non-treated 32 week old SHR. However, total collagen content in captopril-treated SHR reduced significantly compared with non-treated 32 week old SHR (16.8 +/- 2.0 vs 21.3 +/- 0.8 mg, P < 0.01). The relative proportion of type V collagen was significantly higher in both captopril-treated (58.6 +/- 3.4 vs 46.8 +/- 1.3%, P < 0.01) and non-treated 32 week old SHR (59.9 +/- 3.1 vs 46.8 +/- 1.3%, P < 0.01) compared with WKY rats. However, there were no significant differences between captopril-treated SHR and non-treated 32 week old SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic administration of antihypertensive drugs on vasodilation mediated by calcitonin gene-related peptide-containing vasodilator nerves in spontaneously hypertensive rats.

1. The effects of chronic administration of antihypertensive drugs on the vasodilator response mediated by calcitonin gene-related peptide (CGRP)-containing nerves were investigated in spontaneously hypertensive rats (SHR). 2. A 7 week period of antihypertensive treatment with captopril, nicardipine or propranolol during the developmental phase (8-15 weeks of age) significantly lowered the mean blood pressure of SHR when compared with non-treated SHR. 3. The mesenteric vascular beds isolated from SHR, which were chronically administered with captopril, propranolol or nicardipine, were perfused with Krebs' solution containing 7 mumol/L methoxamine to produce active tone and 5 mumol/L guanethidine to block adrenergic neurotransmission. 4. In the mesenteric vascular bed with active tone, perivascular nerve stimulation (PNS; 0.5-8 Hz) caused a frequency-dependent vasodilator response that was abolished by 100 nmol/L tetrodotoxin (neurotoxin) or 1 mumol/L CGRP (8-37), a CGRP receptor antagonist. 5. CGRP-containing nerve-mediated vasodilator responses were significantly greater in captopril-treated SHR and significantly smaller in nicardipine-treated SHR than in non-treated SHR. There was no difference between the response between propranolol-treated SHR and non-treated SHR. 6. These results suggest that chronic treatment with captopril reverses the reduced neurogenic vasodilation mediated by CGRP-containing nerves in SHR.

Changes in aortic levels of tropoelastin mRNA following treatment of rats with the antihypertensive drugs captopril and hydralazine

This manuscript describes changes in the steady state levels of aortic tropoelastin mRNA in spontaneously hypertensive rats (SHR) and normotensive controls (WKY) following treatment with two antihypertensive drugs. Three-week-old WKY and SHR rats were treated with hydralazine (15 mg/kg/day) or captopril (25 mg/kg/day). Tail artery blood pressure was monitored twice weekly. Both drugs prevented the development of hypertension in the SHR rat. At 6 weeks of age, total aortic RNA was extracted and the steady state levels of mRNAs coding for tropoelastin and pro α 1 (III) collagen were determined by slot blot hybridization analysis using radiolabeled tropoelastin and pro α 1 (III) collagen cDNA clones. Hydralazine treatment resulted in a threefold increase in tropoelastin mRNA levels in both the SHR and the WKY animals ( P < 0.01). Captopril-treated SHR animals demonstrated a similar significant increase. In contrast, no differences in pro α 1 (III) collagen mRNA levels were observed in the aorta of SHR or WKY rats following treatment with either captopril or hydralazine. These data suggest that antihypertensive agents can act specifically to directly induce tropoelastin mRNA levels in large arteries and thus may induce vascular remodeling independent of an increase in blood pressure.