Captopril reduces aortic and microvascular growth in hypertensive and normotensive rats

This experiment was designed to investigate the effect of converting enzyme inhibition on functional and structural vascular alterations in one-kidney, one clip hypertensive rats and in normotensive rats. Starting 1 day before surgery, 100 mg/kg/day captopril was given chronically to half of the hypertensive and normotensive groups in their drinking water. With use of intravital microscopy in the cremaster muscle, arteriolar dimensions were measured 4 weeks later, both before and after topical application of 10(-3) M adenosine. Mean blood pressure was 124 +/- 4 mm Hg in control rats and 103 +/- 5 mm Hg in captopril-treated control rats (p less than 0.05). Mean blood pressure was significantly elevated to 183 +/- 5 mm Hg in captopril-treated one-kidney, one clip hypertensive rats and 193 +/- 5 mm Hg in one-kidney, one clip hypertensive rats. With use of histological techniques, a marked reduction of medial-intimal area of the abdominal aorta was found in captopril-treated control rats (24%), and hypertrophy of the aortic wall in one-kidney, one clip hypertensive rats was decreased 26% by captopril. Structural diameter reductions occurred in large arterioles of the captopril-treated control and hypertensive groups and the nontreated hypertensive group. In spite of a significant increase in wall-to-lumen ratio of first-order arterioles in all captopril-treated rats, captopril decreased cross-sectional wall area of these vessels 37% in hypertensive and 20% in control rats, respectively. Measured by stereological techniques, small arteriolar density decreased 30% in captopril-treated hypertensive rats and 17% in captopril-treated control rats. Therefore, smaller arteriolar lumens, decreased aortic and arteriolar cross-sectional wall area, and arteriolar rarefaction after converting enzyme inhibition, in spite of rising or falling blood pressure, are evidence that vascular growth was inhibited in vivo.     

Role of endothelium-derived prostanoid in angiotensin-induced vasoconstriction

To test the hypothesis that prostanoids contribute to angiotensin II-induced vascular contraction, we compared the effect of angiotensin II on isometric tension development by rings of descending thoracic aorta bathed in Krebs' bicarbonate buffer with and without indomethacin (10 microM) to inhibit cyclooxygenase, CGS13080 (10 microM) to inhibit thromboxane A2 synthesis, or SQ29548 (1 microM) to block thromboxane A2/prostaglandin endoperoxide receptors. The comparisons were made in rings of aorta taken from normotensive rats and from rats with aortic coarctation-induced hypertension at 12 days and 90-113 days after coarctation. These rings released thromboxane B2, which was found to be endothelium dependent, increased in hypertensive rats, and stimulated by angiotensin II (10(-6) M) in normotensive rats and in hypertensive rats at 12 days after coarctation. The angiotensin II (10(-6) to 10(-5)M)-induced contraction of aortic rings was increased by about 30% at 12 days after coarctation and decreased at 90-113 days after coarctation. Removal of the endothelium increased the contractile effect of angiotensin II (10(-6) M) in aortic rings of normotensive rats and hypertensive rats at 90-113 days after coarctation but decreased the effect in aortic rings of hypertensive rats at 12 days after coarctation. In rats at 12 days after coarctation, the angiotensin II (10(-6) M)-induced contraction of aortic rings with endothelium was attenuated by indomethacin and SQ29548 but not by CGS13080. These data suggest that a prostanoid-mediated and endothelium-dependent mechanism of vasoconstriction contributes to the constrictor effect of angiotensin II in aortic rings of rats in the early phase of aortic coarctation-induced hypertension.     

Induction of angiotensin I-converting enzyme in rat lung with captopril: the effect of adrenalectomy

In spontaneously hypertensive rats, treatment with captopril, 0.2 g/liter of drinking fluid for 12 to 24 weeks, caused a threefold increase in serum angiotensin I-converting enzyme activity. Angiotensin I-converting enzyme increased 25 to 120 percent in lung plasma membranes. The elution profile of angiotensin I-converting enzyme on DEAE cellulose and after gel filtration on Sepharose 4B was unchanged by captopril. The Km value value also remained unchanged. In Wistar rats subjected to bilateral adrenalectomy, treatment with the same dose of captopril for 3 days resulted in increased serum angiotensin I-converting enzyme activity in both sham-operated and adrenalectomized rats, but angiotensin I-converting enzyme concentration increased in lung plasma membranes from sham-operated rats and captopril-treated rats only. We conclude that captopril causes induction of angiotensin-converting enzyme biosynthesis in spontaneously hypertensive and Wistar rats. The change is a quantitative one. Intact adrenal glands may be important for the incorporation of angiotensin I-converting enzyme into lung membranes.     

Effect of angiotensin converting enzyme inhibitors upon brain angiotensin II binding.

OBJECTIVE: The major objective of the current study was to determine whether administration of converting enzyme (CEI) inhibitors produces an alteration in angiotensin II receptor binding in the spontaneously hypertensive rat (SHR). DESIGN: These studies were designed to test the hypothesis that administration of CEI to SHR is associated with a downregulation of the brain angiotensin II receptor. METHODS: Ten to fifteen rats per group were used as mating pairs to produce the pups used for cell culture. The specific binding of 125I-angiotensin II to cell membranes was determined in primary neuronal enriched cultures (PNC) developed from whole brains of 1-day-old SHR pups treated in utero with captopril compared with control SHR pups. We then determined the effect of short-term incubation of PNC with captopril or lisinopril upon angiotensin II binding kinetics. RESULTS: 125I-angiotensin II binding in PNC from captopril-treated SHR was decreased compared with cells from control rats. Scatchard analysis revealed no differences in receptor affinity but maximum density of binding sites was less in captopril-treated rats than in controls. Short-term incubation of cells with captopril or lisinopril did not affect angiotensin II binding in neuronal cultures from normotensive rats; however, angiotensin II binding was decreased in SHR cells treated with captopril. Angiotensin II binding was also decreased in SHR treated in utero with captopril. CONCLUSIONS: These data suggest that CEI decrease 125I-angiotensin II binding in brains from SHR and, furthermore, that the angiotensin II receptor in SHR may be regulated differently from that of normotensive rats.     

Endothelium-dependent relaxation and L-arginine metabolism in genetic hypertension.

This study characterizes the effects of L-arginine and NG-monomethyl L-arginine on dilator responsiveness of vascular tissue from Wistar-Kyoto rats and stroke-prone spontaneously hypertensive rats. Rings of abdominal aorta were suspended in tissue baths for measurement of isometric force. After contraction induced by phenylephrine, cumulative addition of acetylcholine, L-arginine, or A23187 to the muscle bath caused a similar relaxation of aortic rings in both animal groups. To test the hypothesis that arginine metabolism is altered in hypertension, aortic rings were incubated with NG-monomethyl L-arginine. NG-monomethyl L-arginine (10-300 microM) did not affect contractile responses to phenylephrine (10(-10) to 10(-4) M) in either animal group (EC50, 10(-7) M). Exposure of aortic rings to NG-monomethyl L-arginine resulted in a greater inhibition of relaxation response to acetylcholine (10(-10) to 10(-6) M) in hypertensive animals. NG-monomethyl L-arginine (300 microM) caused complete inhibition of relaxation to acetylcholine in the hypertension group. Incubation with L-arginine (10-100 microM) overcame the inhibition of acetylcholine-induced relaxation produced by NG-monomethyl L-arginine in both groups. Exposure of aortic ring segments to NG-monomethyl L-arginine attenuated relaxation responses to A23187 (10(-10) to 3 x 10(-6) M) in both groups. L-Arginine-induced reversal of the inhibitory effect of NG-monomethyl L-arginine on the relaxation responses to A23187 was similar between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in the Vasoreactivity of Hypertensive Rat Aortic Rings: Role of Nitric Oxide and Superoxide Radicals

Objectives:Present study was undertaken to investigate involvement of nitric oxide (NO) and superoxide radicals in the modulation of vasoreactivity in a model of renal hypertension

Method:Hypertension was induced in the male Sprague Dawley rats by aortic banding just above the left kidney. Relaxation or contraction following cumulative addition of acetylcholine (Ach, 1 × 10^-8to 1 x^-5M) or phenylephrine (PE, 1 × 10^-8to 1 × 10^-5mol/1) was studied in the aortic rings obtained from sharn operated normotensive, hypertensive and captopril pretreated rats. Ach and PE responses were taken in the presence or absence of NO synthase inhibitor (L-NAME; 1 × 10^-5and 1 × 10^-4mol/1). Spontaneous release of NO from the aortic rings was evaluated by studying the inhibition of adenosine phosphate stundated platelet aggregation, while superoxide radcals were estunated by cytochrome c reduction method

Results:Ach induced vasorelaxation in PE precontracted rings was impaired followmg 8 wk alter aorbc bandmg, while spontaneous release of NO remained unaffected. Captopril pretreatment restored the aortic ring responsiveness to Ach. An increase in the superoxide radicalgeneration and PE induced contraction following L-NAME treatment in the hypertensive rat aortic rings was observed

Conclusion:Attenuation in the Ach induced NO release and augmentation in the superoxide radcal generation seems to play an important role in the modulation of vasoreactivity following renal hypertension in rats     

Cardiovascular effects of Helichrysum ceres S Moore [Asteraceae] ethanolic leaf extract in some experimental animal paradigms

The aim of this study was to examine some in vivo and in vitro cardiovascular effects of Helichrysum ceres leaf ethanolic extract (HCE) in experimental animal paradigms. The acute effects of HCE on blood pressure were studied in anaesthetised normotensive male Wistar rats challenged with intravenous hypotonic saline infusion after a 3.5-hour equilibration for four hours of one-hour control, 1.5-hour treatment and 1.5-hour recovery periods. HCE was added to the infusate during the treatment period. Sub-chronic hypotensive effects of HCE were examined in weanling Dahl saltsensitive (DSS) genetically hypertensive rats, which progressively develop hypertension with age, treated with HCE (80 mg/kg) every third consecutive day for seven weeks. Isolated atrial muscle strips, portal veins and descending thoracic aortic rings of healthy normotensive Wistar rats were used to investigate the vascular effects of HCE. Acute HCE administration caused a significant (p < 0.05) fall in blood pressure in the normotensive anaesthetised Wistar rats. DSS hypertensive rats treated with HCE displayed low arterial blood pressure and heart rate values from weeks five to seven. HCE produced concentrationdependent negative inotropic and chronotropic effects on rat isolated electrically driven left, and spontaneously beating right atrial muscle preparations, respectively. HCE also evoked concentration-dependent relaxation responses of endothelium-intact aortic rings and portal veins isolated from healthy normotensive Wistar rats. The vasorelaxant effects of HCE in intact aortic rings were significantly reduced, but not completely abolished by adding endothelial- derived factor (EDRF) inhibitor, L-NAME, suggesting that the vasorelaxant effect of the extract is mediated via EDRF-dependent and independent mechanisms. The results of the study suggest that the hypotensive action of HCE is elicited, in part, directly by decreasing myocardial contractile performance and total peripheral vascular resistance due to its negative inotropic and chronotropic effects on rat isolated atrial muscle strips; and vasorelaxant effects on isolated vascular smooth muscles. The observed cardiovascular effects of HCE partly support the basis for its use in the management of high blood pressure in folkloric medicine.     

Inhibitory actions of captopril on norepinephrine release from adrenergic nerve endings in spontaneously hypertensive rats

The purpose of the present study was to investigate the mechanisms of the hypotensive actions of an angiotensin converting enzyme inhibitor of the hypotensive actions of an angiotensin converting enzyme inhibitor (captopril) in hypertension. In perfused mesenteric vasculatures from spontaneously hypertensive rats (SHR, Okamoto and Aoki strain, 10-13 weeks of age) and age-matched normotensive Wistar Kyoto rats (WKY), the effects of captopril on vascular responsiveness and norepinephrine release from the adrenergic nerve endings were examined. The vasoconstrictor responses and norepinephrine release during the electrical nerve stimulation were significantly enhanced in SHR compared to those in age-matched WKY. Captopril reduced both vasoconstrictor responses and norepinephrine release during the electrical nerve stimulation, dose-dependently. These inhibitory effects of captopril were significantly greater in SHR than in WKY. The results demonstrate that captopril affects presynaptic sites on the resistance vessels and causes a decrease in electrically-stimulated norepinephrine release from the adrenergic nerve endings. The marked reduction of both pressor responses and norepinephrine release by captopril in SHR suggests an enhanced renin-angiotensin system in the vascular walls of hypertension.     

The effects of short-term nifedipine treatment on responsiveness of aortic rings of cadmium-hypertensive rats.

The effects of short-term antihypertensive treatment with nifedipine on blood pressure and vascular responsiveness were studied in cadmium-hypertensive and normotensive control rats. Cadmium administration caused a significant increase in mean arterial blood pressure. Endothelin-1, noradrenaline and angiotensin II produced concentration dependent contractions of aortic rings that attained a lower maximal contraction in cadmium-hypertensive rats. Responses of aortic rings to KCl did not show a significant difference between the groups. Nifedipine administered simultaneously with cadmium inhibited the induction of hypertension. Nifedipine treatment for 5 days significantly reduced the blood pressure in cadmium-hypertensive and normotensive rats. Neither inhibition of hypertension nor normalization of blood pressure in cadmium-hypertensive rats caused an alteration in contractile responses of aortic rings to vasoconstrictors which suggested that development of decreased vascular reactivity and of hypertension occurs simultaneously in cadmium-hypertensive rats but the role of decreased vascular reactivity in maintenance of hypertension is questionable in cadmium-hypertension.     

Calcium Supplementation Is Associated With Endothelium Dependent Attenuation of Vascular Smooth Muscle Reactivity in Normotensive Pregnant and Nonpregnant Rats

The study tests the hypothesis that the blood pressure lowering effect of a high calcium diet is mediated through attenuation of vascular reactivity and examined the mechanisms involved in both normotensive pregnant and nonpregnant rats. The contractile responses of aortic rings of Wistar rats fed on high (1.7%, 2.1%) and normal (0.9%) calcium diets to phenylephrine, angiotensin II, KCl, and CaCl₂ were studied. The relaxations to acetylcholine and potassium chloride, as well as the effects of endothelial denudation, pretreatment with indomethacin (10⁻⁶ mol/L), methylene blue (10⁻⁶ mol/L), and calcium free solution on the responses to phenylephrine were also examined.In both pregnant and nonpregnant rats, the contractile responses of aortic rings of animals fed a high calcium diet to all the agents were significantly attenuated, compared with those of controls. After endothelial denudation, or treatment with methylene blue, but not with indomethacin, the responses of the rings to phenylephrine were enhanced and not different from similarly treated rings from rats on a normal calcium diet. There was no difference in the contractile responses to phenylpehrine in calcium free solution. The relaxation to acetylcholine, but not to potassium chloride, was enhanced in rings from rats on a high calcium diet. The diminution in reactivity was not associated with corresponding changes in sensitivity of the tissues.It is concluded that in normotensive rats a high calcium diet is associated with diminished vascular smooth muscle reactivity that is endothelium dependent, and involves increased stimulation of the nitric oxide–guanylate cyclase pathway but not of the sodium–potassium ATPase or prostacyclin.     

Long-term inhibition of angiotensin converting enzyme suppresses calcium channel agonist-induced contraction of aorta in hypertensive rats

To elucidate functional changes in the vascular smooth muscle of spontaneously hypertensive rats (SHR) after chronic inhibition of angiotensin converting enzyme, we examined the contractile responses to different pharmacological interventions in the isolated aortas from SHR treated with a novel angiotensin converting enzyme inhibitor, CS-622 (10 mg/kg/day) for 20 weeks. In normal K+ medium, a marked contraction was elicited by increasing Ca2+ concentration from 0 to 3 mM in aortas from a control group of SHR, but not in aortas from SHR treated with CS-622. In 60 mM K+ medium, however, the sensitivity of aorta to Ca2+ was almost the same in the two groups. A calcium channel activator, CGP-28392 (10(-7) to 10(-6) M), induced a marked contraction in the aortas from control SHR, but not in the aortas from CS-622-treated SHR. When slightly depolarized in 10 or 12 mM K+ solution, the aortas from CS-622-treated SHR contracted in response to CGP-28392. The aortic sensitivity to KCl contraction was much lower in CS-622-treated SHR than in untreated SHR, whereas the sensitivity to phenylephrine contraction was little different in the two groups. These contractile profiles of aortas from CS-622-treated SHR were very similar to those from normotensive Wistar-Kyoto rats but not to those from hydralazine-treated SHR. These data suggest that contractions due to Ca2+ through voltage-dependent calcium channels are exaggerated in SHR aorta and that long-term treatment with angiotensin converting enzyme inhibitor suppresses the abnormal contractility of SHR vascular smooth muscle, probably through alterations of voltage-related functions of calcium channels.     

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.     

Role of endogenous angiotensin II on glutamatergic actions in the rostral ventrolateral medulla in Goldblatt hypertensive rats

In this study, we investigated the cardiovascular responses mediated by rostral ventrolateral medulla neurons (RVLM) in the Goldblatt hypertension model (2K-1C) treated or not treated with captopril. The actions of glutamate into the RVLM were tested, injecting glutamate (0.1 mol/L, 100 nL) and its antagonist kynurenic acid (0.02 mol/L, 100 nL). Glycine (0.5 mol/L, 100 nL) was also microinjected. Experiments were performed in male Wistar rats (weight, 250 to 300 g); 5 groups were studied: (1) 2K-1C nontreated (H, n=6); (2) 2K-1C treated with captopril, 10 mg/kg per day (Ht10, n=10); (3) 2K-1C treated with captopril, 50 mg/kg per day (Ht50, n=7); (4) control normotensive rats (N, n=7); and (5) normotensive rats treated with captopril, 50 mg/kg per day (Nt50, n=8). All experiments in 2K-1C were performed 6 weeks after renal surgery; captopril treatment lasted for the last 2 weeks. In urethane-anesthetized rats (1.2 g/kg IV), bilateral microinjection of glycine into the RVLM caused a depressor response; there was no difference between groups in relation to the change of variation (N: 54+/-2; H: 46+/-12; Ht10: 50+/-3, and Ht50: 42+/-7 mm Hg). Only in the H group, kynurenic acid microinjection into the RVLM caused a depressor response (H: 158+/-8 to 132+/-8 mm Hg). Glutamate response was larger in hypertensive than in normotensive rats (N: 38+/-2.6 and H: 55+/-6); no difference was observed between hypertensive groups. The data suggest that glutamate acts tonically to drive the RVLM in 2K-1C rats, and this action is modulated by endogenous angiotensin II. The increase in the glutamate actions within the RVLM may contribute to the pathogenesis of renovascular hypertension.     

Dietary gamma-linolenic acid lowers blood pressure and alters aortic reactivity and cholesterol metabolism in hypertension.

OBJECTIVE: To determine the effects of dietary gamma-linolenic acid upon blood pressure, aortic reactivity and cholesterol metabolism in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. DESIGN: Randomized parallel-group study. METHODS: SHR and WKY rats were fed a purified diet containing either sesame or borage oil rich in gamma-linolenic acid for 7 weeks. Blood pressure measured by the tail-cuff method and weight were monitored weekly. At the end of the study, intra-arterial pressor responses to norepinephrine and angiotensin II, and reactivity of isolated aortic rings to norepinephrine, angiotensin II, KCl and acetylcholine were determined. Serum cholesterol and triglycerides were measured. Hepatic and intestinal enzymes and receptors of cholesterol metabolism were also measured. RESULTS: Dietary borage oil significantly decreased blood pressure in SHR and WKY rats compared with sesame oil-fed rats. Pressor responses to norepinephrine and angiotensin II, and aortic reactivity to norepinephrine, angiotensin II, KCl and acetylcholine were not significantly different. The borage oil diet increased serum cholesterol levels in WKY rats and hepatic B-hydroxy-3-methylglutaryl coenzyme A reductase in SHR. CONCLUSION: These data indicate that dietary borage oil has a blood pressure lowering effect in hypertensive and normotensive rats. However, the effect cannot be explained by altered sensitivity to humoral and neural vasoconstrictors or changes in cholesterol metabolism. Other mechanisms should be investigated.     

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.     

Comparison of converting enzyme inhibitor and calcium channel blocker in hypertensive glomerular injury

The protective effect of converting enzyme inhibitors in experimental hypertensive glomerular injury is associated with decreased systemic arterial and glomerular capillary pressure. Although calcium channel blockers effectively lower systemic blood pressure, their effect on glomerular capillary pressure and on hypertensive glomerular injury is uncertain. We compared equihypotensive treatment with the calcium antagonist TA 3090 or the converting enzyme inhibitor captopril in post-salt hypertensive Dahl salt-sensitive (DS) rats for up to 5 weeks after five sixths nephrectomy. Before the nephrectomy, all rats demonstrated hypertension (mean 177 mm Hg), proteinuria (mean 175 mg/day), and mild glomerulosclerosis (mean injury score 35). Rats treated with captopril or TA 3090 demonstrated a significant and equivalent decrease in systolic blood pressure compared with untreated rats at 2, 3, and 5 weeks after five sixths nephrectomy; however, only captopril reduced proteinuria. Final proteinuria was actually increased in rats treated with TA 3090 compared with untreated rats. Glomerular injury score was significantly decreased in captopril-treated compared with untreated rats at 2 weeks (33 +/- 9 versus 117 +/- 10, p less than 0.05) and 5 weeks (46 +/- 9 versus 94 +/- 24, p less than 0.05), whereas treatment with TA 3090 delayed but did not prevent progressive glomerular injury (2-week score 35 +/- 7, p less than 0.05 versus untreated; 5-week score 109 +/- 19, p = NS versus untreated). Thus, in hypertensive DS rats after subtotal nephrectomy, treatment with a converting enzyme inhibitor reduced systemic blood pressure, proteinuria, and glomerulosclerosis. However, equihypotensive treatment with a calcium channel blocker did not reduce proteinuria and delayed but did not prevent glomerulosclerosis. Thus, in the rat similar reductions in systemic blood pressure with these two classes of agents have disparate effects on the progression of chronic renal failure.     

Dissociation between in vivo and in vitro measurements of converting enzyme activity after chronic oral treatment with captopril in rats

Intravenous administration of captopril (20 micrograms) produced inhibition of angiontensin I pressor responses by 70 percent and of plasma-converting enzyme activity by 72 percent. Oral treatment with captopril (50 mg/kg/day) for 1 week inhibited angiotensin I pressor responses more (84 percent) than plasma-converting enzyme activity (23 percent). Four month oral treatment of normotensive and spontaneously hypertensive rats with captopril (50 mg/kg/day) led to 68 and 71 percent inhibition of angiotensin I pressor responses, but produced increases in plasma-converting enzyme activity of 123 and 94 percent, respectively. In spontaneously hypertensive rats, elevated converting enzyme activity in the medulla oblongata was measured after this treatment. It is concluded that plasma-converting enzyme activity measurements can be dissociated from the in vivo inhibition of converting enzyme. Chronic oral captopril treatment results in an induction of converting enzyme biosynthesis not only in peripheral tissue but also in the brain.     

Chronic captopril administration decreases vasodilator responses in skeletal muscle arterioles.

Changes in arteriolar reactivity to dilator agonists were assessed in the cremaster muscle of Sprague-Dawley rats fed normal rat chow with captopril (100 mg/kg/day) in the drinking water for 8 weeks and in nontreated controls. The in situ cremaster muscle was prepared, superfused with physiologic salt solution, and arteriolar diameter was measured using television microscopy. Changes in the diameter of distal arterioles in response to topical application of iloprost, forskolin, cholera toxin, acetylcholine, and nitroprusside were measured with a video micrometer. Arteriolar responses to each of the vasodilator agonists used in this study were significantly reduced in the captopril-treated rats, relative to the untreated controls. The maximum dilation of the arterioles, determined during superfusion with Ca2+-free physiologic salt solution containing 10(-4) mol/L adenosine, was also reduced in the captopril-treated rats, suggesting structural remodeling of the arteriolar wall. These observations indicate that chronic angiotensin converting enzyme inhibition with captopril leads to significant alterations in arteriolar structure and reactivity, and that angiotensin II may play a protective role in maintaining normal vascular structure and vasodilator reactivity in the microcirculation.     

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, post-prandial 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.     

Angiotensin II receptor antagonist losartan has persistent effects on blood pressure in the young spontaneously hypertensive rat: lack of relation to vascular structure.

The persistent effects on blood pressure of the angiotensin II receptor antagonist losartan and the converting enzyme inhibitor captopril were compared in the young spontaneously hypertensive rat (SHR). Losartan (DuP753/MK954, 15 mg/kg/day) and captopril (100 mg/kg/day) were given in the drinking water of 3-week-old SHRs for 4- and 10-week durations. Blood pressure was measured during treatment and after treatment was stopped until the age of 30 weeks. Both losartan and captopril given for 4 and 10 weeks prevented the development of hypertension during treatment and redevelopment of hypertension after treatment was stopped. Treatment for 10 weeks was more effective than for 4 weeks in lowering long-term pressure. Four weeks of treatment did not affect the mesenteric resistance artery media/lumen (m1/l1) ratio. In contrast, both losartan and captopril given for 10 weeks resulted in large and significant reductions in m1/l1 [5.3 +/- 0.8 and 5.63 +/- 0.8 vs 7.7 +/- 0.8 x 10(-2) (SD), p less than 0.001]. In losartan-treated rats, plasma renin and angiotensin II concentration were increased between 4- and 7-fold at the end of both treatment periods. These findings show losartan to be an effective antihypertensive agent and support data implicating angiotensin II in the early events leading to hypertension in this model. The abilities of losartan and captopril to affect blood pressure without affecting vascular structure suggest that the latter is a poor predictor of long-term hypertensive levels in the SHR.