Effects of azimilide on cardiovascular tissues from normo- and hypertensive rats

We tested whether azimilide has potential for use in the treatment of heart failure. Azimilide, > or =3 x 10(-5) M, had no effect on the quiescent Wistar-Kyoto (WKY) rat aorta, or mesenteric and intralobar pulmonary arteries. Azimilide > or =3 x 10(-5) M relaxed the KCl-contracted aorta and portal vein. Azimilide, 10(-7)-10(-5) M, prolonged the WKY left ventricular action potential and augmented the force of contraction of left ventricle strips from 12- and 22-month-old WKY rats. Spontaneously hypertensive rats (SHRs), at ages 12 and 22 months, are models of cardiac hypertrophy and failure, respectively. The augmentation of force with azimilide was similar on 12- and 22-month-old WKY rats and 12-month-old SHRs but reduced on the 22-month-old SHR left ventricle. Azimilide, 3 x 10(-6) and 10(-5) M, augmented the force responses of the 22-month-old SHR left ventricle by 40 and 50%, respectively. As azimilide is a vasodilator and positive inotrope in the rat, and the positive inotropic effect is present in heart failure, azimilide should undergo further testing as a positive inotrope for the treatment of heart failure.     

Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats

The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at < or = 3 x 10(-5) M had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10(-6) to 3 x 10(-5) M relaxed the KCl-contracted aorta. Dofetilide at 10(-9)-10(-7) M augmented the force of contraction of leftventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17-21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12- and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10(-7)-10(-5) M reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure.     

Effects of clofilium on cardiovascular tissues from normo‐ and hypertensive rats

1 The overall aim was to test whether clofilium has some potential as a positive inotrope for heart failure. We used Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs) and studied the effects of clofilium on isolated blood vessels, left ventricular action potentials and left ventricular contractility.
2 Clofilium at ≤10^?6 m had no effect on WKY portal vein contractions and at ≤3×10?4 m had no effect on WKY or SHR quiescent mesenteric and intralobar pulmonary arteries.
3 Clofilium at 10^?7–10^?5 m prolonged the WKY left ventricular action potentials and with 10^?6 and 10^?5 m this included after‐depolarizations.
4 Clofilium at ≤3×10^?5 m augmented the peak force, prolonged the contractions and did not cause arrhythmias in the absence and presence of isoprenaline on left ventricle strips from 12‐month‐old WKY.
5 The 12‐month‐old SHR has hypertrophy of the left ventricle with reduced peak force and prolongation of relaxation. The effects of clofilium on 12‐month‐old SHR left ventricle contractility were similar to those in the age‐matched WKY. 6 In summary, clofilium has positive inotropic effects on the rat left ventricle that are maintained in hypertrophy. Clofilium does not have effects on blood vessels that would be detrimental in heart failure. Clofilium prolongs the rat left ventricle action potential and causes after‐depolarizations. The pro‐arrhythmic potential of clofilium, however, makes it unlikely that it could be used as a positive inotrope in the treatment of heart failure.     

Effects of tetraethylammonium, 4-aminopyridine and bretylium on cardiovascular tissues from normo- and hypertensive rats.

Our objective was to test whether potassium-channel blockade is a potential positive inotropic mechanism for heart failure. Thus we studied the effects of tetraethylammonium, 4-aminopyridine and bretylium on left ventricular action potentials, left ventricular contractility in the absence and presence of hypertrophy, and on isolated blood vessels from Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs). Tetraethylammonium at 10(-3)-10(-2) M, 4-aminopyridine at 10(-4)-10(-3) M and bretylium at 10(-6)-10(-4) M prolonged the action potentials of the WKY left ventricular strip. Similar concentrations of tetraethylammonium, 4-aminopyridine and bretylium augmented the peak force, prolonged the contractions, and did not cause arrhythmias in the absence or presence of isoprenaline on left ventricular strips from 12-month-old WKY. The 12-month-old SHR has hypertrophy of the left ventricle with reduced contractility and prolongation of relaxation. The effects of tetraethylammonium and bretylium were similar on WKY and SHR, whereas the effects of 4-aminopyridine were reduced on SHR left ventricular contractility, which suggests that the function of the transient outward-blocking potassium channel may be impaired in hypertrophy. Bretylium at < or = 10(-4) M had no effect on the portal vein, intralobar or mesenteric arteries. Tetraethylammonium and 4-aminopyridine at > or = 10(-5) M increased the duration or amplitude, or both, of the portal vein contractions. Tetraethylammonium at > or = 10(-2) M and 4-aminopyridine at > or = 3 x 10(-4) M contracted the mesenteric artery, and 4-aminopyridine also contracted the intralobar pulmonary artery. In summary, we have demonstrated that the action potential prolonging effects of potassium-channel blockade is associated with a positive inotropic effect on the rat left ventricle. The non-specific blockers, tetraethylammonium and 4-aminopyridine, do not have potential as positive inotropes in heart failure because of their widespread effects, including vasoconstriction. The potential of bretylium and some of the newer selective potassium-channel blockers as positive inotropes requires further evaluation.     

Effects of BDF 9148 on the action potentials and contractions of left ventricles from normo- and hypertensive rats

1. The aim of the present study was to test the hypothesis that responses to BDF 9148, which prolongs the opening of sodium channels, are reduced in the spontaneously hypertensive rat (SHR) left ventricle in the presence of hypertrophy and failure. 2. We studied the effects of BDF 9148 on the action potentials and contractions of left ventricles from 5-week-old prehypertensive, 14-week-old hypertensive, 6- and 12-month-old hypertension-associated hypertrophy and 18-month-old hypertension-induced heart failure SHR and age-matched Wistar-Kyoto normotensive (WKY) rats. 3. Action potentials and left ventricular contractions did not alter in the early stages of hypertension (14-week-old SHR). The diastolic membrane potential did not change with hypertension-associated hypertrophy, but there was a reduction in amplitude and a prolongation of action potentials in the left ventricles of 6-18-month-old SHR. Cardiac stimulation responses and maximum contractions to 10(-6) mol/L isoprenaline were reduced at 6 months, whereas the maximum contractions to 10(-2) mol/L CaCl2 were only reduced in left ventricles of 18-month-old SHR. 4. At concentrations ranging from 10(-7) to 3 x 10(-6) mol/L, BDF 9148 increased the amplitude and prolonged the duration of action potentials and augmented the force in WKY rat left ventricles. The augmenting effects of BDF 9148 at 3 x 10(-6) mol/L were smaller than at 10(-6) mol/L, possibly because the high concentration of BDF 9148 was also blocking calcium channels. Similar effects were observed with BDF 9148 in the early stages of hypertension (14-week-old SHR). 5. In the presence of persistent hypertension-associated hypertrophy of the SHR left ventricle at > or = 6 months, the effects of BDF 9148 on action potentials and contractions were significantly reduced to a small extent. This impairment of the response to BDF 9148 may reflect the reduced contractility of the SHR left ventricle and/or it may indicate that the response to the opening of sodium channels is altered from 6 months of age. 6. In summary, most of the response of BDF 9148 is maintained in the presence of hypertrophy and failure. Thus, BDF 9148 may have some potential for the treatment of heart failure.     

Properties of adenylate cyclase in the cardiovascular tissues of renal hypertensive rats

Adenylate cyclase activity in the myocardium and aorta of Grollman one-kidney renal hypertensive rats (RHR) and sham-operated control rats was compared. The experimental rats revealed significantly higher blood pressure and cardiac hypertrophy 6-8 weeks postoperation as compared to controls. Basal, guanine nucleotide-, fluoride-, and isoproterenol-stimulated adenylate cyclase activities were consistently decreased in the myocardium of RHR as compared to control rats. Similar changes were observed in aorta of RHR; however, the magnitude of difference was greater in aorta as compared to myocardium. The kinetic properties of enzyme with regard to the Ka (quantity of agonist required for half-maximal stimulation of adenylate cyclase) values for GTP, Gpp (NH)p, and GTP-gamma-S in the absence and presence of isoproterenol and the Ka values for isoproterenol in the presence of GTP, Gpp(NH)p, or GTP-gamma-S were comparable in RHR and control rats. However, Vmax of adenylate cyclase stimulation by guanine nucleotides, isoproterenol, and fluoride was reduced in RHR as compared to control rats. No differences between RHR and control rat myocardial membranes were observed in the affinity of [3H]DHA binding. However, the number of binding sites was reduced 20-25% in RHR as compared to control rats. These data would suggest that the number of receptor--cyclase complexes may be reduced in the RHR.     

Responsiveness, affinity constants and beta-adrenoceptor reserves for isoprenaline on aortae from normo-, pre- and hypertensive rats

The objective of this study was to determine the responsiveness, affinity constants and beta-adrenoceptor reserves for isoprenaline on the isolated aorta in the maturation of normotensive and hypertensive rats. The effects of a very slowly reversible antagonist, bromoacetylal-prenololmenthane (BAAM), on the relaxant responses of the aortae of 5- and 14-week-old Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs) to isoprenaline were determined. Five-week-old SHRs are pre-hypertensive and the aortic rings are less responsive to isoprenalinethan age-matched WKY (pD2 values: WKY, 8.40; SHRs, 8.03). Similar relaxant responses to forskol in were obtained on the aortae of 5- and 14-week-old WKY and SHRs. The K(A) value for isoprenaline at the aortic beta2-adrenoceptors of the 5-week-old WKY was 2.1 x 10(-7) M, and similar values were obtained on the aortae of 5-week-old SHR and 14-week-old WKY and SHRs. In the maturation of the WKY aortae from 5 to 14 weeks, there was a reduction in the maximum response, a major loss of sensitivity and a loss of beta2-adrenoceptor reserve for isoprenaline. On 5-week-old SHR aorta, the sensitivity to isoprenaline was 2.5-fold lower, and the beta2-adrenoceptor reserve was less than on age-matched WKY. In the development of hypertension on the SHR aorta from 5 to 14 weeks, there was a reduction in the maximum response to isoprenaline. At 14 weeks, the sensitivity and the beta-adrenoceptor reserve to isoprenaline were similar, but the maximum responses were lower on the SHR than WKY. As there are differences in pre-hypertensive SHR and age-matched WKY aortic responses to isoprenaline, it is no longer valid to consider that the loss of responsiveness to isoprenaline in hypertension is solely owing to the hypertension. There are no changes in affinity, but major changes in the sensitivity, maximum responses and aortic beta2-adrenoceptor reserves to isoprenaline in the maturation of normotensive and pre-hypertensive aortae.     

Potency, affinity constants and receptor reserves for noradrenaline and adrenaline on aortae from aged normo- and hypertensive rats

Previously we have determined the potency, affinity constants (K(A) values), and alpha1-adrenoceptor reserves for noradrenaline and adrenaline on the thoracic aortae of 20-week-old Wistar Kyoto normotensive (WKY) and spontaneously hypertensive rats (SHRs). This study has investigated whether these parameters were altered on the thoracic aortae by ageing, and in hypertension/heart failure. The effects of phenoxybenzamine on the contractile responses of the aortae of 20-month-old WKYs and SHRs were determined. The pD2 values for noradrenaline and adrenaline were 7.1 and 7.0, respectively, on the aortae of 20-month-old WKYs, and similar values were obtained on age-matched SHRs. On the aortae of 20-month-old WKYs, the K(A) values for noradrenaline and adrenaline were 1.85 and 1.95 x 10(-6) M, and the receptor occupancies required for 50% maximum responses were 16 and 24%, respectively. There were lower affinities, by approximately twofold, but similar receptor reserves for noradrenaline and adrenaline on the aortae of age-matched SHRs. In comparison with the aortae of 20-week-old WKYs and SHRs, there was a 5-fold loss of sensitivity to noradrenaline and adrenaline between 20 weeks and 20 months. Between 20 weeks and 20 months there was a 50-fold loss of affinity with ageing and a further twofold loss with hypertension/heart failure, and an increase in alpha1-adrenoceptor reserves for noradrenaline and adrenaline between 20 weeks and 20 months. There were no differences in the sensitivity and affinity, and minor changes in the alpha1-adrenoceptor reserves for noradrenaline and adrenaline between the aortae of 20-month-old WKYs and SHRs. In contrast there were major changes in these parameters in the ageing of the WKY aorta from 20 weeks to 20 months. There were no additional changes in the sensitivity and alpha1-adrenoceptor reserves, but a small additional change in affinity for noradrenaline and adrenaline in hypertension/heart failure on the aortae of 20-month-old SHRs.     

培哚普利和螺内酯对高血压大鼠心血管重构及纤溶的影响

目的：探讨血管紧张素转换酶抑制剂培哚普利（ perindopril ）和醛固酮受体拮抗剂螺内酯（ spironlactone ）对实验性高血压大鼠心脏、血管重构的逆转作用及纤溶系统的影响。方法腹主动脉缩窄法建立高血压动物模型,44只雄性Wistar 大鼠随机分为高血压模型组、培哚普利组（2 mg · kg^-1· d^-1,螺内酯组（20 mg· kg-1· d-1）和假手术组对照组。治疗12周后,各组分别应用超声检测心脏结构和功能,主动脉内径,壁厚,病理检测主动脉形态,测定纤溶酶原激活物抑制物-1（plasminogen activator inhibitor-1, PAI-1）,组织纤溶酶原激活剂（tissure plasminogen activator,t-PA）。结果心脏超声结果显示,螺内酯组和培哚普利组同高血压模型组比较,舒张末期室间隔厚度,左心室后壁厚度,相对室壁厚度,左心室质量,左心室内径,左心房内径明显下降（ P ＜0殮．05或＜0．01）;胸主动脉壁厚明显下降（ P ＜0．01）,病理检测胸主动脉内中膜厚度,胸主动脉内中膜厚度/内径明显下降（ P ＜0．01）。血浆PAI-1水平培哚普利组,螺内酯组同假手术组比较明显升高（ P ＜0．01）,2组同高血压组比较差异无统计学意义（ P ＞0．05）。 t-PA 4组差异无统计学意义（ P ＞0．05）。结论高血压导致心脏、血管重构,纤溶活性降低,培哚普利和螺内酯均能逆转心脏和血管重构,但对高血压导致的低纤溶状态未产生明显逆转作用。     

The effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles from normo- and hypertensive rats.

The objective was to test the hypothesis that the effects of the sodium channel blockers lignocaine and tetrodotoxin are modified in the presence of hypertension-induced hypertrophy. We describe the effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles isolated from 6-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The upstroke velocity, amplitude, and overshoot of the action potential were reduced; action potentials were prolonged; and the contractions were reduced on the hypertrophied left ventricles of the SHRs. Lignocaine and tetrodotoxin reduced the upstroke velocity, amplitude, and overshoot and prolonged the left ventricular action potentials. These effects of lignocaine and tetrodotoxin on the SHR were less than those on the WKY left ventricle, possibly because the action potential was already modified by hypertrophy. Lignocaine also reduced the left ventricular contractions and the concentrations producing this reduction were lower for the hypertrophied than those for the normal left ventricle. Tetrodotoxin at 3 x 10(-6)-10(-5) M caused similar attenuation of the WKY and SHR left ventricle contractions. Our study shows that the effects of lignocaine on contraction are enhanced in the hypertrophied left ventricle of the SHR, which suggests that the binding is increased or the access of lignocaine to the receptor is enhanced in hypertrophy. In contrast, the effects of tetrodotoxin on contractions are similar, and thus the binding or access of tetrodotoxin to the receptor is not altered in the hypertrophied left ventricle of the SHR.     

The effects of bromoacetylalprenololmenthane on the responses to isoprenaline of the left ventricle from normo-, prehyper- and hypertensive rats

1 We have studied the effects of bromoacetylalprenololmenthane (BAAM), a very slowly reversible β-adrenoceptor antagonist, on the responses of the left ventricle of 5 and 22 week old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) to isoprenaline. At 5 weeks the SHRs were prehypertensive and at 22 weeks they had hypertension-induced hypertrophy of the left ventricle. 2 The mean potency of isoprenaline on the left ventricle from 5 week old WKY was similar to that obtained on left ventricles from 22 week old WKY, and 5 and 22 week old SHRs. 3 Following treatment of the left ventricle with BAAM at 10^?6m for 30 min, there was a parallel rightward shift of the isoprenaline concentration–response curves. Treatment with a higher concentration of BAAM (10^?5m) caused non-parallel rightward shifts of the concentration–response curves, with a depression of the isoprenaline maximum responses. These data were used to derive affinity (K_A) values for isoprenaline. The mean isoprenaline K_A value on the left ventricle from 5 week old WKY was 2.44 × 10^?6m , and similar K_A values were obtained on the left ventricles from 22 week old WKY and 5 and 22 week old SHRs. On all the left ventricles tested, isoprenaline produced a half maximal response by occupying less than 1%, and a near maximal response by occupying about 5% of the available β₁-adrenoceptors. 4 This study has shown that there are no differences in the cardiac responses to isoprenaline at β₁-adrenoceptors, isoprenaline K_A values or the β₁-adrenoceptor reserve for isoprenaline on the SHR left ventricle in prehypertension or in the early stages of hypertension-induced hypertrophy.     

Responsiveness, affinity constants and beta 2-adrenoceptor reserves for isoprenaline on portal veins from normo- and pre- and hypertensive rats

1. This study used contractility methods with the portal veins of 5- and 14-week-old Wistar-Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs). The SHRs are prehypertensive at 5 weeks. 2. The first part of our study was to determine whether the responsiveness to isoprenaline and forskolin was altered in the maturation of portal veins from normo- and prehypertensive rats. The responses to forskolin were similar on the portal veins of 5- and 14-week-old WKY and SHRs. 3. The sensitivity and maximum responses to isoprenaline were similar on portal veins of 5- and 14-week-old WKY. The sensitivity and maximum responses to isoprenaline were lower on the portal veins of 5-week-old SHRs (pD2 = 8.25, maximum = 85%) than age-matched WKY (pD2 = 8.79, maximum = 96%); these differences are not caused by hypertension. At 14 weeks, the sensitivity was similar (WKY pD2 = 8.74, SHR pD2 = 8.65) but the maximum responses to isoprenaline were lower on the portal veins SHRs (77%) than WKY (97%). Thus, the sensitivity to isoprenaline increases with the development of hypertension in the SHR portal vein. 4. The second part of the study was to determine whether the affinity for isoprenaline at beta2-adrenoceptors and the fractional beta2-adrenoceptor occupancy-response relationships on the portal vein were altered in maturation from normo- and pre-hypertensive rats. The effects of bromoacetylalprenololmenthane (BAAM), an irreversible beta-adrenoceptor blocker, on the isoprenaline responses of 5- and 14-week-old WKY and SHRs were studied. Maturation of the WKY portal vein between 5 and 14 weeks was associated with a loss of affinity for isoprenaline (from pKA of 7.13 to 7.87), and increase in beta2-adrenoceptor reserve (from 72 to 92% at the 95% response). There were similar affinity and reserve findings in the maturation of the SHR portal vein. Thus, there are major changes in beta2-adrenoceptor structure and reserve in maturation on the portal vein that are irrespective of the development of hypertension.     

培哚普利、普萘洛尔与双氢氯噻嗪对自发性高血压大鼠心血管结构重塑的影响(英文)

目的:探讨培哚普利,普萘洛尔与双氢氯噻嗪对SHR大鼠心血管重塑的影响。方法:16周龄的雄性SHR分别接受培哚普利(5mg·kg~(-1)·d~(-1)),普萘洛尔(40mg·kg~(-1)·d~(-1)),与双氢氯噻嗪(100mg·kg~(-1)·d~(-1))治疗12周,治疗结束后测收缩压,左心室重与体重比。天狼星红染色分析心肌胶原形态与含量;形态计量法分析血管肥厚程度。结果:各治疗组动物的血压治疗后均接近正常水平,3种降压药均可逆转左心室和动脉壁肥厚,培哚普利和普萘洛尔能防止心肌纤维化,双氢氯噻嗪则促进心肌纤维化的进展。结论:培哚普利,普萘洛尔能有效逆转心肌纤维化,双氢氯噻嗪对心肌纤维化有不良影响。     

The interaction between noradrenaline and ATP upon polyphosphoinositide metabolism and contraction in tail arteries from normo- and hypertensive rats.

The effects of, and interaction between, noradrenaline and alpha,beta-methylene ATP upon polyphosphoinositide (PPI) breakdown, investigated by measuring the accumulation of inositol phosphates, and contraction, were studied in tail arteries from normo- (WKY) and spontaneously-hypertensive (SHR) rats. Noradrenaline (10(-7)-10(-3) M) evoked a prazosin (10(-6) M)-sensitive, concentration-dependent increase in total inositol phosphate accumulation in both WKY and SHR rats. No significant differences were observed in either the maximal response or in the concentration range over which noradrenaline evoked this response, between these two populations. Noradrenaline (5 x 10(-7)-5 x 10(-5) M) evoked a concentration-dependent contraction of arteries from both SHR and WKY rats. The responses to noradrenaline were about 2-fold greater at all effective concentrations of noradrenaline in SHR compared with WKY rats. alpha,beta-Methylene ATP (10(-6) M) did not alter noradrenaline-stimulated total inositol phosphate accumulation, in arteries from either SHR or WKY rats, measured either as the maximal response or as the EC50. alpha,beta-Methylene ATP (5 x 10(-6) M), by itself, evoked a contractile response, which was quantitatively similar in SHR and WKY rats, and was additive with the contractile responses to noradrenaline (5 x 10(-7)-5 x 10(-5) M). The maximum response produced by a combination of noradrenaline and alpha,beta-Methylene ATP was quantitatively similar to that produced by noradrenaline alone. No evidence of synergism between alpha,beta-Methylene ATP and noradrenaline upon contraction was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

培哚普利,普萘洛尔与双氢氯噻嗪对自发性高血压大鼠心血管结？…

AIM: To investigate the effects of perindopril, propranolol, and dihydrochlorothiazide on artery wall thickening, left ventricular hypertrophy, and cardiac fibrosis in spontaneously hypertensive rats (SHR). METHODS: After measurement of systolic blood pressure (SBP), 16-wk-old Male SHR were randomly divided into 3 groups (each n = 10), given perindopril (Per, 5 mg.kg-1.d-1), propranolol (Pro, 40 mg.kg-1.d-1), dihydrochlorothiazide (DCT, 100 mg.kg-1.d-1) respectively by gavage for 12 wk. Sex-, age-, and number-matched untreated SHR and normotensive Wistar Kyoto rats (WKY) served as controls. When the treatment finished, body weights (BW) and SBP were measured before decapitation of the rats. The heart was excised rapidly, the left ventricle was weighed and then subjected to collagen content analysis. Vascular wall and lumen ratio from aorta, renal arteries and branch III vessels of mesenteric arteries were determined morphometrically. RESULTS: Treated rats in 3 groups showed a lower SBP and the ratio of left ventricle weight to body weight (LVW/BW) compared with WKY. Artery wall thickening was similarly inhibited in the treated groups. Per and Pro inhibited cardiac fibrosis, but collagen concentration increased in DCT treated SHR [collagen volume fraction (CVF): 19 +/- 4 vs SHR 14 +/- 4, P < 0.05; perivascular collagen fraction(PVCF): 84 +/- 7 vs SHR 79 +/- 5, P < 0.05]. CONCLUSION: Per and Pro inhibited, but DCT promoted, cardiac fibrosis.     

Effects of early perturbation of the renin-angiotensin system on cardiovascular remodeling in spontaneously hypertensive rats

RATIONALE: The goal of this study was to analyze cardiovascular (CV) remodeling in early, short-term CAP treated SHR and their offspring. METHODS: We treated SHR with Captopril (CAP, 100 mg/kg) from in utero to 1 month of age (OCAP). Some of these rats were mated at 3-4 months of age and we used their offspring (2nd G). Controls were untreated SHR, normotensive Wistar Kyoto rats (WKY) and SHR maintained on CAP (SCAP). At 12-14 months of age, rats were cannulated for mean arterial blood pressure (MAP) measurements. An image analysis system was used to quantitate changes in cardiac and vascular (wall-to-lumen ratios, w/l) morphology and fibrosis. RESULTS: Early, short-term CAP treatment prevented the full expression of hypertension in treated rats and their offspring. MAPs were: SHR (180+/-2.2 mm Hg); WKY 125+/-3 mm Hg); SCAP 112+/-2.5mm Hg; OCAP 138+/-2.3 mm Hg; and 2nd G (145+/-2.0 mm Hg). There were significant decreases in heart weight/body weight ratios, large and small vessel morphology, and interstitial and perivascular fibrosis in CAP-treated animals and their offspring in comparison to untreated SHR. CONCLUSIONS: The CV protective properties of early, short-term CAP treatment were not solely due to a reduction in MAP. Although MAP was higher in OCAP and 2nd G, CV structure resembled that found in WKY and SCAP. The effects of our early treatment appear to be due to chronic blockade of the renin-angiotensin system and its effects on growth of CV tissues and the development of fibrosis.     

盐酸埃他卡林对自发性高血压大鼠肾组织KATP通道基因表达的影响

目的:从分子生物学水平探讨盐酸埃他卡林(iptakalimhydrohloride,Ipt)对自发性高血压大鼠(spontaneouslyhypertensiverats,SHR)肾组织KATP亚型表达的影响。方法:SHR于第12周龄进入实验,实验设Ipt1、3和9mg·kg-1·d-13个剂量组,盐酸苯那普利(benazepril)3mg·kg-1·d-1治疗组及SHR空白对照组,另设同周龄同种属正常血压大鼠(wistarKyotorat,WKY)为正常对照组,灌胃给药每天1次,连续12周,观察盐酸埃他卡林对血压和肾组织KATP亚型表达的影响。结果:SHR肾组织SUR2、Kir6.1、Kir1.1mRNA表达较WKY大鼠明显升高,盐酸埃他卡林1、3、9mg·kg-1·d-13个剂量组治疗后均可明显降低血压同时下调肾脏高表达的Kir6.1、Kir1.1mRNA水平,而对SUR2表达无明显影响。结论:盐酸埃他卡林对SHR降压治疗对肾脏的保护作用可能与其影响Kir6.1、Kir1.1基因表达有关。