ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The effect of chronic low- and high-dose treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril (0.01 and 1 mg/kg per day) on the development of hypertension and left ventricular hypertrophy as well as on functional and biochemical alterations of the heart was studied in stroke-prone spontaneously hypertensive rats treated prenatally and subsequently up to the age of 20 weeks. The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment of rats with the bradykinin B2-receptor antagonist Hoe 140 (500 μg/kg per day SC) from 6 to 20 weeks of age. High- but not low-dose ACE inhibitor treatment prevented the development of hypertension and left ventricular hypertrophy. Chronic bradykinin receptor blockade did not attenuate the antihypertensive and antihypertrophic actions of ramipril. High-dose ramipril treatment improved cardiac function, as demonstrated by an increase in left ventricular pressure (29.9%), dP/dtmax(34.9%), and coronary flow (22.1%), without a change in heart rate. The activities of lactate dehydrogenase and creatine kinase and lactate concentration in the coronary effluent were reduced by 39.3%, 55.5%, and 66.7%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 31.3%, 39.9%, and 73.7%, respectively, whereas lactate was decreased by 20.8%. Chronic low-dose ACE inhibitor treatment led to a pattern of changes in cardiodynamics and cardiac metabolism similar to that observed with the high dose. All ACE inhibitorinduced effects on cardiac function and metabolism were abolished by chronic bradykinin receptor blockade. Our results demonstrate that chronic ACE inhibitor treatment in stroke-prone spontaneously hypertensive rats improves cardiac function even at low doses that do not affect the development of hypertension and left ventricular hypertrophy. These effects of the ACE inhibitor are due to bradykinin potentiation. However, bradykinin does not seem to contribute to the antihypertensive and antihypertrophic actions of the ACE inhibitor in this model of hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The transgenic rat TGR(mRen-2)27, in which theRen-2mouse renin gene is transfected into the genome of the rat, develops severe hypertension with high adrenal renin and low kidney renin. These animals express both mouse and rat renin. To investigate the cause of hypertension in the TGR rat, we compared the kinetics of mouse renin acting on mouse and rat angiotensinogens. The optimum pH of the renin reaction in the Sprague-Dawley rat was 6.5, whereas the optimum pH of the reaction in the TGR rat was approximately 8.5. The optimum pH of the renin reaction in the DBA mouse was 6.0. Purified mouseRen-2 renin acting on rat angiotensinogen showed a pH profile similar to that for the renin reaction in the TGR rat. The angiotensinogen concentration in pooled plasma from eight DBA mice was 104.5 ng angiotensin I/mL and was clearly lower than that in Sprague-Dawley rats (772.4±37.3 ng angiotensin I/mL, n=4). The reaction of purified mouseRen-2 renin with rat angiotensinogen was 10 times faster than with mouse angiotensinogen. Plasma renin activity in DBA mice increased dramatically on addition of rat angiotensinogen (from 253.4±66.7 to 225 000±48 000 ng angiotensin I/mL per hour). Intravenous injection of 2 or 10 μL of DBA mouse plasma into the nephrectomized Sprague-Dawley rat increased the mean arterial pressure of the rat by 27.7±4.7 and 61.8±2.7 mm Hg, respectively, whereas injection of 200 μL of Sprague-Dawley rat plasma did not change the mean arterial pressure of the rat. From these measurements and from the kinetic parameters measured by Poulsen and Jacobsen (J Hypertens. 1986;4:175-180), we conclude that the molar concentration of mouse renin in the TGR rat is low compared with that of rat renin (1.5 versus 5.0 pmol/L) but that this low level of circulating mouse renin contributes significantly to plasma renin activity in the TGR rat. The elevation of renin activity and resulting hypertension in the TGR rat therefore can be attributed to the enhanced kinetics of mouse renin acting on rat angiotensinogen.

ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Several different investigators have reported increased stroke mortality in the southeastern United States, leading to the introduction of the term “Stroke Belt.” The results presented here from the Veterans Administration Hypertension Screening and Treatment Program (HSTP) demonstrate an increased all-cause mortality among hypertensive patients seen in HSTP clinics in the southeastern United States when compared with similar patients from other HSTP clinics. Several different groupings of southeastern states were examined and compared with nine states west of the Mississippi River. A total of 11 936 male veterans, 5737 of whom were black, were identified as hypertensive during 1974-1976 in 32 HSTP clinics. Their mean age was 52.4±10.4 years, and their mean pretreatment blood pressure was 153.8±19.1/100.4±9.8 mm Hg. During a minimum of 13.9 years of followup, 5360 (44.9%) of these patients died. Proportional hazards modeling was used to fit a basic survival model with terms representing race, age, blood pressure, smoking, and obesity. Risk was increased with higher blood pressure, age, and smoking and with lower body mass index. For 6 HSTP clinics in an 11-state Stroke Belt (defined as states with stroke mortality >10% above the United States average), the relative risk of death was 1.226 (95% confidence interval, 1.106-1.358) when compared with 9 states west of the Mississippi River. For two different groupings of southeastern states with 10 and 8 HSTP clinics the relative risk of death was 1.231 and 1.295. Mean martingale residuals were used to indicate the relative risk at each clinic after applying statistical controls for age, race, blood pressure, smoking, and body mass index. Four of the 6 Stroke Belt clinics had positive means, indicating that there was excess all-cause mortality among the patients of those clinics. In contrast, only 2 of the 10 non-Stroke Belt clinics had positive means.

ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We examined the dose-related effects of angiotensin-converting enzyme inhibitors on circulating and tissue levels of angiotensin and bradykinin peptides by administering perindopril or lisinopril to rats in drinking water for 7 days. A reduction in the ratio of plasma angiotensin II (Ang II) to Ang I was seen for 0.006 mg/kg per day perindopril, with an increase in plasma renin and Ang I at 0.017 mg/kg per day. Plasma Ang II levels did not decrease until 1.4 mg/kg per day perindopril, at which dose plasma Ang I levels reached a plateau of an approximate 25-fold increase. The effects of perindopril on Ang II and Ang I levels in heart, lung, aorta, and brown adipose tissue were parallel to those observed for plasma. By contrast, renal Ang I levels did not increase, and renal Ang II levels decreased by 40% at 0.017 mg/kg per day, the same threshold seen for the increase in plasma renin. Perindopril increased circulating bradykinin-(l-9) levels approximately eightfold, with a threshold dose of 0.052 mg/kg per day, and increased bradykinin-(l-9) levels in kidney, heart, and lung in parallel with the changes observed for plasma. By contrast, aortic and brown adipose tissue bradykinin-(l-9) and bradykinin-(l-7) levels increased severalfold for perindopril doses as low as 0.006 mg/kg per day. Lisinopril also increased aortic bradykinin-(l-9) and bradykinin-(l-7) levels at doses below the threshold for the decrease in the ratio of Ang II to Ang I. These data indicate that renal Ang II levels and vascular bradykinin-(l-9) levels respond to low doses of converting enzyme inhibitor and may be important mediators of the effects of these compounds. The parallel increases in bradykinin-(l-9) and bradykinin-(l-7) levels in aorta and brown adipose tissue, at inhibitor doses below the threshold for inhibition of Ang I conversion, may result from a mechanism different from inhibition of “classic” angiotensin-converting enzyme.

ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Although angiotensin converting enzyme inhibitors and α1-blockers have been reported to improve insulin sensitivity, their mechanisms of action have not been elucidated. To investigate the role of kinins in insulin sensitivity, we treated 4-week-old spontaneously hypertensive rats with either an angiotensin converting enzyme inhibitor (enalapril), an α1-blocker (doxazosin), or an angiotensin II antagonist (losartan) for 3 weeks. A control group received no drugs. In addition, 18 rats treated with enalapril or doxazosin received a simultaneous administration of a kinin antagonist (Hoe 140). Glucose clamp testing was performed in each group. Enalapril (128±1 mmHg) and doxazosin (132±2 mm Hg) decreased mean blood pressure compared with control levels (148±1 mm Hg) (P<.01). The glucose requirement for the clamp test during the administration of enalapril (25.8±0.5 mg/kg per minute) or doxazosin (28.6±0.7 mg/kg per minute) was higher than that of the control group (19.8±0.5 mg/kg per minute) (P<.05). Although Hoe 140 did not alter the glucose requirement of doxazosin (27.8±0.5 mg/kg per minute), it decreased that of enalapril (22.6±0.9 mg/kg per minute) (P<.05) without affecting the changes in mean blood pressure induced by enalapril. In addition, losartan decreased mean blood pressure but did not affect the glucose requirement. Thus, the improvement in insulin sensitivity produced by an angiotensin converting enzyme inhibitor is mostly dependent on kinins but not on angiotensin II antagonism, and an α1-blocker improves insulin sensitivity irrespective of kinins.

ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

To determine whether chronic high-fructose feeding causes insulin resistance and hypertension in normal dogs, we fed 10 male dogs a normosodic diet containing 60% of the calories as fructose for 20 to 28 days; a control group of 8 dogs was fed a similar diet containing dextrose instead of fructose. In the fructose-fed group, (1) fasting triglyceridemia increased from 35.3±0.63 to 91.9±11.55 mg/dL after 25 days (P<.001); (2) fasting insulinemia increased from 19.0±1.9 to 58.9±7.22 μU/mL after 25 days (P<.001); (3) insulin resistance, which was estimated by steady-state glycemia during an insulin suppression test, increased from 105.8±21.5 to 187.8±32.6 mg/dL after 15 days (P<.001), whereas steady-state insulinemia did not change; (4) mean arterial pressure increased from 100.4±1.6 to 122.6±2.3 mm Hg after 28 days (P<.0l); and (5) cumulative sodium balance was increased on days 7 through 11 (111.60±4.44 mEq on day 8,P<.01), returning to normal for the rest of the experiment. All these parameters were similar between the fructose-fed and dextrose-fed groups before the diets were started and remained constant in the dextrose-fed group. Neither group showed any change in body weight, fasting plasma glucose, atrial natriuretic factor, or endothelin-1 levels. We conclude that chronic high-fructose feeding elicits hypertriglyceridemia, insulin resistance, hyperinsulinemia, hypertension, and a transient sodium retention in dogs without fostering fasting hyperglycemia or weight gain. Endothelin and atrial natriuretic factor do not appear to play a role in the development of hypertension in this model.

ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Arterial hypertension is known to be an important risk factor for cerebral and cardiovascular disease. Previous studies in rats have demonstrated that changes in both capillary density and vessel diameter may contribute to increased vascular resistance in hypertension. In vivo studies of human subjects with essential hypertension revealed a reduction in the number of arterioles in the skin and conjunctiva; no other in vivo data are available from other tissues. By means of a new imaging technique, capillary density and capillary blood flow velocity can now be assessed in the human retina. We undertook the present investigation to determine whether patients with essential hypertension and only minor clinical retinal vascular alterations have decreased retinal capillary density and altered capillary flow velocity. Seventeen hypertensive patients with only minor retinal vascular alterations and 17 healthy volunteers matched for age were selected. All study participants underwent ophthalmologic examination and fluorescein angiographic studies by means of scanning laser ophthalmoscopy. Capillary density and capillary blood flow velocity in the perifoveal network were evaluated from the angiograms. The retinal microcirculation in the perifoveal capillary network of hypertensive patients showed significant alterations. Both the capillary density and capillary flow velocities were significantly reduced compared with the control group. For the first time alterations of capillary blood flow and capillary density in a vascular network very similar to that of the brain have been demonstrated in hypertensive patients in vivo. Further studies with this technique may help identify patients at high risk for cerebrovascular diseases.

ISSN:0194-911X    

出版商:OVID    

年代:1994

数据来源: OVID