Apoptosis and glomerular injury after prolonged nitric oxide synthase inhibition in spontaneously hypertensive rats.

This study was designed to investigate the relationship between apoptosis and glomerular injury in spontaneously hypertensive rats (SHR) with hypertensive disease that was exacerbated by inhibition of NO synthesis. Development of glomerular cell apoptosis was evaluated by assessment of renal hemodynamics, glomerular morphometric changes, and participation of the renin-angiotensin system. Three groups of 20-week-old SHR were investigated: control male SHR and 2 similar groups given 2 doses of N(G)-nitro-L-arginine methyl ester (L-NAME, 50 or 80 mg/L, respectively) for 3 weeks. Mean arterial pressure and renal vascular resistance increased, whereas effective renal plasma flow and glomerular filtration rate were diminished by L-NAME. The small artery wall/lumen ratio increased as the glomerular-tuft area diminished. Renal cortical tissue levels of angiotensin II increased in response to the L-NAME, thereby inducing afferent arteriolar injury. Apoptosis and proliferative index (PCNA) of nonsclerotic glomeruli were induced by the low-dose L-NAME as the glomerular cell number decreased. In contrast, the PCNA index was downregulated with the high-dose L-NAME. These results indicate that angiotensin II activation, induced by L-NAME, was related to glomerular cell deletion and apoptosis together with the pathophysiological changes of severe nephrosclerosis and impaired renal dynamics.

Local hemodynamic changes in hypertension: insights for therapeutic preservation of target organs.

As a result of antihypertensive therapy, there has been a remarkable decrease in morbidity and mortality from such cardiovascular endpoints as stroke, coronary heart disease, and major hypertensive emergencies. In contrast, there has been no relenting in the increasing prevalence of cardiac failure and end-stage renal disease (ESRD) associated with hypertensive cardiovascular disease. Recent experience in our laboratories that involved the natural development of the cardiac and renal hemodynamic alterations in spontaneously hypertensive rats demonstrated that the natural history and pathophysiological lesions associated with cardiac failure and ESRD may be vastly different from the heretofore more pressure-dependent brain and other cardiac endpoints reported in earlier years. These initial antihypertensive agents (eg, diuretics, beta-adrenergic receptor inhibitors) had minimal anti-ischemic and antifibrotic effects on heart and kidney and did not exert the cardiac and nephroprotective hemodynamic effects of the newer classes of agents. The cardiac and renal endpoints resulting in organ failure today are more related to ischemia, intraorgan fibrosis, and aging. Our experimental studies summarized herein strongly suggest that the newer classes of antihypertensive drugs (ie, ACE inhibitors, angiotensin II type 1 receptor antagonists, certain calcium antagonists, and perhaps L-arginine) may reverse these pathophysiological lesions through improving blood flow and flow reserve, their antifibrotic and other actions. To this end, we look forward to the results of ongoing, well-controlled, and prospectively conducted multicenter clinical studies designed to demonstrate prevention of cardiac and renal failure.

Isolated systolic hypertension in elderly WKY is reversed with L-arginine and ACE inhibition.

This study was designed to examine the preventability of progressive deterioration of cardiovascular structure and function in very old Wistar-Kyoto (WKY) rats with isolated systolic hypertension (ISH). To this end, male 18-month-old normotensive WKY rats were given either placebo or L-arginine (70 mg. kg(-1). d(-1)) and an ACE inhibitor (enalapril, 30 mg. kg(-1). d(-1)) for 6 months. These control and treated rats were studied at the age of 2 years by examining: cardiovascular mass and collagen content, cardiac function, and systemic and regional (including coronary) hemodynamics. Additional data obtained in adult, 35-week-old WKY are included for comparison. ISH associated with increased total peripheral resistance was found in the old, untreated WKY, and this was prevented by the combined treatment. The untreated rats also exhibited impaired left ventricular function, as denoted by increased left ventricular end-diastolic pressure and reduced maximal rates of rise and fall of left ventricular pressure. These functional changes were also ameliorated with the combined treatment. Coronary hemodynamics were also compromised in the untreated WKY; and therapy improved coronary flow reserve and minimal coronary vascular resistance in both ventricles of the old WKY in parallel with reduction of arterial pressure. Blood flow to various other organs was uncompromised in the old rats, although increased vascular resistances were observed in untreated old WKY with ISH. These changes were also improved by the combined therapy. Finally, therapy diminished left ventricular mass and collagen concentration in old WKY compared with the untreated WKY. However, when compared with the 35-week-old WKY, both groups of old WKY (untreated and treated) demonstrated myocardial fibrosis, depressed ventricular function, and compromised coronary hemodynamics. Therefore, L-arginine and ACE inhibitory therapy ameliorated the hypertensive and associated adverse cardiovascular changes in old WKY, although it failed to improve totally the progressive deterioration of cardiovascular structure and function that occurred with aging. The results suggest that different mechanisms may be responsible for the hypertension- and age-related cardiovascular changes, although they may appear to be similar.

Low-dose ACE with alpha- or beta-adrenergic receptor inhibitors have beneficial SHR cardiovascular effects.

BACKGROUND: There are no data regarding the prolonged effect of alpha-1 adrenergic receptor antagonists on ventricular collagen content and coronary hemodynamics in spontaneously hypertensive rats (SHR). This study, therefore, was designed to determine the effects of chronic treatment with the alpha-1 adrenergic receptor inhibitor doxazosin on SHR systemic and regional (especially coronary) hemodynamics, cardiovascular mass, and ventricular collagen. The effects of the combination of doxazosin with low-dose angiotensin-converting enzyme inhibitor were studied versus the alpha-1 antagonist alone. These effects were compared with those of a beta-1 adrenergic receptor inhibitor. METHODS AND RESULTS: Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular weight, hydroxyproline concentration, and aortic weight were measured at age 35 weeks. Doxazosin reduced arterial pressure and total peripheral resistance without changing left ventricular mass and collagen content, whereas monotherapies with the beta-1 antagonist metoprolol or a subdepressor dose of the ACE inhibitor enalapril were effective in reducing left ventricular mass and hydroxyproline without altering pressure. Doxazosin combined with the same low-dose ACE inhibitor reduced left ventricular mass and hydroxyproline without potentiating the hypotensive effect of doxazosin. By contrast, the combination of beta-1 antagonist with the low-dose ACE inhibitor reduced pressure, unlike either agent alone. Aortic weight index was significantly reduced only by doxazosin whether when used alone or with the ACE inhibitor. Low-dose ACE inhibitor with doxazosin or the beta-1 receptor antagonist as well as doxazosin alone decreased renal vascular resistance. CONCLUSION: These data show that the low subdepressor dose ACE inhibitor with an alpha- or beta-adrenergic receptor antagonist provides beneficial cardiovascular effects in SHR.

Fibrosis and ischemia: the real risks in hypertensive heart disease.

The increased cardiovascular morbidity and mortality in hypertension are related to the target organs (ie, heart, brain, kidneys) involvement from vascular disease. Left ventricular hypertrophy (LVH), the major expression of cardiac involvement, is both a structural and functional adaptation to the afterload imposed by the vascular disease. Without this adaptation, cardiac failure would result much earlier in the natural history of hypertensive heart disease (HHD). However, LVH imposes an independent risk that is even greater than the risk associated with the height of systolic or diastolic pressure. The mechanisms that explain this risk have not been defined precisely; several have been postulated. Among these are the following: 1) coronary hemodynamic alterations associated with HHD (ie, increased coronary vascular and minimal vascular resistance, reduced coronary blood flow and flow reserve, and increased blood viscosity); 2) enhanced predisposition for lethal cardiac arrhythmias, cardiac failure, and accelerated atherosclerosis of the coronary arteries (with exacerbation of the ischemia); and 3) collagen deposition and ventricular fibrosis. From the earliest controlled therapeutic trials, deaths from stroke and coronary heart disease were significantly reduced. However, more recent data have indicated that the prevalence of cardiac failure (CHF) continues to rise progressively. The nature of the CHF is no longer primarily from systolic dysfunction, but is now chiefly from diastolic dysfunction. Diastolic dysfunction occurs primarily in the elderly hypertensive patient or in the patient with ischemic heart disease, both of which are associated with increased collagen deposition. Indeed, these effects continue to be suggested by the data from the Framingham Heart Study as well as NHANES-III that indicate CHF is the most common diagnosis occurring in hospitalized patients over 65 years of age. In this report, both experimental and clinical evidence demonstrating that increased ventricular fibrosis occurs in the spontaneously hypertensive rats and in hypertensive patients are provided, and that treatment with the newer antihypertensive agents reduce ventricular hydroxyproline (ie, collagen) content while, at the same time, improve coronary hemodynamics.

Renin-angiotensin system inhibition improves coronary flow reserve in hypertension.

Angiotensin II not only elevates arterial pressure, it adversely alters hemodynamics and cardiovascular structure and exacerbates the course of hypertensive disease. Alterations in coronary hemodynamics, including reductions in coronary blood flow and flow reserve, reflect the pathophysiology of arteriolar disease and associated endothelial dysfunction thereby promoting coronary insufficiency and increasing overall cardiovascular risk. In spontaneously hypertensive rats, coronary flow reserve, the difference between basal coronary blood flow and the flow achieved during maximal coronary vasodilation achieved by physiological or pharmacological interventions, is drastically impaired at rest; however, it can be improved significantly by pharmacological agents that inhibit the renin-angiotensin system, alone or in combination. The combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin-II (type 1) receptor blocker, in equidepressor doses, markedly improved coronary flow reserve to levels seen in normotensive Wistar Kyoto rats after 12 weeks of treatment, while diminishing cardiovascular mass and improving systemic hemodynamics and ventricular metabolic demands. These findings suggest the potential merits for clinical studies employing the combination of ACE inhibitor and angiotensin receptor blocker therapy in patients with hypertension and hypertensive heart disease.

Coronary hemodynamic and ventricular responses to angiotensin type 1 receptor inhibition in SHR: interaction with angiotensin type 2 receptors.

This study was designed to determine the effects of angiotensin II type 1 (AT(1)) receptor inhibition on coronary hemodynamics and ventricular mass and hydroxyproline content and the additive effects of angiotensin II type 2 (AT(2)) receptor inhibition in spontaneously hypertensive rats (SHR). The selective AT(1) receptor antagonist candesartan (10 mg/kg per day) was administered alone or in combination with the AT(2) receptor antagonist PD 123319 (50 mg/kg per day) for 12 weeks. Control SHR received placebo for the same period. Left and right ventricular coronary blood flow, blood flow reserve, and minimal coronary vascular resistance were determined by using radiomicrospheres in male 35-week-old rats. Mean arterial pressure; total peripheral resistance; left and right ventricular, renal, and aortic weights; and hydroxyproline concentration were also determined. Candesartan reduced mean arterial pressure and left ventricular, renal, and aortic masses, as well as hydroxyproline concentration and minimal coronary vascular resistance of both ventricles. PD 123319 partially prevented the hypotensive effect of AT(1) receptor inhibition and reversed the effect on myocardial hydroxyproline concentration. These data suggest that AT(2) receptors contribute to the hypotensive and antifibrotic effects but not the coronary hemodynamic improvement or reduced left ventricular mass of AT(1) receptor inhibition in these adult SHR.

Angiotensin type 1 receptor antagonism and ACE inhibition produce similar renoprotection in N(omega)-nitro-L>-arginine methyl ester/spontaneously hypertensive rats.

This study was conducted to determine potentially differential effects between an angiotensin II type 1 (AT(1)) receptor antagonist and an ACE inhibitor on systemic, renal, and glomerular hemodynamics and pathological changes in spontaneously hypertensive rats (SHR) with N(omega)-nitro-L>-arginine methyl ester (L-NAME)-exacerbated nephrosclerosis. The hemodynamic, renal micropuncture, and pathological studies were performed in 9 groups of 17-week-old male SHR treated as follows: group 1, controls (n=16); group 2, candesartan (10 mg/kg per day for 3 weeks) (n=7); group 3, enalapril (30 mg/kg per day for 3 weeks) (n=8); group 4, candesartan (5 mg/kg per day) plus enalapril (15 mg/kg per day for 3 weeks) (n=9); group 5, L-NAME (50 mg/L in drinking water for 3 weeks) (n=17); group 6, L-NAME (50 mg/L) plus candesartan (10 mg/kg per day for 3 weeks) (n=7); group 7, L-NAME (50 mg/L) for 3 weeks followed by candesartan (10 mg/kg per day) for another 3 weeks (n=8); group 8, L-NAME (50 mg/L) plus enalapril (30 mg/kg per day for 3 weeks) (n=7); and group 9, L-NAME (50 mg/L) plus enalapril (30 mg/kg per day) and the bradykinin antagonist icatibant (500 microg/kg SC per day via osmotic minipump for 3 weeks) (n=7). Both candesartan and enalapril similarly reduced mean arterial pressure and total peripheral resistance index. These changes were associated with significant decreases in afferent and efferent glomerular arteriolar resistances as well as glomerular capillary pressure. Histopathologically, the glomerular and arterial injury scores were decreased significantly, and left ventricular and aortic masses also were diminished significantly in all treated groups. L-NAME-induced urinary protein excretion was prevented by both candesartan and enalapril. Thus, both AT(1) receptor and ACE inhibition prevented and reversed the pathophysiological alterations of L-NAME-exacerbated nephrosclerosis in SHR. Itatibant only blunted the antihypertensive effects of enalapril but did not attenuate the beneficial effects of ACE inhibition on the L-NAME-induced nephrosclerosis. Thus, the AT(1) receptor antagonism and ACE inhibition have similar renal preventive effects, which most likely were achieved through reduction in the effects of angiotensin II, and ACE inhibition of bradykinin degradation demonstrated little evidence of renoprotection.

Diabetes, hypertension, and cardiovascular disease: an update.

Cardiovascular diseases (CVDs) are the major causes of mortality in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of CVD. Hypertension is approximately twice as frequent in patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive persons are more predisposed to the development of diabetes than are normotensive persons. Furthermore, up to 75% of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment (ie, reducing blood pressure to <130/85 mm Hg) in persons with coexistent diabetes and hypertension. Other important risk factors for CVD in these patients include the following: obesity, atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and "diabetic cardiomyopathy." The cardiomyopathy associated with diabetes is a unique myopathic state that appears to be independent of macrovascular/microvascular disease and contributes significantly to CVD morbidity and mortality in diabetic patients, especially those with coexistent hypertension. This update reviews the current knowledge regarding these risk factors and their treatment, with special emphasis on the cardiometabolic syndrome, hypertension, microalbuminuria, and diabetic cardiomyopathy. This update also examines the role of the renin-angiotensin system in the increased risk for CVD in diabetic patients and the impact of interrupting this system on the development of clinical diabetes as well as CVD.

Abnormal renal vascular responses to dipyridamole-induced vasodilation in spontaneously hypertensive rats.

The objective of this study was to determine whether there were differences in hemodynamic responses of different vascular beds to systemic administration of dipyridamole between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. To this end, systemic hemodynamics and organ blood flows (using labeled microspheres) were determined in conscious rats before and 10 minutes after dipyridamole (4 mg. kg(-1). min(-1)) infusion. In both the normotensive and hypertensive rats, the dipyridamole infusion reduced arterial pressure by approximately 20 mm Hg, associated with a decreased total peripheral resistance and an increased cardiac output. Renal blood flow decreased significantly in SHR after dipyridamole but remained unchanged or increased slightly in the WKY rats. There were no other differences in regional hemodynamics, including those of brain, liver, skin, and muscle, between the WKY and SHR. Antihypertensive treatment completely restored normal renal vascular response to dipyridamole. Previous reports had demonstrated an abnormal coronary hemodynamic response of the SHR. Our data demonstrate that, as with coronary hemodynamics, hypertension selectively induced alterations in renal vasculature. These findings may be of importance in identifying the earliest hemodynamic evidence of developing hypertensive nephrosclerosis.

Hypertension and the heart.

Sustained increase in arterial pressure causes left ventricular hypertrophy and adversely affects all myocardial compartments: myocytes, interstitium, and coronary vasculature. Ventricular hypertrophy significantly increases the risk for cardiovascular morbidity and mortality in hypertensive disease. Impairments in coronary circulation and ventricular fibrosis, which are an essential part of hypertensive disease, contribute to that increased risk. This report discusses the mechanisms of hypertension-induced myocardial collagen accumulation and impairments in coronary hemodynamics. Particular attention is given to the interaction of hypertension and aging because aging aggravates hypertensive changes and the incidence of hypertension increases with aging. The effect of therapy on hypertension-induced ventricular fibrosis and impairment in coronary hemodynamics and the risk associated with these changes are also discussed.