Vascular response to angiotensin II in upper body obesity

Upper body obesity is associated with insulin resistance, hypertension, and endothelial dysfunction. We examined forearm vascular function in response to vasodilator (endothelium-dependent and endothelium-independent) and vasoconstrictor stimuli in 8 normotensive, upper body/viscerally obese men with a positive family history of hypertension and 8 age-matched nonobese men. We also measured body composition and insulin regulation of free fatty acid (FFA) and glucose metabolism. Forearm blood flow was measured before and during brachial artery infusions of acetylcholine (Ach), sodium nitroprusside (NTP), and angiotensin II (+/-nitric oxide synthase [NO]) synthase blockade with N(G)-monomethyl L-arginine [L-NMMA]). On a separate day, baseline and insulin-regulated glucose ([3-3H]glucose) and FFA ([9,10-3H]palmitate) turnover were measured. The vasoconstrictor response to angiotensin II was greater (P<0.05) in obese men than in nonobese men, whereas endothelium-dependent vasodilation was similar. The slope of the angiotensin II dose-response curve correlated significantly with the basal plasma palmitate concentration. Basal and insulin-mediated glucose disposal was significantly reduced and FFA turnover significantly increased in viscerally obese men. No differences in endothelium-independent vasodilation or relationships between vascular responsivity and palmitate and glucose kinetics or body composition were found. Angiotensin II-stimulated forearm vasoconstriction is increased in viscerally obese normotensive men.     

Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis

The renin-angiotensin system has been studied and recognized as one of the major blood pressure-regulating systems for the past century. In the last quarter century, however, many alternative pathways of angiotensin II formation have been found, and among them, chymase has been a focus of interest because of its specificity and potency in the human cardiovascular system. Chymase evidently is not involved in functional regulation of blood pressure at least in the short term, but evidence is accumulating that it may be involved in structural remodeling of the cardiovascular system. We found increased vascular chymase activity in atherosclerotic lesions of the human aorta as well as in cardiac remodeling after myocardial infarction. We found a significant positive correlation between serum total or LDL cholesterol levels and arterial chymase-dependent angiotensin II-forming activity in patients who were undergoing coronary artery bypass operation, suggesting that high serum cholesterol may trigger upregulation of vascular chymase and facilitate the development of atherosclerosis. This hypothesis was tested in Syrian hamsters fed a high cholesterol diet containing 0.5% cholesterol: A marked lipid deposition in the aortic cusp developed and the plasma cholesterol levels were positively correlated with aortic chymase activity. An orally active nonpeptide chymase inhibitor almost canceled this lipid deposition. These clinical and experimental data indicated an association between cholesterol and vascular chymase upregulation that may facilitate the development of atherosclerosis.     

Vascular angiotensin II receptors in SHR

We investigated the density (Bmax) of angiotensin II (ANG II) receptors in the mesenteric vascular bed of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) control rats. In 12-week-old SHR, the Bmax and the dissociation constant (Kd) of ANG II binding sites were not different from those of WKY rats in the sodium replete state or after sodium depletion. In prehypertensive (4- and 6-week-old) SHR, the Bmax of the vascular ANG II receptors was significantly higher (p less than 0.05) than in age-matched WKY rats. This result could not be attributed entirely to differences in the circulating renin-angiotensin-aldosterone system in 4-week-old-rats. In 6-week-old WKY rats, the plasma renin activity was significantly higher (p less than 0.05), which may account in part for the higher density of ANG II binding sites in SHR. There was an age-related decrease in the number of ANG II receptors in SHR. The increased density of vascular ANG II receptors in young SHR may play a role in the development of high blood pressure in this model of spontaneous hypertension. The higher number of ANG II binding sites in young SHR is not selective for ANG II receptors, since an increased density of alpha 1-adrenergic receptors was also found in the mesenteric arteries of 4-week-old SHR.     

Vascular response to angiotensin II predicts long-term prognosis in patients undergoing coronary artery bypass grafting

Persistent activation of the renin-angiotensin system leads to downregulation of the angiotensin type-1 receptor, and consequently, to a decreased response to exogenous angiotensin II. In the present study, we investigated the association of angiotensin II responsiveness to clinical outcome after coronary artery bypass grafting (CABG). We studied the responsiveness to exogenous angiotensin II in human thoracic artery preparations of 114 CABG patients. Mean duration of follow-up was 7.3+/-0.1 years, during which 21 patients experienced a cardiovascular event. A diminished response to angiotensin II remained in multivariate Cox regression analysis, after adjustment for sex, age, blood pressure, and number of diseased coronary arteries, the strongest predictor for cardiovascular events (relative risk, 3.37 [95% confidence interval, 1.20 to 9.51]; P=0.022). Furthermore, diminished response to angiotensin II was associated with an increased mean arterial pressure (102.85+/-1.38 versus 97.40+/-1.37; P=0.003) and a nonsignificant increase in angiotensin-converting enzyme activity, suggestive for a persistently activated renin-angiotensin system. In conclusion, these results suggest that in patients undergoing CABG, a diminished vascular responsiveness of the thoracic artery to exogenous angiotensin II is related to an increased risk of future cardiovascular events.     

Vascular angiotensin II actions mediated by angiotensin II type 2 receptors

Angiotensin II (Ang II) is the major effector peptide of the renin-angiotensin system and acts at two major receptors known as Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R). Increasingly, there is evidence suggesting that the AT2R counter-regulates the excitatory effects of AT1R stimulation. In this review, we have focused on pharmacodynamic and trophic components of AT2R with respect to vascular function, and put the current status of vascular AT2R research in the context of a potential role for this ATR subtype in the therapeutic effects of AT1R antagonists.     

Tissue-specific response to interstitial angiotensin II in humans

Angiotensin II is synthesized locally in various tissues; however, the role of interstitial angiotensin II in the regulation of regional metabolism and tissue perfusion is not clear. We characterized the effect of interstially applied angiotensin II in skeletal muscle and subcutaneous adipose tissue of young, normal-weight, healthy subjects by using the microdialysis technique. Furthermore, we tested the hypothesis that the effect of interstitial angiotensin II is modulated by nitric oxide. Tissues were perfused with 0.01, 0.1, and 1 micro mol/L angiotensin II in the presence of the L- or D-isomer of N(G)-nitro-arginine-methyl ester (L- or D-NAME), the effective and noneffective isomer, respectively, for blocking nitric oxide synthase. Dialysate ethanol, glycerol, glucose, lactate, and pyruvate concentrations were measured to assess changes in blood flow (ethanol dilution technique), lipolysis, and glycolysis, respectively. Baseline blood flow and dialysate concentrations of the metabolites were similar with L- and D-NAME in both tissues. Blood flow and dialysate glucose and lactate did not change significantly in both tissues during perfusion with angiotensin II. Dialysate glycerol dose-dependently increased in adipose tissue (P<0.0438) but decreased in muscle (P<0.007). In muscle, dialysate pyruvate increased (P<0.0002), whereas lactate/pyruvate ratio decreased (P<0.001), both dose-dependently. All effects were similar with L- and D-NAME and could be reversed by nitroprusside. We conclude that in contrast to the profound hemodynamic effect of intravascular angiotensin II, interstitial angiotensin II has a minimal acute effect on blood flow in both tissues. However, interstitial angiotensin II modulates lipid and carbohydrate metabolism in a tissue specific fashion. Thus, the physiology of interstitial angiotensin II cannot be predicted from intravascular studies.     

Deoxycorticosterone acetate salt hypertension in apolipoprotein E-/- mice results in accelerated atherosclerosis: the role of angiotensin II

Previous studies have shown that administration of angiotensin II to atherosclerosis-prone animal models results in an increase in the extent of atherosclerosis and that this effect may be independent of changes in blood pressure. We sought to determine whether atherosclerosis was increased in the setting of a low renin model of hypertension. Apolipoprotein E-deficient mice were made hypertensive using the deoxycorticosterone acetate salt model. We found that this resulted in a dramatic increase in the atherosclerotic lesion area in the setting of either a low- or high-fat diet. In the hypertensive animals, we observed an increase in angiotensin II staining that was localized to the adventitial macrophages. The increase in atherosclerosis was inhibited by administration of an angiotensin receptor antagonist, an angiotensin-converting enzyme inhibitor, or a renin inhibitor. In addition, blood pressure reduction, with either a calcium channel blocker or hydralazine, reduced the extent of atherosclerosis indicating an important contribution of the mechanical effects of elevated blood pressure. These data suggest that, even in the setting of hypertension that is not associated with activation of the systemic renin-angiotensin system, local generation of angiotensin II within the arterial wall may be of pathophysiological relevance to the development of atherosclerosis.     

Thromboxane mediation of the pressor response to infused angiotensin II

The role of thromboxane A2(Tx) in mediating the pressor response to angiotensin II (AII) was studied in anesthetized rats. Intravenous AII (500 ng/kg/min) increased mean arterial pressure (MAP) by 35 +/- 3 mm Hg and increased the excretion of prostaglandin PGE2, the metabolites of prostacyclin (6kPGF1 alpha) and Tx (TxB2) (P less than .05). A similar pressor infusion of the alpha 1-adrenoreceptor agonist phenylephrine (PE) increased the excretion of PGE2 and 6kPGF1 alpha but not TxB2. The increases in MAP and prostaglandin excretion produced by AII were reversed by the AII-receptor antagonist saralasin (10 micrograms/kg/min) while those produced by PE were reversed by the alpha-adrenoreceptor antagonist phenoxybenzamine (250 micrograms/kg). The Tx receptor antagonist, SQ-29,548 (8 mg/kg) attenuated (P less than .0001) the AII-induced rise in MAP (13 +/- 1 mm Hg) but did not modify the pressor response to PE. The Tx synthetase inhibitor, UK-38,485 (50 mg/kg/d) given for 3 days, reduced basal TxB2 excretion by 75% and also attenuated (P less than .001) the AII-induced rise in MAP (11 +/- 2 mm Hg). However, when given 40 min before the AII infusion, UK-38,485 did not attenuate the pressor response. In separate groups of rats, the log dose-response curve for bolus intravenous injection of AII was shifted to the right by SQ-29,548 while that for PE was unaffected. In conclusion: 1) AII releases Tx; 2) Tx release is not secondary to hypertension; and 3) Tx can mediate up to two-thirds of the short-term pressor response to high-dose AII infusion.     

Enhanced antinatriuresis in response to angiotensin II in essential hypertension

Angiotensin II regulates sodium homeostasis by modulating aldosterone secretion, renal vascular response, and tubular sodium reabsorption. We hypothesized that the antinatriuretic response to angiotensin II is enhanced in human essential hypertension. We therefore studied 48 white men with essential hypertension (defined by ambulatory blood pressure measurement) and 72 normotensive white control persons, and measured mean arterial pressure, sodium excretion, renal plasma flow, glomerular filtration rate, and aldosterone secretion in response to angiotensin II infusion (0.5 and 3.0 ng/kg/min). Hypertensive subjects exhibited a greater increase of mean arterial pressure (16.7+/-8.2 mm Hg v 13.4+/-7.1 mm Hg in normotensives, P < .05) and a greater decrease of renal plasma flow (-151.5+/-73.9 mL/ min v -112.6+/-68.0 mL/min in controls, P < .01) when 3.0 ng/kg/min angiotensin II was infused. The increase of glomerular filtration rate and serum aldosterone concentration was similar in both groups. Sodium excretion in response to 3.0 ng/kg/min angiotensin II was diminished in both groups (P < .01). However, the decrease in sodium excretion was more pronounced in hypertensives than in normotensives (-0.18+/-0.2 mmol/min v -0.09+/-0.2 mmol/min, P < .05), even if baseline mean arterial pressure and body mass index were taken into account (P < .05). We conclude that increased sodium retention in response to angiotensin II exists in subjects with essential hypertension, which is unrelated to changes in glomerular filtration rate and aldosterone concentration. Our data suggest a hyperresponsiveness to angiotensin II in essential hypertension that could lead to increased sodium retention.     

Adrenal response to angiotensin II in black hypertension: lack of sexual dimorphism

Adrenal responsiveness to angiotensin (Ang) II is markedly blunted in black hypertensive patients compared with white hypertensive patients. One characteristic of this blunted adrenal response in whites is a powerful sexual dimorphism: premenopausal white women rarely show blunted responses. This abnormality, most evident when the system is activated by a low-salt diet, is a cardinal feature of the syndrome of nonmodulation, affecting a large percentage of white hypertensive patients. Nonmodulation is also marked by an increase in cardiovascular risk beyond that from hypertension itself. This study investigated whether young black women are likewise spared its expression or whether the adrenal unresponsiveness common among black hypertensive patients is unaccompanied by a gender bias. We compared the adrenal response to Ang II in 382 hypertensive patients (313 white, 69 black; 238 male, 144 female). Ang II was infused when subjects were in balance on a 10-mmol Na(+) intake. As anticipated, white hypertensive patients showed a very strong sexual dimorphism, with women having twice the aldosterone response of men (P=0.0001). Blacks, on the other hand, showed no gender difference (P=0.9). Increasing age had the dramatic effect of reducing responsiveness in white women but not in blacks. Young black women demonstrated the same blunting of adrenal responsiveness as older black women and black men of all ages. Mechanisms protecting against a blunted adrenal response to Ang II in young white women are absent in blacks. These differences may contribute to the markedly increased prevalence of hypertension in young black women.     

Exercise training prevents arterial baroreflex dysfunction in rats treated with central angiotensin II

Angiotensin II (Ang II)-induced arterial baroreflex dysfunction is associated with superoxide generation in the brain. Exercise training (EX) improves baroreflex function and decreases oxidative stress in cardiovascular diseases linked to elevated central Ang II. The aim of this study was to determine whether previous EX prevents baroreflex impairment caused by central administration of exogenous Ang II via an Ang II-superoxide mechanism. Four groups of rats were used: non-EX artificial cerebrospinal fluid infused, non-EX Ang II infused, EX artificial cerebrospinal fluid infused, and EX Ang II infused. Rats were treadmill trained for 3 to 4 weeks and subjected to intracerebroventricular infusion of Ang II over the last 3 days of EX. Twenty-four hours after the end of EX, the arterial baroreflex was assessed in anesthetized rats. Compared with non-EX artificial cerebrospinal fluid-infused rats, Ang II significantly decreased baroreflex sensitivity (maximum gain: 3.0+/-0.2% of maximum per millimeter of mercury versus 1.6+/-0.1% of maximum per millimeter of mercury; P<0.01), which was abolished by acute intracerebroventricular infusion of the Ang II type 1 receptor antagonist losartan and the reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor apocynin. EX prevented the decrease in baroreflex sensitivity and downregulated Ang II type 1 receptor and NADPH oxidase subunit protein expression in the paraventricular nucleus of Ang II-infused rats. Finally, EX decreased superoxide production in the paraventricular nucleus of Ang II-infused rats. These results indicate that EX improves arterial baroreflex function in conditions of high brain Ang II, which is mediated by the central Ang II type 1 receptor and associated with a reduction in central oxidative stress.     

Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep

An adverse environment around conception and implantation influences later fetal growth and development to term in humans and sheep. Indeed, preimplantation undernutrition of rats elevated the systolic blood pressure of the resultant adult offspring. In this study, adult cardiovascular function is examined in a slower growing, non-litter-bearing species after peri-implantation undernutrition. Eight ewes were fed to 50% equivalent food intake of 12 control ewes from 1 to 30 days (term approximately 147 days) only. Following consumption of an adequate diet to term, natural lambing, and then weaning, resting cardiovascular status and baroreflex function were examined in the resultant young adult offspring. Birth weight and postnatal growth to 1 year of age were unaffected by early undernutrition; however, nutrient-restricted sheep had increased pulse pressure, a reduced rate pressure product, and a leftward shift in their baroreflex function curve. Baroreflex sensitivity during angiotensin II infusion was also blunted in early nutrient-restricted sheep but the tachycardia following a reduction in central blood pressure appeared potentiated, relative to controls. The data suggest that peri-implantation undernutrition may program long-term cardiovascular dysfunction that ultimately increases the risk of hypertension later in life. An increase in regional angiotensin II activity during this critical early phase of development is a likely candidate mechanism for the effects observed. The data have broad implications for the health outcome of those offspring from mothers who were poorly nourished during early, often unknown pregnancy and for embryos artificially manipulated because of infertility treatment.     

Escape from mineralocorticoid excess: the role of angiotensin II

Escape from the sodium-retaining action of mineralocorticoids coincides with the suppression of plasma renin and angiotensin II levels. The purpose of this study was to evaluate whether blockade of the renin system accelerates this escape. Eight male normotensive volunteers, aged 24--33 yr, were maintained during two subsequent periods of 12 days each, separated by 3--4 weeks, on a constant intake of sodium and potassium of 140 mmol/day. During both periods, fludrocortisone acetate (0.2 mg) was administered orally three times a day on days 4--12. In addition, on days 3--12, either a converting enzyme inhibitor (MK 421;20 mg orally, twice daily) or a placebo was added in double blind fashion and randomized sequence. During both periods, blood pressures were similar; they tended to increase slightly toward day 12. The weight increase did not differ between the two periods. With MK 421, angiotension II levels were significantly lower than with placebo on days 3--6 (P less than 0.001). On the same days, PRA was increased due to converting enzyme blockade. Despite the significantly different angiotensin II levels on days 3--6, daily urinary sodium excretion on all individual days as well as cumulative sodium balance were the same during both periods. Therefore, we could find no evidence in man that suppression of circulating angiotensin II levels is causally related to escape from mineralocorticoid excess.     

Vascular cell senescence: contribution to atherosclerosis

Cardiologists and most physicians believe that aging is an independent risk factor for human atherosclerosis, whereas atherosclerosis is thought to be a characteristic feature of aging in humans by many gerontologists. Because atherosclerosis is among the age-associated changes that almost always escape the influence of natural selection in humans, it might be reasonable to regard atherosclerosis as a feature of aging. Accordingly, when we investigate the pathogenesis of human atherosclerosis, it may be more important to answer the question of how we age than what specifically promotes atherosclerosis. Recently, genetic analyses using various animal models have identified molecules that are crucial for aging. These include components of the DNA-repair system, the tumor suppressor pathway, the telomere maintenance system, the insulin/Akt pathway, and other metabolic pathways. Interestingly, most of the molecules that influence the phenotypic changes of aging also regulate cellular senescence, suggesting a causative link between cellular senescence and aging. For example, DNA-repair defects can cause phenotypic changes that resemble premature aging, and senescent cells that show DNA damage accumulate in the elderly. Excessive calorie intake can cause diabetes and hyperinsulinemia, whereas dysregulation of the insulin pathway has been shown to induce cellular senescence in vitro. Calorie restriction or a reduction of insulin signals extends the lifespan of various species and decreases biomarkers of cellular senescence in vivo. There is emerging evidence that cellular senescence contributes to the pathogenesis of human atherosclerosis. Senescent vascular cells accumulate in human atheroma tissues and exhibit various features of dysfunction. In this review, we examine the hypothesis that cellular senescence might contribute to atherosclerosis, which is a characteristic of aging in humans.     

Enhanced aldosterone response to angiotensin II in human hypertension.

Adrenal and vascular responsiveness to graded doses of angiotensin II (A II) were recorded for seven normal subjects and 12 patients with essential hypertension while in balance on an intake of 200 mEq sodium/100 mEq potassium. Patients with essential hypertension had been previously studied and known to have normal responses of plasma renin activity to sodium restriction and upright posture. A II was administered for 30 minutes at rates of 0.1, 0.3, 1, and 3 ng/kg per minute and plasma aldosterone responses were assessed 20 and 30 minutes later; blood pressure was monitored at intervals of 1 minute during infusion of A II at each rate. A significant increment in plasma aldosterone occurred at an infusion rate of 0.3 ng/kg per minute in patients with hypertension. This change was not seen until the infusion rate reached 1.0 ng/kg per minute in the normotensive control subjects. Even at an A II infusion rate of 1 ng/kg per minute, the increment in plasma aldosterone levels in normotensive subjects (4.2 +/- 0.6 ng/dl) was significantly less (P less than 0.001) than that in patients with essential hypertension (19 +/- 3 ng/dl). In both groups, a significant rise in mean arterial blood pressure occurred at an A II dose of 0.3 ng/kg per minute, but the pressor response of the hypertensive group was significantly greater at the highest infusion rate (3 ng/kg per minute) (P less than 0.05). Thus, enhanced adrenal and pressor responsiveness to infused A II was observed in the hypertensive subjects, suggesting a change in A II receptor affinity.     

Inhibitory effect of somatostatin on the aldosterone response to angiotensin II: in vitro studies

It has been demonstrated that somatostatin (SRIF) can suppress hypophyseal and extrahypophyseal hormones; moreover, many studies have shown that SRIF inhibits frusemide-induced hyperreninemia in normal man, and renin and aldosterone in renovascular hypertension, possibly through a beta-adrenergic block. To further investigate the possible aldosterone-inhibiting effect of somatostatin, we have carried out in vitro studies using isolated perfused rat zona glomerulosa cells suspended in Bio-gel. Paired columns were set up and the cells stimulated using either angiotensin II, ACTH, serotonin or potassium. One column was perfused with somatostatin (3-4 ng/ml) and the other was used as a control. Aldosterone was measured by highly specific direct radioimmunoassay. Somatostatin significantly blocked the aldosterone response to angiotensin II but not to ACTH, serotonin or potassium. The inhibitory effect of somatostatin persisted as long as it was added to the medium; the aldosterone response to angiotensin II was progressively restored after discontinuation of the SRIF infusion. From these data it might be suggested that the inhibitory effect of somatostatin on aldosterone production is not cAMP-dependent, since ACTH maintains its stimulatory capacity. The recent demonstration of the presence of specific somatostatin receptors on the rat adrenal cells suggests that its inhibitory effect could be mediated by the second messenger system rather that the interaction with angiotensin II receptors.