The relation of premorbid factors to aggressive physical behavior in dementia.

Aggressive physical behaviour (APB) is common in persons with dementia and often leads to negative consequences such as use of restraints and staff member burnout. For the past several years, a group of nurse researchers has collaborated to develop a model that views dementia behaviors as need-driven but dementia-compromised. The model posits that background variables of the demented person interact with proximal (or current situational) variables to produce APB. The purpose of this study was to test a part of that model by addressing the question: Which premorbid factors predict APB in a sample of 84 demented institutionalized elders? This was a cross-sectional descriptive study that obtained measures of the following characteristics of residents: (1) aggressive behavior as assessed by nursing home staff members using the Ryden Aggression Scale, (2) premorbid personality traits as assessed by a member of the resident's family using the NEO Five Factor Inventory and (3) history of psychosocial stress as assessed by a member of the residents' family using the modified Social Readjustment Rating Scale. Of the sample of 84 residents, 44% exhibited physical aggression. Background factors in the model were not predictive of aggressive behavior in late-stage dementia, although the relation between premorbid neuroticism and physical aggression was in the predicted direction.

Regulation of regional norepinephrine spillover in heart failure: the effect of angiotensin II and beta-adrenergic agonists in the forearm circulation.

BACKGROUND: Prejunctional receptors for angiotensin II (A-II) and norepinephrine (NE) have been reported to facilitate NE release. If operative in patients with congestive heart failure (CHF), such receptors could participate in positive feedback cycles amplifying sympathoactivation. METHODS AND RESULTS: A-II and isoproterenol (ISO) would increase regional NE spillover via facilitation of presynaptic release of NE in the forearm circulation of patients with chronic stable CHF. A-II, ISO, and nitroprusside (NP) were sequentially infused into the brachial arteries of 10 patients with chronic stable CHF, which was attributed to dilated cardiomyopathy. Forearm blood flow (FBF) was measured via plethysmography and regional spillover of NE was measured by using the isotope dilution method of Esler. A-II (5 ng/min) produced a nonsignificant decline in FBF (1.87+/-0.14 to 1.46+/-0.1 mL/100 g/min, P = .07) and did not change regional NE spillover (418+/-128 to 409+/-121 ng/min). ISO increased FBF from 1.6+/-0.12 to 4.3+/-0.7 mg/100 g/min (P < .001). Regional NE spillover increased from 337+/-86 to 856+/-300 ng/min (P < .001). Venous NE and regional extraction of NE did not change. NP increased FBF from 2.0+/-0.3 to 6.3+/-1.2 mL/100 g/min (P < .001; P = NS v change with ISO) and also increased regional NE spillover (301+/-99 to 712+/-288 ng/min, P < .001; P = NS v change with ISO). As with ISO, venous NE and extraction of NE were not altered. CONCLUSIONS: Mild vasoconstrictor infusions of A-II do not increase regional NE spillover in the forearm circulation of patients with CHF. The beta-adrenergic agonist ISO does increase regional spillover, but the effect seems to be primarily related to flow rather than presynaptic stimulation of NE release. These data argue against an important positive feedback loop involving A-II and NE on sympathoactivation, at least with the dosages of the agonists studied and in the limb circulation in chronic stable CHF.

Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog.

BACKGROUND: Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock. METHODS AND RESULTS: The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 +/- 3.4 to 65.4 +/- 2.6 g, P = NS; LVV, 45.4 +/- 2.7 to 51.6 +/- 2.7 mL, P = NS; C: LVM, 68.4 +/- 3.2 to 91.4 +/- 2.9 g, P = .0001; LVV, 56.6 +/- 3.0 to 71.9 +/- 2.4 mL, P = .0003). Terazosin, an alpha 1-adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 +/- 4.6 to 105.7 +/- 3.4 g, P = .01; LVV, 61.8 +/- 3.8 to 76.8 +/- 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 +/- 4.6 to 109.7 +/- 5.3 g, P = .0001; LVV, 66.0 +/- 1.9 to 78.4 +/- 3.6 mL, P = .007). CONCLUSIONS: High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. the failure of alpha 1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha 1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.

Lack of contribution of nitric oxide to basal vasomotor tone in heart failure.

Patients with heart failure have reduced forearm vasodilator responses when endothelial cell nitric oxide production is stimulated by muscarinic agonists. The aim of this study was to determine if activity of the nitric oxide pathway was also abnormal under basal conditions. Forearm blood flow (FBF) was measured with strain-gauge plethysmography in response to the intraarterial infusion of a subsystemic dose range of L-N-monomethylarginine (L-NMMA), a competitive inhibitor of nitric oxide synthase. In 18 normal subjects, the baseline FBF of 3.6 +/- 1.4 was decreased by 0.3 +/- 0.5 (p < 0.01), 1.0 +/- 0.7 (p < 0.01), 1.4 +/- 0.9 (p < 0.01), and 1.3 +/- 1.3 (p < 0.01) ml/min/100 ml forearm volume during infusions of 1, 4, 8, and 16 mumol/min of L-NMMA, respectively. In 10 patients with heart failure, the baseline FBF of 2.6 +/- 0.9 was decreased by 0.4 +/- 0.5 (p < 0.05), 0.4 +/- 0.5 (p < 0.05), 0.9 +/- 0.8 (p < 0.01), and 0.9 +/- 0.7 (p < 0.01) ml/min/100 ml forearm volume with the 4 doses of L-NMMA, respectively. There was no difference in the L-NMMA response between the 2 groups in terms of absolute flow, percent change, or with analysis of covariance to adjust for different baselines. The stable end products of nitric oxide (nitrite and nitrate) were measured in the forearm venous effluent. Nitrite and nitrate levels at baseline were not reduced in patients with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of angiotensin II on noradrenaline release in the human forearm.

OBJECTIVE: The aim was to test the hypothesis that in normal humans angiotensin II would stimulate local release of noradrenaline under basal conditions or during a sympathetic stimulus provided by lower body negative pressure (LBNP). METHODS: Nine healthy volunteers received intra-arterial infusions of angiotensin II, 5 ng.min-1, into the non-dominant forearm. Forearm blood flow (strain gauge plethysmography) and regional noradrenaline spillover (using the tracer methodology of Esler) were measured during angiotensin II alone, LBNP alone, and LBNP plus angiotensin II. RESULTS: Angiotensin II and LBNP decreased forearm blood flow comparably: from 3.1(SD 1.5) to 2.4 (0.9) ml.100 g-1.min-1 during angiotensin II, p < 0.05; and from 3.3(1.5) to 2.5(1.0) ml.100 g-1.min-1 during LBNP, p < 0.05 (p = NS, A-II v LBNP). Angiotensin II had no effect on forearm venous noradrenaline or regional noradrenaline spillover. LBNP increased venous noradrenaline outflow from the forearm, from 1.6(0.40) to 2.1(0.6) nmol.min-1 (p < 0.05), while regional noradrenaline spillover tended to increase, rising from 1.5(0.8) to 2.0(1.0) nmol.100 ml-1.min-1. Angiotensin II did not enhance forearm blood flow or noradrenaline responses to LBNP. CONCLUSIONS: In the human forearm, mildly vasoconstrictor infusions of angiotensin II do not increase local release of noradrenaline, either alone or during mild LBNP. At least under these conditions, angiotensin II would not appear to be a potent influence on local sympathetic activity.

Effects of norepinephrine on endothelium-dependent vasodilation of forearm resistance vessels.

BACKGROUND: Endothelium-dependent dilatation of forearm resistance vessels is attenuated in patients with heart failure. Activation of the sympathetic nervous system could cause this abnormality by way of vasoconstriction and chemical inactivation of nitric oxide. METHODS AND RESULTS: The effects of concurrent intra-arterial norepinephrine infusions (25, 50 and 100 ng/min) on forearm blood flow responses to equipotent doses of an endothelium-dependent vasodilator, methacholine (0.3 and 1.5 micrograms/min), and an endothelium-independent vasodilator, nitroprusside (1 and 5 micrograms/min), were studied in 12 normal subjects. Norepinephrine infusions increased the mean plasma norepinephrine from 255 pg/ml at baseline to 460, 629, and 1089 pg/ml, respectively. Basal forearm blood flow was reduced from 2.9 to 1.6 ml/min/100 ml of forearm volume at the highest dose (p < 0.01). The average response to the lowest dose of methacholine (4.5 ml/min/100 ml) was not significantly reduced by concurrent infusion of norepinephrine (4.4, 4.2, and 4.3 ml/min/100 ml, respectively), whereas the response to the higher dose of methacholine (8.9 ml/min/100 ml) tended to be lower (7.2, 6.7, and 7.4 ml/min/100 ml, respectively) but did not attain statistical significance. Methacholine induced vasodilation was not more sensitive to norepinephrine than nitroprusside responses. Lower body negative pressure (-20 mm Hg) also significantly reduced baseline forearm flow and increased plasma norepinephrine but did not effect either methacholine or nitroprusside induced vasodilation. CONCLUSION: Sympathetic stimulation induced by infusion of norepinephrine or lower body negative pressure is not a potent antagonist to endothelium-dependent vasodilation of the forearm vasculature. These data suggest that sympathetic activation does not completely explain the abnormal endothelium-dependent vasodilation seen in patients with heart failure.

Cyclosporine augments renal but not systemic vascular reactivity.

Renal vasoconstriction and hypertension are major side effects of cyclosporine. We tested the acute effects of cyclosporine on renal and systemic vascular reactivity to norepinephrine, angiotensin II, and arginine vasopressin. Renal vascular reactivity was tested in anesthetized Sprague-Dawley rats with denervated kidneys. Renal blood flow was measured with an electromagnetic flow probe in response to graded intra-arterial infusions of vasoconstrictors before and after intravenous administration of cyclosporine. Cyclosporine augmented the decrease in renal blood flow and the increase in renal vascular resistance produced by intrarenal norepinephrine, angiotensin II, and arginine vasopressin. In these studies, systemic blood pressure did not change and cyclosporine caused no direct change in basal renal blood flow. In contrast, in conscious animals, cyclosporine did not increase the pressor response to intravenous norepinephrine or to angiotensin II. Rather, cyclosporine caused enhanced baroreflex slowing of heart rate and a decrease in the pressor response to both norepinephrine and angiotensin II. Even when the baroreceptor reflex was blocked by pentolinium, the pressor response to norepinephrine in cyclosporine-treated animals was diminished compared with vehicle-treated animals. Therefore, although cyclosporine augmented renal vasoconstriction in response to norepinephrine, angiotensin II, and arginine vasopressin, it did not acutely increase the systemic vascular response to these agents. Enhanced renal vascular responsiveness is an additional mechanism for cyclosporine-mediated renal vasoconstriction. Lack of enhanced peripheral vascular responsiveness suggests that hypertension is not likely to be due to direct effects on the systemic vasculature and is more likely to be a consequence of renal functional impairment.