Cardiovascular effects of acute treatment with the antipsychotic drug olanzapine in rats.

Treatment with antipsychotics is associated with adverse cardiovascular effects such as orthostatic hypotension and arrhythmias. Despite the higher prevalence of cardiovascular complications in patients with schizophrenia, the effects of antipsychotic drugs on vascular tone and cardiac contractility have received little attention. In order to better understand the cardiovascular effects of antipsychotic drugs, we investigated if the atypical antipsychotic olanzapine alters in vivo cardiovascular function in rats. Male Sprague-Dawley rats were prepared with indwelling catheters. After 4 h of recovery from surgery, the mean arterial pressure (MAP), mean circulatory filling pressure (MCFP; index of body venous tone), heart rate, left ventricular peak systolic pressure (LVP) and cardiac contractility (±dP/dt) were measured in conscious, unrestrained rats for 60 min after a single injection of olanzapine (3 or 15 mg/kg, i.p.) or vehicle. Cardiovascular measurements were not altered at any time points in the vehicle-treated rats. Olanzapine did not affect heart rate, but dose-dependently decreased MAP, MCFP, LVP and +dP/dt. Acute olanzapine treatment in rats thus reduced blood pressure and venous tone, as well as cardiac contractile function. Decreased venous tone may be a contributing factor to orthostatic hypotension commonly observed in patients during initiation of antipsychotic therapy.

Effects of nimesulide, a selective COX-2 inhibitor, on cardiovascular function in 2 rat models of diabetes.

Cyclooxygenase-2 (COX-2) has been found to be activated in diabetes. We investigated whether nimesulide (selective COX-2 inhibitor) alters cardiovascular responses to adrenaline in 2 rat models of diabetes. Wistar rats (5-week old) were continuously fed a normal or high-fructose diet (60% of caloric intake). At week 2, half of the rats in each diet regimen were given streptozotocin (STZ) (60 mg/kg, intravenously). At week 6, cardiovascular effects of adrenaline (6 and 16 × 10 mol·kg·min, intravenously) were measured in 4 groups of thiobutabarbital-anesthetized rats (control, fructose, STZ, and fructose-streptozotocin [F-STZ]) before and after the injection of nimesulide (3 mg/kg, intravenously). Both the STZ and F-STZ groups exhibited hyperglycemia and significantly (P < 0.05) reduced left ventricular contractility, mean arterial pressure, arterial and venous resistance, and mean circulatory filling pressure (index of venous tone) responses to adrenaline, relative to the control and fructose groups. Nimesulide did not affect responses in the control and fructose groups but increased the venous and, to a less extent, arterial constriction to adrenaline in both the groups of diabetic rats. The cardiac contractile responses, however, were not altered after nimesulide treatment. The results show that nimesulide partially restored arterial and venous constriction to adrenaline in rats with STZ- and F-STZ-induced diabetes.

Cardiovascular side-effects of antipsychotic drugs: the role of the autonomic nervous system.

Cardiovascular disease is the leading cause of death in people with severe mental disorders, and rates are proportionally greater than for other diseases such as cancer. Reports of sudden death in patients receiving antipsychotic treatment have raised concerns about the safety of antipsychotic drugs, leading to a number of recent changes in how such drugs are advertised and marketed. The majority of second generation antipsychotic drugs also have significant metabolic side-effects, such as weight gain, insulin resistance and hyperlipidemia, which may contribute indirectly to cardiovascular complications. As the use of antipsychotic drugs continues to expand into new indications and populations such as children and adolescents, a better understanding is needed of how antipsychotic drugs affect the cardiovascular system. Antipsychotic drugs interact with numerous receptors both centrally and peripherally, including monoamine receptors. The direct, non-specific pharmacological actions of antipsychotic drugs can lead to adverse cardiovascular effects, including orthostatic hypotension, tachycardia and ventricular arrhythmias. The mechanisms responsible for these antipsychotic-induced cardiovascular abnormalities have not been fully elucidated, but likely involve blockade of adrenergic or cholinergic receptors and hERG channels, in addition to impaired autonomic function. The direct and indirect effects of antipsychotic drugs on the cardiovascular system and their possible mechanisms of action are discussed in this review, where both preclinical and clinical findings are integrated.

Attenuated alpha-adrenoceptor-mediated arterial and venous constrictions in rat models of diabetes.

Diabetes is associated with metabolic and vascular abnormalities. We investigated if arterial and venous constrictions are impaired in rat models of diabetes. Wistar rats (5 weeks old) were fed a normal or high-fructose diet (60% of caloric intake). On Day 14, half of the animals in each diet regimen were given streptozotocin (60 mg/kg, i.v.). On Day 35, plasma insulin and triglyceride were measured, and on Day 42, insulin sensitivity (via hyperinsulinemic euglycemic clamp), and pressor as well as mean circulatory filling pressure (index of venous tone) responses to noradrenaline were determined. The rats treated with streptozotocin or fructose-streptozotocin were hyperglycemic, hypoinsulinemic and insulin resistant, and they also had reduced potency (increased ED(50)) of pressor response and reduced venoconstriction to noradrenaline compared to the two groups not given streptozotocin. Plasma triglyceride was unchanged in streptozotocin-treated rats, moderately increased in fructose-fed rats, and markedly increased in fructose-streptozotocin-treated rats. Hyperglycemia, insulin resistance and alpha-adrenoceptor-mediated venous contractile dysfunction were more pronounced in the group given fructose-streptozotocin than that given streptozotocin alone. The presence of marked hypertriglyceridemia, insulin resistance and vascular dysfunction makes the fructose-streptozotocin-treated rats a suitable model for study of metabolic and vascular abnormalities in advanced type 2 diabetes.