Michael J. DePasquale

Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats.

Oral administration of the angiotensin II receptor subtype 1 (AT1) antagonist DuP 753 causes long-lasting lowering of mean arterial pressure in spontaneously hypertensive rats. We examined whether the antihypertensive action of DuP 753 is a result of inhibition of brain angiotensin II. In normal spontaneously hypertensive rats, we found that intracerebroventricular DuP 753 (10 μg) blocked the pressor action of intracerebroventricular angiotensin II (100 ng); however, intracerebroventricular DuP 753 (10 μg) had no effect on the pressor response to 300 ng/kg angiotensin II administered intravenously (48±3 mm Hg in the presence of intracerebroventricular DuP 753 versus 49±4 mm Hg in its absence). In both normal and furosemide-treated spontaneously hypertensive rats (low Na+ diet plus furosemide), intracerebroventricular DuP 753 alone at 10 or 100 μg caused transient but significant pressor responses; however, no significant reduction in pressure (versus controls) was observed over the next 48 hours. In contrast to its central effects, we found that oral DuP 753 (10 or 30 mg/kg) in normal spontaneously hypertensive rats resulted in sustained mean arterial pressure decreases of up to −74 mm Hg. These data suggest that, although the pressor effect of brain angiotensin II is mediated by the AT1 receptor, blockade of these receptors does not lower blood pressure in spontaneously hypertensive rats. In the spontaneously hypertensive rat, DuP 753 depresses blood pressure by blockade of peripheral, not central, AT1 receptors.

Chronic Monitoring of Cardiovascular Function in the Conscious Guinea Pig Using Radio-Telemetry

An implantable radio-telemetry device for chronic monitoring of arterial pressure and heart rate in the conscious guinea pig was validated against measurements using an exteriorized, indwelling catheter. There were no significant differences between simultaneous measurements in animals instrumented with both the telemetry system and the conventional catheter (implanted 24 hrs prior to comparisons) in response to a variety of vasoactive agents. The device was shown to be accurate up to 3 weeks after implantation (longest time point tested). Resting pressures and heart rates in the telemetered guinea pig were stable in 100% of the animals tested. In contrast, animals instrumented with only exteriorized catheters showed a significant decline in pressure by 8 days after surgery and a 39% attrition rate due to loss of catheter patency. Performance of the telemetric device was examined in both normal and sodium-deficient animals, since the latter is a useful normotensive model in which blood pressure is rendered highly renin-dependent for evaluating the efficacy of potential antihypertensive agents that target the renin-angiotensin system. The telemetered guinea pig is an appropriate model for assessing responses to chronic exposure of cardiovascular agents.

Use of bioimpedance for measuring cardiac output in the conscious dog

Cardiovascular profiling of developmental compounds by General Pharmacology/Safety Pharmacology is an integral part of the drug discovery process in support of registration of clinical candidates. Non‐invasive screening tools which provide hemodynamic measurements can facilitate the drug development process. One such method, bioimpedance cardiography, is an indirect means of evaluating cardiac output. Changes in thoracic impedance in response to an applied current are related to changes in volume and velocity of blood flow in the thorax for the determination of stroke volume, which is coupled to heart rate for calculating cardiac output. Commercially available bioimpedance cardiography units have evolved considerably in recent years in step with advances in computing power. The use of these units, with modification, in the preclinical arena for determinations in anesthetized dogs and pigs has shown good correlation with other accepted methodologies for measuring cardiac output. Data presented here are the first to describe the application of this technology in conscious dogs. The utility and limitations of this method as a screening tool in the conscious dog are discussed. These cardiac output measurements combined with arterial pressure and electrocardiogram measurements, provide a simple means for more complete hemodynamic profiling of drug candidates.