Cardiovascular parameters in anaesthetized guinea pigs: a safety pharmacology screening model.

INTRODUCTION: Assessment of cardiovascular functions in vivo is part of the core battery of guideline ICH S7A and is thereby required by regulatory authorities. The haemodynamic effects of repeated intravenous administrations of reference compounds were analyzed in order to validate the guinea pig model for safety pharmacology studies under GLP conditions. METHODS: Male guinea pigs (n=54, weighing 565-762 g) were anaesthetized using 1.5 g/kg, i.p., urethane. Systolic arterial blood pressure (SAP), diastolic arterial blood pressure (DAP), heart rate (HR), left ventricular pressure (LVP), cardiac contractility (dp/dt(max)), and ECG (RR, QT, and QTc intervals) were recorded continuously. Animals received vehicle i.v. followed by cumulative doses of reference compounds. RESULTS: Vehicle did not produce any relevant changes, either in cardiovascular or ECG parameters. Isoproterenol caused a rapid and significant increase in HR, LVP, and dp/dt(max), in contrast to a dose-dependent decrease in SAP and DAP. Epinephrine led to a potent increase in all cardiovascular parameters. Nifedipine produced a slight decrease in HR and LVP, and a potent decrease in blood pressure and dp/dt(max). Verapamil caused a dose-dependent decrease in all cardiovascular parameters. Ouabain resulted in a significant increase in SAP, DAP, LVP, and dp/dt(max); ECG showed an atrioventricular block and arrhythmia. Terfenadine, cisapride, and sotalol prolonged QT and QTc intervals, whereas vehicle and the other tested compounds did not produce any prolongation of the QTc interval. DISCUSSION: Our results on HR, blood pressure, and ECG obtained after i.v. administration of reference compounds show the usefulness of the guinea pig in assessing cardiovascular safety. The anaesthetized guinea pig allows the measurement of cardiac contractility and the use of doses higher than in conscious animals. Using this animal model, several cardiovascular parameters can be recorded simultaneously at a modest cost in terms of test compound and the number of animals required.

Inhibition of human and pig ureter motility in vitro and in vivo by the K(+) channel openers PKF 217-744b and nicorandil.

The relaxing property of the K(+) channel opener and nitric oxide donor nicorandil and the new K(+) channel opener PKF 217-744b was investigated on isolated human ureteral tissue in vitro and in intact ureters of anesthetized pigs in vivo. In addition, nicorandil and its antagonists, glibenclamide and methylene blue, were tested on isolated pig ureter tissue in vitro. Nicorandil decreased the frequency of spontaneous contractions in isolated pig ureter rings. This effect was antagonized by glibenclamide and methylene blue suggesting that the nicorandil induced relaxation of the ureter is mediated by activation of ATP-sensitive K(+) channels and involvement of soluble guanylate cyclase. Moreover, nicorandil and PKF 217-744b reduced the amplitude of electrically induced contractions in isolated human ureter rings. Calculations of EC(50) values showed that PKF 217-744b [EC(50) = 4.83 x 10(-8) M] was more potent than nicorandil [EC(50) = 4.38 x 10(-5) M]. Both drugs reduced the contraction frequency of the pig ureter after intravenous and topical administration in vivo. Intravenous, but not topical, administration of nicorandil and PKF 217-744b significantly decreased arterial blood pressure but did not affect the heart rate. The in vitro findings suggest that K(+) channel opening and nitric oxide release mediate the effect of nicorandil. Our in vivo results indicate that PKF 217-744b and nicorandil are promising drugs for clinical application in patients with acute stone colic to relieve obstruction and facilitate stone passage or to relax the ureter before ureteroscopy.