A conscious-rabbit model for the long-term observation of urethral and arterial pressures.

OBJECTIVE: To describe and evaluate a new experimental model for the simultaneous measurement of urethral (UP) and arterial (AP) pressures in the conscious rabbit, thereby avoiding the interference of anaesthesia which markedly reduces reflex activity and tone of smooth muscle. MATERIALS AND METHODS: Female rabbits were anaesthetized and catheters inserted into the urethra, abdominal aorta, jugular vein and bladder. After recovering from surgery, rabbits were trained to remain static in a sling for a period of 2 h, during which the UP and AP were recorded. The model was validated for short- and long-term stability before the effects of drugs were assessed; UP and AP were recorded for up to 60 min after drug/solvent administration to assess short-term stability, and long-term stability was assessed by comparing 60 min control periods between the first and fifth experimental session up to a month apart. RESULTS: Over 60 min in the control group, the UP remained steady, whereas the AP only decreased slightly. Recordings were made during five subsequent control periods, with at least 3 days of rest between successive assessments, and the UP and AP remained similar for up to 1 month. During a second phase, the effect of alpha 1-adrenoceptor agonists on both pressures were evaluated to characterize their functional uroselectivity. De-glymidodrine and L-phenylephrine (0.1 mg/kg) were administered intravenously; the UP increased by 18 cmH2O (146%) and 21 cmH2O (173%), respectively, whereas AP increased by 22 mmHg (31%) and 47 mmHg (63%), respectively. At 5 min after administering the drugs, the UP remained higher by 16 cmH2O (121%) with de-glymidodrine, whereas it had returned to basal values with L-phenylephrine. CONCLUSIONS: This conscious-animal model allows the simultaneous measurement of UP and AP in the absence of anaesthesia. It provides a useful means to directly evaluate the effects of a drug on the urogenital and cardiovascular systems, and thereby its functional uroselectivity.

Relationship between the effects of alfuzosin on rat urethral and blood pressures and its tissue concentrations.

This study was undertaken in order to establish the alpha1-antagonist effects of alfuzosin on phenylephrine-induced increases in urethral and arterial blood pressures at 1 and 6 hours post dosing (10 mg/kg, p.o.). At each time, plasma and prostatic concentrations of alfuzosin were measured and correlations between tissue concentrations and pharmacological effects were calculated. At one and six hours post dosing, alfuzosin markedly shifted the urethral and arterial dose response curve to phenylephrine. At one hour, prostatic concentration was 4.1 times greater than plasma concentration (363 ng/g vs 88 ng/ml) and at 6 hours this ratio reached 8.6 times (167 ng/g vs 20 ng/ml). By taking together the data points obtained at 1 and 6 hours we showed that the effects of alfuzosin on urethral pressure were correlated with prostate levels (r=0.906, p<0.01) and the effects on arterial blood pressure were correlated with plasma levels (r=0.941, p<0.01). These results suggest that a preferential distribution of alfuzosin in prostatic tissue may play a role in its functional uroselectivity.

Antagonistic effects of epinephrine, glucagon and methylatropine but not calcium chloride against atrio-ventricular conduction disturbances produced by high doses of diltiazem, in conscious dogs.

Conscious dogs (n = 6) with chronically implanted electrocardiogram electrodes and arterial and venous catheters were infused with a large dose of diltiazem (1 mg/dog per min i.v. over 60 min) to evoke hypotension and atrioventricular disturbances (AVII and AVIII blocks) which lasted for several hours. These effects are also observed in humans after accidentally or intentionally taking overdoses of diltiazem and particularly verapamil. In the intoxicated dog, administration of methylatropine (50 micrograms/kg per min i.v. over 10 min), epinephrine (0.2 and 0.4 microgram/kg per min i.v. over 60 min) and glucagon (2 micrograms/kg/min i.v. over 15 min) but not CaCl2 (3 mg/kg/min i.v. over 15 min) abolished almost entirely the AVII and AVIII blocks produced by diltiazem and re-established a normal sinus rhythm. However, these treatments failed to normalize AV conduction, and did not modify the moderate hypotensive effects of diltiazem. These findings support available clinical observations that beta-adrenoceptors agonists, glucagon and atropine rather than calcium salts are beneficial for the successful treatment of cardiovascular toxicity associated with the intake of supratherapeutic doses of diltiazem or verapamil.