Functional and biochemical evidence for the lack of cardiac presynaptic alpha-2 adrenoceptor stimulant properties of cirazoline (LD 3098), a potent alpha-1 adrenoceptor agonist in dogs and rats.

In pithed rats, i.v. injection of cirazoline produced pressure effects which were antagonized in a competitive manner by the relatively selective alpha-1 adrenoceptor blocker, prazosin (0.01--0.1 mg/kg i.v.) but not by the relatively selective alpha-2 adrenoceptor blocker, yohimbine (0.3 mg/kg i.v.). The latter agent, however, inhibited the increases in arterial pressure produced by UK-14,304, a preferential alpha-2 adrenoceptor agonist. In contrast, both yohimbine and prazosin reduced the pressor effects of clonidine. In intact anesthetized, vagotomized rats or in pithed rats with a submaximal tachycardia evoked by electrical stimulation of the spinal cord, clonidine and oxymetazoline, in contrast to cirazoline (5.0 micrograms/kg i.v.), decreased heart rate through excitation of alpha-2 adrenoceptors. This lack of effect of cirazoline was not due to a concomitant pre- or postjunctional action of cirazoline leading to an enhanced chronotropic response to released norepinephrine because in phentolamine-pretreated rats cirazoline did not modify the neural sympathetic tachycardia. Although cirazoline potentiated the heart rate elevated by an i.v. infusion of either norepinephrine, isoproterenol, or aminophylline, this effect was probably of hemodynamic origin. In pithed rats with a submaximal neural tachycardia, cirazoline, like phentolamine (10.0--30.0 micrograms/kg i.v.), inhibited the decrease in heart rate produced by clonidine, suggesting that it possesses alpha-2 adrenoceptor blocking properties. In spinal dogs, cirazoline (10.0 micrograms/kg i.v.) modified neither base-line heart rate nor the tachycardia evoked by an intracoronary artery infusion of norepinephrine. In the same preparation, continuous electrical stimulation of cardioaccelerator sympathetic nerve fibers produced a sustained positive chronotropic effect accompanied by an increase in the coronary sinus venous plasma norepinephrine content. Neither parameter was significantly changed by cirazoline; however, clonidine at the same dose as used for cirazoline produced approximately 50% inhibition of the experimental neural tachycardia. Finally, cirazoline, like phentolamine at 10.0 micrograms/kg i.v., failed to block, cardiac presynaptic alpha-2 adrenoceptors in the spinal dog. These results indicate that cirazoline is a potent alpha-1 adrenoceptor agonist that lacks cardiac presynaptic alpha-2 adrenoceptor stimulant properties in either dogs or rats. In the latter species, cirazoline was found also to block cardiac presynaptic alpha-2 adrenoceptors.