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1. In pentobarbitone-anaesthetized dogs, prazosin (2 x 1-3 micronmol day-1 kg-1; 2 x 0-5 mg day-1 kg-1) administered orally for 3 days reduced resting aortic blood pressure as well as the pressor response to bilateral carotid occlusion. Prazosin neither affected resting heart rate nor the tachycardia induced by intravenous isoprenaline, noradrenaline and electrical stimulation of preganglionic and postganglionic sympathetic nerve fibres. Prazosin significantly attenuated the fall in perfusion pressure in a perfused hind leg resulting from the section of the ipsilateral sympathetic lumbar chain. Furthermore, the drug inhibited by about 50% the hind-leg pressor responses elicited by intra-arterial administration of alpha-adrenoreceptor agonists and by stimulation of the lumbar sympathetic chain, without altering the effects of angiotension II. 2. Acute administration of prazosin into the innervated hind leg provoked a dose-related reduction in vascular resistance. However, after spinal anaesthesia no such an effect was observed even when vascular tone was increased by infusion of vasopressin. Under the same experimental conditions administration of papaverine induced a vasodilatation. 3. This study confirms that prazosin impairs the function of vascular alpha-adrenoreceptors, and strongly challenges the claim that this compound produces a directly mediated vasodilatation of the leg vascular bed.

In cats, dogs and rats, clonidine (20.0 microgram/Kg, i.v.) reduced the sustained tachycardia evoked by a continuous electrical stimulation of cardiac sympathetic nerve fibres. This effect of clonidine resulting from stimulation of cardiac presynaptic alpha-adrenoceptors could be completely antagonized by phentolamine and prazosin in the dog and the cat, whereas in the rat, prazosin, unlike phentolamine, failed to effectively inhibit the clonidine induced reduction in heart rate. The calculated doses of phentolamine and prazosin needed to produce a 50% antagonism were of similar magnitude in the dog, but in the cat prazosin was about three times less potent than phentolamine. As opposed to clonidine, LD 3098, a potent vascular postsynaptic alpha-adrenoceptor stimulating imidazoline, and phenylephrine (20.0 microgram/Kg, i.v.) did not significantly alter the sympathetic tachycardia in the pithed rat and the spinal dog. These results indicate that compounds stimulating postsynaptic alpha-adrenoceptors may be inactive as agonists of cardiac presynaptic alpha-adrenoceptors within the same animal species. Furthermore, a compound showing selective activity as an antagonist of vascular alpha-adrenoceptors in one species may not necessarily exert the same selective effects in other animals as demonstrated here for prazosin.

A series of N2-[(acylamino)alkyl]-6,7-dimethoxy-2,4-quinazolinediamines was synthesized as potential alpha 1-adrenoceptor antagonists. When administered to spontaneously hypertensive rats at 10 mg/kg po, a number of propanediamine derivatives showed good antihypertensive activity, whereas the ethanediamine derivatives, albeit being structurally more closely related to prazosin, were devoid of this property. The most active derivative, N-[3-[(4-amino-6, 7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarbo xamide hydrochloride, alfuzosin (12), showed high selectivity for peripheral alpha 1-postjunctional adrenoceptors. At equiactive antihypertensive doses, its effect on the pressor response to postural changes in conscious dog was less marked than that shown by prazosin. In the light of these results, alfuzosin was selected for clinical evaluation.

In pentobarbital (35.0 mg/kg) anaesthetised dogs, bolus injections of prazosin into the femoral artery (3.0--300.0 microgram) provoked a dose-related fall in the vascular resistance of the innervated hind limb. In contrast to papaverine, prazosin failed to produce the same effect in dogs under spinal anaesthesia even when the intrinsic femoral vascular tone was increased with vasopressin. However, vasodilator effects of prazosin were again observed when the tone of the limb was elevated by either stimulating the sympathetic lumbar chain or by infusing alpha-adrenoceptor agonists. A significant reduction of both aortic blood pressure and pressor response to bilateral carotid artery occlusion was noted in a group of normotensive dogs anaesthetised 12 h after the last dose of prazosin given twice daily at 0.5 mg/kg, p.o., for 3 day period. This short-term treatment modified neither the resting heart rate nor the positive chronotropic effect induced by either intravenous noradrenaline or electrical stimulation of pre- and post-ganglionic nerve fibres of the right stellate ganglion. However, it prevented the larger increase in heart rate in response to bilateral carotid occlusion in placebo-treated dogs after section of the vagi. A decrease in baseline sympathetic tone of the perfused hind limb as well as vasoconstrictor effects produced by i.a. injections of several alpha-adrenoceptor agonists and electrical stimulation of the lumbar sympathetic chain was observed in prazosin-treated animals. The dose--pressor response profiles to these alpha-adrenoceptor stimulants after prazosin were not parallel to those obtained in the control group. The vasoconstrictor response to angiotensin II was not changed by prazosin. In rabbit aortic strips, prazosin (0.1--3.0 micrometer) produced competitive antagonism of the contractile responses induced by cirazoline, noradrenaline and phenylephrine. In contrast to papaverine, prazosin in concentrations up to 100.0 micrometer neither relaxed the aortic strips contracted by potassium ions nor modified the concentration-response curve to calcium ions. These studies indicate that blood pressure lowering effects of prazosin given acutely or for three days can be accounted for by a clear-cut functional impairment of vascular postsynaptic alpha-adrenoceptors. No evidence for a direct myorelaxant property of prazosin could be obtained in these studies.

In conscious rabbits prepared for continuous arterial pressure measurements by means of a catheter placed into the main ear artery, intravenous administration of prazosin (5.0 micrograms/kg, i.v. over 20 min) produced a significant decrease in arterial pressure and cardioacceleration. This dose of prazosin inhibited by approximately 70% the pressor effects of phenylephrine. However, prazosin failed to produce significant functional modifications of either the bradycardia or the tachycardia which accompanied the changes in arterial pressure evoked, respectively, by intravenous bolus injections of angiotensin II or acetylcholine. It is concluded that prazosin in the dose studied does not appear to interfere with reflex heart rate responses to vasodepressor or vasopressor stimuli in conscious rabbits.

In conscious, spontaneously hypertensive rats (SHR) oral prazosin (0.03-3.0 mg/kg) resulted in dose-related reductions of systolic blood pressure measured with a tail cuff. In SHR whose tail artery blood pressure was continuously monitored the antihypertensive effect of prazosin (1.0 mg/kg, p.o.) was accompanied by a significant increase in heart rate. Several groups of SHR were pithed 2 hr after oral prazosin (1.0 mg/kg) or placebo. In this preparation the mean carotid blood pressure increases following i.v. injections of angiotensin II or 5-hydroxytryptamine and the positive chronotropic responses to i.v. norepinephrine or electrical stimulation of the spinal cord were similar in control and prazosin-pretreated animals. However, the dose-pressor response curves to i.v. norepinephrine or electrical stimulation of the spinal cord from prazosin-pretreated SHR lay to the right of the control curves. In addition, the slopes of the linear portion of these curves were flatter after prazosin and remained so even after i.v. propranolol was given alone or with cocaine. Prazosin-pretreated SHR responded to phenylephrine with a fall followed by a rise in carotid blood pressure. The depressor effect was abolished and the pressor phase enhanced by i.v. propranolol. The pressor responses to i.v. cirazoline or clonidine were significantly inhibited by prazosin. Finally, prazosin failed to significantly modify the negative chronotropic effects of clonidine observed in pithed SHR whose heart rate was raised by continuous electrical stimulation of the thoracic spinal cord. These results indicate that oral prazosin exerts pronounced antihypertensive effects in the SHR. This action apparently results from impairment of the sympathetic nervous system at the level of vascular postsynaptic alpha-adrenoceptors.

1 In spinal dogs, continuous electrical stimulation of the cardioaccelerator nerve produced a transient rise in aortic blood pressure and a sustained increase in both heart rate and coronary sinus blood flow. The latter effects were accompanied by a significant elevation in the coronary sinus plasma noradrenaline concentration without significant changes in the levels of dopamine and adrenaline. The concentrations of the three catecholamines in thoracic aorta plasma were not significantly changed by cardioaccelerator nerve stimulation.2 Clonidine (20 mug/kg, i.v.), given during cardioaccelerator nerve stimulation, increased both mean aortic blood pressure and coronary sinus blood flow and decreased heart rate and coronary sinus venous plasma noradrenaline overflow.3 Phentolamine (0.3 mg/kg, i.v.) completely antagonized these effects of clonidine. Prazosin (0.3 mg/kg, i.v.) inhibited by only 43 and 38% the respective reductions in heart rate and noradrenaline overflow elicited by clonidine.4 On termination of cardioaccelerator stimulation (about 10 min after either prazosin or phentolamine), heart rate and coronary sinus noradrenaline overflow returned to control prestimulation levels.5 Phentolamine or prazosin, administered alone during stimulation of the cardioaccelerator nerve, increased heart rate and noradrenaline overflow into the coronary sinus plasma. However, intravenous phentolamine and prazosin, in contrast to desipramine (0.3 mg/kg, i.v.) or tyramine (1.0 mg, i.a.), failed to change the tachycardia resulting from the local administration of noradrenaline into the sinus node artery (i.a.).6 These results show that in spinal dogs the clonidine-induced reduction in heart rate (elevated by electrical stimulation of the cardioaccelerator nerve) is accompanied by a fall in the quantity of noradrenaline overflowing into the coronary sinus plasma. The latter effect is presumably the result of an action of clonidine on cardiac presynaptic alpha-adrenoceptors, the activation of which is followed by a reduction in the release of noradrenaline per nerve impulse. Phentolamine and prazosin are both antagonists of cardiac presynaptic alpha-adrenoceptors in spinal dogs, as suggested by their action against clonidine and by their positive chronotropic effect when administered during stimulation of the cardioaccelerator nerve.