The evolution of hypertensive therapy.

1. During the past 30 years many antihypertensive agents, acting at differing levels on the mechanisms controlling arterial blood pressure, have been introduced. 2. Whereas the usefulness of early drugs was limited by side effects, the discovery of successive classes of agents has resulted in the gradual introduction of drugs causing fewer adverse effects with consequent improvements in patient compliance. 3. The recent appearance of angiotensin II antagonists and potassium channel openers, together with increased knowledge of the roles played by atrial natriuretic factor and endothelial cell-derived autacoids in control of vascular tone, hold prospects for still further improvements in therapy.

Dopaminergic mediation of the diuretic and natriuretic effects of ANF in the rat.

Atrial natriuretic factor (ANF) increases sodium (Na+) and water excretion 8-10 fold on repeated administration to anesthetized rats. SCH-23390 (80 micrograms/kg i.v.) and R-sulpiride (80 micrograms/kg i.v.), selective antagonists of dopamine receptors in the renal vasculature, inhibited diuresis and natriuresis induced by AP III and dopamine. These findings suggest that ANF exerts its effects on renal Na+ and water handling via a dopaminergic mechanism; however, changes in intrarenal hemodynamics secondary to dopamine receptor blockade may attenuate the actions of ANF.

Inhibition of thromboxane biosynthesis in splanchnic ischemia shock.

Administration of dazoxiben (5 mg/kg, i.v.), which effectively suppressed plasma thromboxane concentrations, decreased the number of dogs that deteriorated into shock following a temporary (3-hr) splanchnic artery occlusion (SAO). Dazoxiben pretreatment also moderated the rise of plasma prostacyclin, but it augmented circulating prostaglandin E2 following the release of SAO. These alterations in arachidonic acid metabolism were accompanied by a moderation in the rise of plasma beta-glucuronidase activity, suggesting a moderation of tissue damage in the ischemic splanchnic region, and mitigation of the progressive hemodynamic deterioration caused by the SAO. The possible existence of causal relationships between the plasma eicosanoid concentrations, extent of damage in the ischemic splanchnic region, hemodynamic deterioration, and ultimate production of circulatory failure in dogs subjected to SAO are discussed.

Elevated arterial cyclic AMP levels during the development of spontaneous hypertension in rats.

Vascular cyclic AMP alterations were studied during the initiation of vascular hypertrophy and hyperplasia in spontaneously hypertensive rats (SHR). The onset of hypertension at 6 weeks of age coexisted with a three-fold elevation in the aortic content and concentration of cyclic AMP, whereas aortic DNA and protein contents were identical to those of WKY controls. A similar cyclic AMP elevation was present in 12-week-old SHR when vascular hypertrophy and hyperplasia were already established. These experiments suggest the participation of cyclic AMP in the process of hypertensive vascular growth.

CGS 7525A, a new, centrally active alpha 2 adrenoceptor antagonist.

CGS 7525A, a new tetracyclic compound, was evaluated for alpha 2 adrenoceptor antagonism in receptor binding assays and in behavioral and electrophysiological tests. 3H-Clonidine, but not 3H-prazosin, binding was potently inhibited in vitro by CGS 7525A. In vivo, CGS 7525A attenuated the suppressant action of clonidine on phenylquinone-induced writhing and on locus coeruleus neuronal firing rate. Mianserin was nearly equipotent with CGS 7525A in the 3H-clonidine binding assay, but considerably less potent in the measures of alpha 2 adrenoceptor antagonism in vivo. Both CGS 7525A and mianserin displaced 3H-spiroperidol binding from frontal cortex 5-HT2 binding sites. Although yohimbine resembled CGS 7525A in most respects, its activity at 5-HT2 binding sites was relatively low, CGS 7525A was not associated with any appreciable blockade of norepinephrine or serotonin uptake in vitro. Thus, CGS 7525A appears to be a promising new pharmacological tool for investigating the behavioral function of brain alpha 2 adrenoceptors.

Oxaprotiline: induction of central noradrenergic subsensitivity of its (+)-enantiomer.

The effects of the tetracyclic antidepressant oxaprotiline and its two optically active enantiomers on the norepinephrine (NE) receptor coupled adenylate cyclase system were determined in slices of the rat cerebral cortex. While oxaprotiline does not change the response of the cyclic AMP generating system to NE after a single dose, chronic administration of the drug for 3 to 14 days down-regulates the receptor system. The noradrenergic subsensitivity is linked to a reduction in the Bmax value of beta-adrenergic receptors as assessed by (3H)-dihydroalprenolol binding without changes in the Kd value. The action of oxaprotiline on the NE receptor coupled adenylate cyclase system resides entirely in the (+)-enantiomer which is a potent inhibitor of the neuronal uptake of NE. The (-)-enantiomer of oxaprotiline which is a weak inhibitor of NE reuptake, failed, even in high doses, to modify the noradrenergic receptor system. Though not excluding co-regulatory factors in addition to NE, the studies support the view that an enhanced and persistent NE receptor interaction is one of the prerequisites for the in vivo down-regulation of central noradrenergic receptor function. The results also suggest that the therapeutic activity of oxaprotiline may reside in its (+)-enantiomer.

Antagonism by mianserin and classical alpha-adrenoceptor blocking drugs of some cardiovascular and behavioral effects of clonidine.

Antagonism of pressor responses to sympathetic outflow stimulation and alpha-adrenoceptor agonists in pithed spontaneously hypertensive rats was used to estimate postsynaptic alpha-adrenoceptor blocking activity of mianserin, phentolamine, phenoxybenzamine, piperoxan and yohimbine. Estimation of presynaptic alpha-adrenoceptor blocking activity of these drugs was obtained by studying their ability to antagonize clonidine-induced suppression of positive chronotropic responses to sympathetic outflow stimulation. In this manner, evidence was obtained that mianserin causes selective presynaptic alpha-adrenoceptor blockade. Mianserin, piperoxan and yohimbine antagonized clonidine-induced avoidance blockade or hypotension in spontaneously hypertensive rats, but methysergide, phenoxybenzamine and phentolamine were ineffective. These results suggest that mianserin may antagonize the central effects of clonidine by blockade of noradrenergic presynaptic or autoreceptors and possibly explain the antidepressant effect of mianserin as due to indirect activation of central noradrenergic neurons.

Centrally-mediated cardiovascular effects of 5-hydroxytryptophan in MAO-inhibited dogs: modification by autonomic antagonists.

In MAO-inhibited dogs, 5-hydroxytryptophan (5-HTP), either 5 or 10 mg/kg i.v., caused hypotension with variable effects on heart rate. Reflex responses to bilateral carotid artery occlusion (BCO) were greatly inhibited by 5-HTP. The hypotensive effects were markedly inhibited by cerebral and extracerebral decarboxylase inhibition with RO 4-4602 and the inhibition of BCO was delayed. Selective extracerebral decarboxylase inhibitation with MK 486 did not prevent either the hypotensive action of 5-HTP or the effect on BCO, although the amino acid now consistently caused bradycardia. Left ventricular pressure and dP/dt were reduced, but cardiac output was maintained by an increase in stroke volume. Hypotension was due predominantly to decreased peripheral resistance. The hypotensive action of 5-HTP was abolished or greatly attenuated after pretreatment with either yohimbine or methysergide, but was unaffected by haloperidol. These results indicate that cerebral decarboxylation and formation of 5-HT are responsible for the hypotension after 5-HTP in MAO inhibited dogs.

Timolol maleate, a new beta-adrenergic receptor blocking agent.

Some pharmacodynamic properties of an oxypropanolamine substituted novel heterocyclic compound are described. Initial studies involve comparison of the racemic mixture, dl-timolol maleate, with the beta-adrenergic receptor blocking agent propranolol in the rat, dog and cat. dl-Timolol maleate is shown to be a potent inhibitor of cardiovascular beta-adrenergic receptors activated by isoproterenol or adrenergic nerve stimulation. Blockade of alpha-adrenergic receptors is not observed even after extremely high doses. The compound is approximately 3 times more potent than propranolol in suppressing isoproterenol-induced cardioacceleration by the i.v. route of administration. dl-Timolol maleate is also extremely well absorbed when given orally, being then about 10 times more active than propranolol. Unlike propranolol, neither dl-timolol maleate nor its optical isomers possess demonstrable local anesthetic activity. Similar to propranolol and other beta-adrenergic receptor blocking agents, activity of the compound resides predominantly in the l-isomer (timolol maleate.

Effects of clonidine on baroreceptor function in anesthetized dogs.

The effects of clonidine (15-30 mug/kg i.v.) on carotid sinus and other baroreceptors were investigated in anesthetized dogs. In 14 control dogs, right carotid sinus pressure was controlled by retrograde perfusion through the common carotid artery at constant flow with femoral arterial blood. Graded reductions in heart rate and blood pressure induced by graded increases in carotid sinus pressure were prevented, whereas reflex bradycardias associated with norepinephrine pressor activity were potentiated by clonidine. Norepinephrine-induced bradycardia, although reduced, still persisted after chronic bilateral sinusectomy and these responses were also potentiated by clonidine. In contrast, clonidine did not potentiate reflex bradycardia in dogs 20 days after aortic stripping. In intact dogs, clonidine inhibited the response to bilateral carotid artery occlusion and to carotid sinus nerve stimulation. These studies suggest that clonidine can inhibit carotid sinus baroreceptor function and simultaneously potentiate other, presumably aortic, baroreceptor activity.

An analysis of the peripheral effects of l-DOPA on autonomic nerve function.

1 The ability of intravenous L-DOPA to block sympathetic and parsympathetic nerves has been studied in cats and dogs pretreated with a monoamine oxidase inhibitor.2 L-DOPA inhibited positive chronotropic and pressor responses to dimethylphenylpiperazinium (DMPP) and McN-A-343 in dogs, and contractions of the nictitating membrane produced by these ganglion stimulants in cats.3 Responses of the cat nictitating membrane to preganglionic stimulation were inhibited by L-DOPA to a greater extent than those to postganglionic stimulation of the cervical sympathetic chain.4 In dogs, L-DOPA had no vagolytic action, but depressed vasoconstrictor responses elicited in the perfused hind-limb by electrical stimulation of the lumbar sympathetic chain.5 The degree of lumbar sympathetic chain inhibition correlated with the pressor response following L-DOPA, and both effects were prevented by prior decarboxylase inhibition.6 These results suggest that the decarboxylation products of L-DOPA do not impair parasympathetic nerve activity but depress sympathetic nerve function predominantly by inhibiting both muscarinic and nicotinic sites of sympathetic ganglia.