Enkephalinase 'A' inhibition by thiorphan: central and peripheral cardiovascular effects.

On the basis of the distribution of enkephalins within the central and peripheral nervous systems as well as on responses to their administration, it has been suggested that these peptides participate in the regulation of the circulation. The present series of experiments examined the effects of thiorphan, an inhibitor of enkephalinase A, on cardiovascular responses to intracerebroventricular (i.c.v.) administration of [D-Ala2,Met5]enkephalin (DAME) and its amide and on peripheral interactions with the sympathetic nervous system and vasoactive peptides. Thiorphan (30 micrograms i.c.v.) potentiated the pressor response to i.c.v. DAME and DAMEamide in conscious spontaneously hypertensive rats. Responses to i.c.v. angiotensin I (AI) were unaffected suggesting lack of inhibition of central angiotensin converting enzyme (ACE). Peripheral administration of relatively large doses of thiorphan (30 and 100 mg/kg s.c.) attenuated the pressor response to i.v. AI by 30-40% and enhanced the depressor effect of i.v. bradykinin in anesthetized normotensive rats indicating inhibition of peripheral ACE. Pressor and tachycardic responses to activation of spinal sympathetic outflow were not altered by thiorphan in pithed normotensive rats. Thiorphan itself did not affect baseline blood pressure or heart rate in any of these experiments. In conclusion, inhibition of central enkephalinase A by i.c.v. administration of thiorphan potentiates the pressor response to i.c.v. DAME. The compound inhibits peripheral ACE but has little direct cardiovascular activity in its own right.

Antihypertensive activity of SCH 31846, a non-sulfhydryl angiotensin-converting enzyme inhibitor.

The antihypertensive, hemodynamic, and autonomic actions of SCH 31846, a new, potent and long-acting non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, were evaluated in several experimental preparations. Oral administration of 0.3-3 mg/kg caused dose-related decreases in blood pressure in spontaneously hypertensive rats (SHRs). Pretreatment with a diuretic augmented the maximum hypotensive response attainable. Single doses (3 mg/kg) of SCH 31846 reduced pressure for over 24 h. Five-day treatment lowered pressure progressively. Single oral doses of 3.2 and 10 mg/kg reduced blood pressure of conscious normotensive dogs. Diuretic pretreatment also enhanced the response. The antihypertensive action of SCH 31846 in SHRs was eliminated by nephrectomy, but not attenuated by indomethacin, indicating its dependency on renal renin but not on prostaglandin synthesis. Other studies using SHRs pointed to an absence of a central effect. SCH 31846 (1 mg/kg i.v.) decreased blood pressure and peripheral resistance of anesthetized dogs but did not alter cardiac output. Autonomic interactions were examined in normal and diuretic-pretreated SHRs and anesthetized dogs. SCH 31846 affected the response to sympathetic nerve stimulation and cardiovascular reflexes only minimally. It is concluded that SCH 31846 is a potent and long-lasting antihypertensive agent, the action of which is mediated, in all probability, by ACE inhibition.

Attenuation of pressor responses to intracerebroventricular angiotensin I by angiotensin converting enzyme inhibitors and their effects on systemic blood pressure in conscious rats.

The components of the renin-angiotensin system exist in the brain but their physiological role is uncertain. The effects of two angiotensin converting enzyme (ACE) inhibitors, MK 421 (or its diacid) and captopril, on brain ACE activity, as measured by inhibition of the pressor response to intracerebroventricularly (i.c.v.) administered angiotensin I (AI), and the potential contribution of the central nervous system to their antihypertensive activity were evaluated in the present series of experiments. The diacid of MK 421 (1 and 10 micrograms) and captopril (3 and 10 micrograms) given i.c.v. to conscious normotensive rats reduced the pressor response to i.c.v. AI indicating that they can inhibit brain ACE. Responses to AII were unaffected. Oral administration of maximal antihypertensive doses of MK 421 (10 mg/kg) and of captopril (30 mg/kg) to normotensive rats did not attenuate pressor responses to i.c.v. AI indicating that brain ACE was not inhibited under these circumstances. Intracerebroventricular administration of MK 421 diacid, (10 and 30 micrograms) and captopril (30 and 100 micrograms) did not lower baseline blood pressure of spontaneously hypertensive rats. These experiments indicate that MK 421 and captopril can inhibit brain ACE but that the central renin-angiotensin system probably does not contribute to their antihypertensive activity.

Suppression of a somatosympathetic reflex by the gamma-aminobutyric acid agonist muscimol and by clonidine.

gamma-Aminobutyric acid (GABA) and GABA agonists, e.g., muscimol, reduce blood pressure and sympathetic outflow and inhibit the "carotid occlusion reflex." In contrast, muscimol exerted only marginal effects on postural reflexes in a prior study. The somatosympathetic reflex, i.e., potentials evoked in sympathetic nerves in response to sensory nerve stimulation, is a useful model for studying centrally acting drugs. Effects of muscimol on the reflex were examined in anesthetized normotensive rats. At doses which had previously been shown to reduce blood pressure but to produce only minimal attenuation of postural reflexes in conscious hypertensive rats, muscimol, administered intracerebroventricularly, reduced blood pressure and inhibited the somatosympathetic reflex in the present study. The time course of the evoked potential was not altered. Baroreceptor activation and intracerebroventricular clonidine also suppressed the reflex. The inhibitory effect of muscimol but not that of clonidine was prevented by pretreatment with the GABA antagonist bicuculline. Thus, the marked suppression of the somatosympathetic reflex by muscimol and by clonidine, in contrast to minimal effects on postural reflexes, point to the selectivity of their central inhibitory actions.

Hypotensive and postural effects of the gamma-aminobutyric acid agonist muscimol and of clonidine.

gamma-Aminobutyric acid (GABA) and GABA agonists, e.g., muscimol, have been shown to reduce blood pressure by a centrally mediated mechanism. The present series of experiments compared cardiovascular responses to muscimol with those of clonidine in anesthetized and conscious spontaneously hypertensive rats. Both agents given intraventricularly reduced blood pressure, heart rate, and spontaneous sympathetic outflow in anesthetized animals. Muscimol also produced marked hypotension in conscious rats. However, compensatory adjustments to upright tilt were inhibited only slightly at most by both agents, even at high doses. Therefore, muscimol, like other centrally acting hypotensive agents, appears to inhibit the sympathetic nervous system selectively.

Alpha-Adrenergic and 5-hydroxytryptaminergic receptor stimulants as new antihypertensive drugs, with observations on involvement of opiate receptors.

Cardiovascular actions of central alpha-adrenergic and 5-hydroxytryptaminergic stimulants are discussed in terms of overall effects, correlation of various activities, receptor activation and side-effects. The involvement of opiate receptors in their actions is also examined.

Evidence for selective inhibition of sympathetic outflow by oxotremorine.

Unlike numerous centrally acting hypotensive substances which decrease blood pressure and sympathetic outflow, the muscarinic agonist oxotremorine failed to reduce heart rate in a prior study. In the present series of experiments oxotremorine decreased blood pressure and efferent renal nerve activity in anesthetized cats but, in contrast to clonidine, it did not inhibit cardiac sympathetic nerve activity or lower heart rate. Therefore, it is concluded that oxotremorine does not produce uniform sympathetic inhibition and that outflow is depressed selectively.

Apomorphine: selective inhibition of the aversive component of lateral hypothalamic self-stimulation.

The effects of dopamine agonists on self-stimulation are a matter of considerable dispute. Apomorphine has variously been reported to inhibit, have no effect on, or to facilitate lever-press self-stimulation. To investigate the possibility that these discrepancies may reflect peculiarities of the lever-press test situation, the present study investigated the effects of apomorphine on locomotor initiation of and escape from lateral hypothalamic stimulation in a shuttle-box. Apomorphine had relatively little effect on the initiation behavior, but it produced a large and dose-dependent inhibition of escape. These data suggest that apomorphine acts to inhibit the aversive component of lateral hypothalamic stimulation. The implications of these findings for the usefulness of the shuttle-box in investigating the pharmacology of self-stimulation are discussed.

alpha-Adrenergic modulation of hypothalamic self-stimulation: effects of phenoxybenzamine, yohimbine, dexamphetamine and their interactions with clonidine.

The alpha-adrenoceptor agonist clonidine (12.5--50.0 microgram/kg) produced a dose-dependent increase in the latency to initiate lateral hypothalamic stimulation. The insurmountable postsynaptic alpha-adrenoceptor antagonist phenoxybenzamine (0.2-0.8 mg/kg) had no effect on self-stimulation by itself, but potentiated the inhibitory effects of clonidine. The fact that the concurrent escape behavior to the intracranial stimulation was unchanged by either clonidine or the phenoxybenzamine-clonidine combination suggests that the inhibition is specific to the rewarding component of hypothalamic stimulation. Yohimbine (0.5--2.0 mg/kg) produced a dose-dependent increase in both response latencies. This lack of behavioral specificity may reflect yohimbine's wide range of pharmacological activity, Dexamphetamine (0.25--0.50 mg/kg) reversed clonidine's inhibition of self-stimulation reward in a specific and dose-dependent fashion. This reversal could be blocked by previous inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine. These data support the concept that the alpha-adrenoceptors play a critical role in the modulation of hypothalamic self-stimulation reward. They further suggest that the inhibitory effects of clonidine on self-stimulation reward represent an agonist effect on presynaptic alpha-adrenoceptors.

Cardiovascular responses and lateral hypothalamic self-stimulation: anatomical differentiation and functional significance.

Heart rate was telemetrically recorded from rats self-stimulating in a two-day shuttle-box. Blood pressure changes to intracranial stimulation (ICS) were determined in acute studies with the same subjects. Stimulus-bound heart rate decreases were found only at sites in the anterodorsal aspect of the lateral hypothalamus, whereas no changes in heart rate were observed at ventral or posterior sites. In the acute experiments, stimulation of the anterodorsal sites produced either decreases or no change in blood pressure. Stimulus-bound blood pressure increases were observed only in the ventrolateral hypothalamus. The differential topographical distribution of the electrode sites producing the heart rate and blood pressure changes suggests that these two aspects of cardiovascular function are subserved by separate neural systems in the hypothalamus and that the bradycardia during self-stimulation is a primary response to ICS and is not a reflex elicited by blood pressure increases. Blockade of the bradycardia with the peripheral cholinergic blocker methyl-hyoscine HBr had no effect on the initiation of or escape from ICS indicating that peripheral parasympathetic activity is not causally related to either the rewarding or aversive components of hypothalamic ICS.

Alpha-noradrenergic modulation of hypothalamic self-stimulation: studies employing clonidine, 1-phenylephrine and alpha-methyl-p-tyrosine.

An alpha-noradrenergic substrate of rewarding intracranial stimulation (ICS) has been hypothesized based on the observation that the alpha-antagonist phentolamine produced an inhibition of self-stimulation. The present experiment investigated the effects on hypothalamic self-stimulation of the alpha agonist clonidine in normal and in catecholamine-depleted rats. Using a shuttle-box technique that provides a rate-independent index of the rewarding and aversive components of ICS, it was demonstrated that clonidine produces a dose-dependent inhibition of reward that is clearly dissociable from any non-specific effects of the drug. The ineffectiveness of the peripheral alpha-agonist 1-phenylephrine indicates that the inhibition of reward produced by clonidine is mediated centrally. Clonidine and the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine act together in a synergistic manner to greatly increase the magnitude and prolong the duration of the inhibition of reward while leaving the aversive component unaffected. These data are interpreted as supporting an alpha-noradrenergic basis of ICS reward while indicating that the aversive component of ICS is essentially independent of noradrenergic transmission.

Assessing the aversiveness of intracranial stimulation.

A comparison was made between rats' performance to escape intracranial stimulation in a shuttle-box, two-lever box and a single-lever Sidman avoidance situation. The former two tasks also provided concurrent rate-independent measures of the rewarding properties of ICS. The rate-independent measures of aversion (latency to escape ICS) obtained in the shuttle-box and two-lever task were significantly correlated with each other but were not significantly correlated with the lever-press rates on Sidman avoidance. A number of animals that would not lever-press to initiate ICS would perform the locomotor response very vigorously to initiate the same ICS suggesting that even rate-independent lever-press measures may not accurately reflect the motivational characteristics of ICS. These data are discussed in the context of the problem as to why animals escape rewarding ICS and it is suggested that the escape behaviour is an independent phenomenon which merits further study in its own right.