Depressor Effect of Kappa Opioid Agonist on Hypertension Induced by Isolation in the Rat

Shen, Su; Ingenito, Alphonse J.

doi:10.3109/10641969909068667

Cited by 12 publications

(7 citation statements)

References 32 publications

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“…Further investigations revealed that, by hippocampal microinjections, spiradoline (5 nmol) decreased blood pressure and heart rate in spontaneously hypertensive, isolation-induced hypertensive, as well as in normotensive rats. This effect of spiradoline was blocked by pretreatment with norbinaltorphimine (54,55). Intrahippocampal spiradoline (10 nmol) prior to, and during, isolation also prevented the development of isolation-induced hypertension (67), suggesting an involvement, at least in this situation, of hippocampal ê receptors in the regulation of blood pressure.…”

Section: Cardiovascular Effectsmentioning

confidence: 96%

A Review of the Properties of Spiradoline: A Potent and Selective k‐Opioid Receptor Agonist

2003

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The selective ê-opioid receptor agonist spiradoline mesylate (U62,066E), an arylacetamide, was synthesized with the intention of creating an analgesic that, while still retaining its analgesic properties, would be devoid of the, mainly ì receptor mediated, side effects such as physical dependence and respiratory depression associated with morphine. Spiradoline is highly selective for the ê receptor with K i of 8.6 nM in guinea pig. Examination of the enantiomers of spiradoline, showed the (-)enantiomer to be responsible for the ê agonist properties. Spiradoline easily penetrates the blood brain barrier, and does not seem to have any significant active metabolites. In preclinical studies, spiradoline has a short duration of action with a peak at around 30 min after administration.The analgesic properties of spiradoline are well documented in mice and rats. Antitussive properties have also been reported in rats. Furthermore, spiradoline was reported to display effects suggestive of neuroprotective properties in animal models of ischemia. In humans, spiradoline is a potent diuretic. It also produces significant sedation presumably due to its antihistamine properties. Preclinical studies have shown that spiradoline reduces blood pressure and heart rate, and has possible antiarrhythmic properties. Clinical studies did not confirm these findings.ê Receptors inhibit dopaminergic neurotransmission. Spiradoline, given systematically to rats, produces a significant and long lasting decrease in dopamine release, and in locomotor activity. It has also antipsychotic-like effect in animal behavioral tests. At low doses spiradoline was reported to decrease tics in patients with Tourette's syndrome. Although spiradoline had promising effects in animal tests of analgesia, and a reasonably good safety profile in preliminary studies, it did not replace morphine as an analgesic. The available clinical data suggest that spiradoline produces disturbing adverse effects such as diuresis, sedation, and dysphoria at doses lower than those needed for analgesic effects. Thus, future development of spiradoline-like analgesic compounds should preferably focus on reduction of unwanted effects on the central nervous system. Spiradoline, which currently is commercially available for preclinical research, might prove useful in some psychiatric conditions and possibly as a neuroprotective agent.

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Section: Cardiovascular Effectsmentioning

confidence: 96%

A Review of the Properties of Spiradoline: A Potent and Selective k‐Opioid Receptor Agonist

2003

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“…However, a limited number of studies investigated the effects of chronic stress during adolescence in cardiovascular function. Preclinical studies demonstrated increased arterial pressure in adolescent animals subjected to social isolation (Shen and Ingenito, ; Maslova et al, ). Although these studies indicated an influence of social stress in cardiovascular function of adolescent, to the best of our knowledge, a possible vulnerability of adolescent to cardiovascular consequences of chronic stress evaluated through comparison of the effects in adolescent and adult has never been examined.…”

Section: Introductionmentioning

confidence: 99%

Adolescent vulnerability to cardiovascular consequences of chronic social stress: Immediate and long‐term effects of social isolation during adolescence

Cruz

Duarte

Leão

et al. 2015

Developmental Neurobiology

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It has been demonstrated that disruption of social bonds and perceived isolation (loneliness) are associated with an increased risk of cardiovascular morbidity and mortality. Adolescence is proposed as a period of vulnerability to stress. Nevertheless, the impact of chronic social stress during this ontogenic period in cardiovascular function is poorly understood. Therefore, the purpose of this study was to compare the impact in cardiovascular function of social isolation for 3 weeks in adolescent and adult male rats. Also, the long-term effects of social isolation during adolescence were investigated longitudinally. Social isolation reduced body weight in adolescent, but not in adult animals. Disruption of social bonds during adolescence increased arterial pressure without affecting heart rate and pulse pressure (PP). Nevertheless, social isolation in adulthood reduced systolic arterial pressure and increased diastolic arterial pressure, which in turn decreased PP without affecting mean arterial pressure. Cardiovascular changes in adolescents, but not adults, were followed by facilitation of both baroreflex sensitivity and vascular reactivity to the vasodilator agent acetylcholine. Vascular responsiveness to either the vasodilator agent sodium nitroprusside or the vasoconstrictor agent phenylephrine was not affected by social isolation. Except for the changes in body weight and baroreflex sensitivity, all alterations evoked by social isolation during adolescence were reversed in adulthood after moving animals from isolated to collective housing. These findings suggest a vulnerability of adolescents to the effects of chronic social isolation in cardiovascular function. However, results indicate minimal cardiovascular consequences in adulthood of disruption of social bonds during adolescence.

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“…The exact central andaor peripheral effects depend on the site of administration and other physiological factors in the animals (Feuerstein & Faden 1982;Holaday 1983). Our own studies have established that when non-peptide k-agonists are given chronically subcutaneously and intraperitoneally to conscious rats they lower arterial pressure in the spontaneously hypertensive rat (SHR) (Zhai & Ingenito 1997;Shen & Ingenito 1999). The sites and mechanisms involved in the depressor response, however, are unclear.…”

mentioning

confidence: 99%

k-Opioid Receptors Behind the Blood-brain Barrier are Involved in the Anti-hypertensive Effects of Systemically Administered k-Agonists in the Conscious Spontaneously Hypertensive Rat

Shen

Ingenito

1999

Journal of Pharmacy and Pharmacology

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We have shown previously that chronic intrahippocampal, intraperitoneal and subcutaneous administrations of non-peptide opioid receptor agonists induced depressor responses in the spontaneously hypertensive rat (SHR). However, it is not clear whether the hypotensive effect of systemic administration involves kappa receptors behind the blood-brain barrier. In this study, the relative roles of central vs peripheral kappa-opioid receptors in the hypotensive effect of kappa-agonists was examined in conscious SHRs following chronic subcutaneous administration of two selective kappa-agonists, BRL 52656 which freely penetrates the blood-brain barrier, and BRL 52974 which has only limited ability to do so. Initial studies determined the dose-response relationship for each of the two drugs given intraperitoneally twice a day, while monitoring systolic arterial pressure (SAP), mean arterial pressure (MAP) and heart rate (HR) measured by the tail-cuff method. Both drugs caused biphasic arterial pressure responses, with lower doses of BRL 52656 causing depressor effects and higher doses resulting in pressor effects. By contrast, lower doses of BRL 52974 caused pressor effects and higher doses depressor effects. The biphasic effects occurred with BRL 52656 from 0.01 to 3.0 mg kg(-1) and that for BRL 52974 from 0.1 to 30 mg kg(-1). In subsequent studies the drugs were infused chronically, subcutaneously via osmotic minipumps over a 14-day period, BRL 52656 at 0.2 or 0.5 mg kg(-1)/day and BRL 52974 at 0.2 mg kg(-1)/day. At lower doses, BRL 52656 decreased SAP, MAP and HR but at higher doses only bradycardia was observed. BRL 52974 given chronically subcutaneously over 14 days had no significant effects on arterial pressure and decreased heart rate only after seven days of treatment. Collectively, the results established that only the kappa-agonist, which gained access to the central nervous system, lowered arterial pressure and heart rate, whereas the compound with limited ability to cross the blood-brain barrier was ineffective at equivalent doses. The complex dose-response pattern found with both drugs suggests that kappa-agonists have central hypotensive and bradycardic actions at low doses but at higher doses a mixture of both central and peripheral actions leads to hypertension and tachycardia.

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Depressor Effect of Kappa Opioid Agonist on Hypertension Induced by Isolation in the Rat

Cited by 12 publications

References 32 publications

A Review of the Properties of Spiradoline: A Potent and Selective k‐Opioid Receptor Agonist

A Review of the Properties of Spiradoline: A Potent and Selective k‐Opioid Receptor Agonist

Adolescent vulnerability to cardiovascular consequences of chronic social stress: Immediate and long‐term effects of social isolation during adolescence

k-Opioid Receptors Behind the Blood-brain Barrier are Involved in the Anti-hypertensive Effects of Systemically Administered k-Agonists in the Conscious Spontaneously Hypertensive Rat

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