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

Abstract

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.

Prevention of isolation‐induced hypertension by intrahippocampal administration of a nonpeptide kappa‐opioid receptor agonist

“…However, at low doses (0.8 g/kg), patients were asymptomatic and had none of the undesirable side effects. Our studies (Shen and Ingenito, 1999a) also showed that in rats, low doses of systemically administered kappa agonists, which freely penetrate the blood-brain barrier, are capable of selectively producing hypotension and bradycardia, compared with a lack of hypotensive effect with kappa agonist analogues which do not gain access to the brain. These findings confirmed that systemically administered kappa agonists cause hypotension by central mechanisms.…”

“…These findings confirmed that systemically administered kappa agonists cause hypotension by central mechanisms. Higher doses cause peripherally mediated hypertensive effects (Shen and Ingenito, 1999a), suggesting that at low doses kappa agonists can selectively produce desirable hypotensive effects. Even so, there is a lack of research into the potentially protective cardiovascular effects of kappa opioid receptor agonists.…”