Sustained antihypertensive effects of chronic administration of two kappa-opioid agonists in spontaneously hypertensive rats.
The ability of two nonpeptide kappa-opioid receptor agonists, U-50, 488H and U-62,O66E (spiradoline), to lower arterial pressure on chronic administration to 12-week-old male spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar Kyoto (WKY) rats was assessed. Each drug was infused subcutaneously at approximately 9.6 mg/kg/d, over a 14-day period with Alzet osmotic pumps in each strain of rat. Arterial pressures were determined daily in each rat by photoelectric tail-cuff plethysmography. Control rats received similar infusions of 0.9% NaCl. Body weights and water consumption were also recorded daily. Both drugs effected a 10% to 20% sustained lowering of arterial pressure beginning on the second day of infusion, until explantation of the pumps on day 14. Heart rates similarly were decreased by 10% to 15% in SHRs. By contrast, neither drug caused significant decrements in arterial pressure or heart rate in the normotensive WKY group. Control infusions of 0.9% NaCl had no significant effects on arterial pressure or heart rate in either SHRs or WKY rats. U-62,066E, but not U-50,488H, caused sustained increased water consumption in both SHRs and WKY rats, with a greater effect in the SHR strain. This likely was accompanied by a water diuresis. Body weight gains over the 14-day period were similar for both strains of rats treated with U-50,488H, compared with saline-treated controls, but rats of both strains infused with U-62,066E gained significantly less weight than saline controls over the 14-day period. The results are supportive of further experimental evaluations of the potential antihypertensive use of nonpeptide kappa-opioid agonist drugs.
Zhai
Q Z
QZ
School of Medicine, East Carolina University, Greenville, NC 27858, USA.
Ingenito
A J
AJ
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004343:Drug Implants; D006128:Growth / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D008297:Male; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017473:Receptors, Opioid, kappa / Q000819:agonists*
D000959:Antihypertensive Agents; D004343:Drug Implants; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C051272:spiradoline