Abstract
It is generally thought that the cardiovascular and renal effects of clonidine, an alpha-2 adrenergic agonist, are mediated by central mechanisms. Our previous work has shown that diuresis and natriuresis caused by central administration of clonidine are mediated by an enhanced release of atrial natriuretic factor (ANF). Because clonidine has been shown to have peripheral actions the objective of the present study was to determine whether ANF is also involved in these actions. Studies were performed with use of a structural clonidine analog, ST-91, which does not cross the blood-brain barrier. Intravenous injection of various doses (0–250 μg/rat) of ST-91 into conscious, normally hydrated female Sprague-Dawley rats (200–250 g) produced dose-related increases in urinary output, which were accompanied by significant increases in urinary sodium, potassium and cGMP excretion. Compared with saline, the highest dose of ST-91 (250 μg/rat) during the first hour of treatment significantly (P < .001, n = 18) enhanced urinary output (0.2 ± 0.1 vs. 3.0 ± 1.1 ml/h) and excretion of sodium (28 ± 4 vs. 345 ± 50 μmol/h), potassium (10 ± 4 vs. 165 ± 37 μmol/h) and cGMP (191 ± 29 vs. 1340 ± 322 pmol/h), the biological marker of ANF. These renal responses were associated with increased plasma ANF (59 ± 7 vs. 810 ± 28 pg/ml, P < .001, n = 12), measured 10 min after ST-91 (250 μg/rat), which remained elevated for at least 1 h (P < .01, n = 6). The enhanced renal responses that were induced by 10 μg ST-91 were partially, yet significantly inhibited by yohimbine (50 μg), analpha-2 antagonist. On the other hand, efaroxan (500 μg), an I1 imidazoline receptor antagonist, showed a stronger inhibitory effect, whereas naloxone (0.8 mg) had no effect. Pretreatment of rats with anti-ANF reduced the diuretic and natriuretic effects of ST-91. These results indicate that the renal effects of ST-91 are mediated by imidazoline as well as by alpha-2 adrenergic receptors, but not by opioid receptors. Furthermore, the renal effects evoked by ST-91 are mediated by ANF.
Footnotes
-
Send reprint requests to: Dr Jolanta Gutkowska, Laboratory of Cardiovascular Biochemistry, Centre de Recherche Hótel-Dieu de Montréal, 3850 St. Urbain Street, Marie-de-la-Ferre Pavilion, Montreal, Quebec H2W 1T8, Canada.
-
↵1 This study was supported by grants from the Medical Research Council of Canada (MT-10337 to J.G. and MT-11463 to J.T.), the Kidney Foundation of Canada and Heart and Stroke Foundation of Canada (to J.G.).
- Abbreviations:
- ANF
- atrial natriuretic factor
- ST-91
- 2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride
- Received July 24, 1996.
- Accepted January 21, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
