Sympathoadrenal stimulation, not endothelin, plays a role in acute pressor response to cyclosporine in anesthetized rats.
The possible role of sympathoadrenal stimulation and endothelin release in cyclosporine (CS)-induced hypertension was ascertained in intact and pithed rats. CS (20 and 40 mg/kg), administered by i.v. infusion over 10 min, produced a dose-dependent increase in blood pressure: 19 +/- 5 and 31 +/- 2 mm Hg in intact rats and 13 +/- 4 and 18 +/- 2 mm Hg in pithed rats. In intact rats, pretreatment with reserpine (5 mg/kg, i.p.) or hexamethonium (10 mg/kg, i.v.) greatly blunted the pressor responses to CS (40 mg/kg) (7 +/- 3 and 11 +/- 2 mm Hg, respectively). In pithed rats, the blood pressure responses to CS (40 mg/kg) were significantly impaired, but were not further modified by phenoxybenzamine (3 mg/kg, i.v.), whereas adrenalectomy completely abolished the CS-induced pressor responses (0 +/- 1 mm Hg). CS (40 mg/kg) did not potentiate pressor responses to sympathetic nerve stimulation (0.1 and 0.3 Hz) or vasoconstrictors, including angiotensin II (0.03 microgram/kg, i.v.), phenylephrine (1 microgram/kg, i.v.) and arginine vasopressin (0.075 microgram/kg) in pithed rats. In addition, CS (40 mg/kg, i.v.) did not cause elevation of plasma immunoreactive endothelin-1 and -3. Furthermore, phosphoramidon (0.25 mg/kg/min x 30) abolished pressor response to big endothelin-1 (5 micrograms/kg, i.v.) but failed to affect CS-induced hypertension. It is concluded that the acute blood pressure response to CS manifests great dependence on sympathetic nervous system but appears independent of endothelin release.
Chiu
P J
PJ
Department of Pharmacology, Schering-Plough Research Institute, Bloomfield, New Jersey.
Vemulapalli
S
S
Sabin
C
C
Rivelli
M
M
Bernardino
V
V
Sybertz
E J
EJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D016232:Endothelins / Q000097:blood / Q000502:physiology*; D006020:Glycopeptides / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D011311:Pressoreceptors / Q000187:drug effects*; D011863:Radioimmunoassay; D051381:Rats; D013564:Sympathetic Nervous System / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D016232:Endothelins; D006020:Glycopeptides; D016572:Cyclosporine; C008890:phosphoramidon