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  • Title: Acute hypertension after nitric oxide synthase inhibition is mediated primarily by increased endothelin vasoconstriction.
    Author: Banting JD, Friberg P, Adams MA.
    Journal: J Hypertens; 1996 Aug; 14(8):975-81. PubMed ID: 8884552.
    Abstract:
    OBJECTIVE: To determine the quantitative roles played by the different vasoconstrictor systems in the acute pressor response in conscious rats before and after inhibition of nitric oxide synthase with Nw-nitro-L-arginine methyl ester (L-NAME). METHODS: In conscious male Sprague-Dawley rats, previously instrumented with aortic and venous catheters, the contributions of the different systems were assessed by maximal cumulative pharmacological blockade of alpha 1-adrenoceptors (1 mg/kg prazosin intraperitoneally), AT1 receptors (30 mg/kg losartan intraperitoneally) and V1/V2 receptors (10 mg/kg [beta-mercapto-beta, beta-cyclopenta-methylenepropionyl1, O-Et-Tyr2-Val4-Arg8]-vasopressin per min intravenously). In addition, the contribution of endothelin-1-induced vasoconstriction in response to 100 mg/kg L-NAME intraperitoneally to the hypertension was assessed by administering 5-100 mg/kg ETA/ETB receptor antagonist PD 145 065 intravenously under three different conditions: as the last step of a series of antagonists in the cumulative pharmacological blockade after having induced the L-NAME pressor response; alone before L-NAME treatment; and alone after the full development of the L-NAME pressor response. A separate group of rats was treated acutely with 30 mg/kg losartan intraperitoneally or pretreated for 3 days with 30 mg/kg angiotensin I converting enzyme inhibitor enalapril via drinking water alone or in combination with 1% salt was used to assess the role of the renin-angiotensin system in the L-NAME-induced hypertension. RESULTS: Short-term administration of the combined ETA/ETB receptor antagonist PD 145065 did not change the arterial pressure under control conditions. Inhibition of the renin-angiotensin system, alpha 1-adrenoceptors or vasopressin receptors alone or in combination did not alter the magnitude of the L-NAME pressor response. In contrast, our results show that both treatments before and during acute nitric oxide synthase blockade hypertension using the ETA/ETB receptor antagonist PD 145065 abolished almost completely (approximately 85%) the pressor response. CONCLUSIONS: These studies indicate that the predominant mechanism of hypertension, at least in the acute phase, after acute nitric oxide synthase blockade with L-NAME is associated with a marked increase in ETA/ETB receptor activation rather than with increases in alpha 1, AT1 and V1/V2 receptor activation. It remains to be determined whether endothelin participates also in the chronic phase of nitric oxide-deficient hypertension.
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