The capacity of the vasodilating drugs, minoxidil and hydralazine, for inducing renin release was characterized in rats according to chronology and dose response. Propranolol inhibition of this renin release was also characterized and related to serum levels of propranolol. Minoxidil and hydralazine (1.0 mg/kg) induced sevenfold elevations of serum renin activity. Treatment with propranolol, resulting in plasma propranolol concentrations as low as 50 ng/ml, impaired vasodilatory drug-induced renin release. The propranolol inhibition suggests a beta-adrenergic component to this type of renin release and the potential for a clinically efficacious drug interaction.
KEY WORDS hydralazineangiotensin beta-receptor blockade propranolol minoxidil• The combination of a vasodilating drug and propranolol can control hypertension in man without precipitating many untoward effects (1-5).Vasodilating agents elicit renin release from the kidney which results in elevated serum renin activity and increased angiotensin formation (6, 7). The angiotensin thus formed probably antagonizes the antihypertensive effect of vasodilating drugs (8) such as hydralazine and minoxidil. Since combined therapy with propranolol and vasodilating drugs has been found to be particularly effective (1-5), this study was designed to characterize vasodilatory drug-induced renin release in the rat and to determine the effect of beta-receptor blockade on this release.Methods Male Wistar rats (180-250 g) were housed in individual cages and exposed to light by an automated system from 6 AM to 6 PM. The rats ingested tap water and Purina rat chow containing 152 mEq sodium/kg ad libitum.Both hydralazine and minoxidil were administered intraperitoneally, and propranolol was injected subcutaneously. An equal volume (0.5 ml) of saline was administered as a placebo to the control rats. Doses of drugs were calculated for the salt in mg/kg.Propranolol was solubilized in 0.9% NaCl by adding several drops of glacial acetic acid. Propranolol was administered subcutaneously because of the constant, sustained plasma levels following this route of administration (Fig. 1). Intraperitoneal injection of propranolol resulted in a rapid rise and fall and a high degree of variability in serum levels among the rats. Alternatively, subcutaneous administration resulted in more sustained plasma propranolol levels with minimal variability among the rats. Thus, the sustained plateau (Fig. 1) from the subcutaneous administration permitted the experiments to be done at relatively constant, predictable propranolol serum levels.In the experiments involving beta-receptor blockade, propranolol was injected at 0 time and the vasodilating drug was injected at 10 minutes; the rats were decapitated at 30 minutes. The rats treated with a vasodilating drug alone or with saline were killed 20 minutes after injection.At the times indicated in Results, the unanesthetized rats were decapitated, and aortic blood samples were collected in iced, siliconized glass tubes during the first 4 secon...