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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...

A B S T R A C T Vasodilating antihypertensive drugs induce hypotension with reflex tachycardia, renin release, and fluid and electrolyte retention. Propranolol can impair this renin release. The studies described here were designed to determine the hemodynamic role of vasodilatory drug-induced renin release and inhibition thereof by propranolol in two animals models, the unanesthetized, normotensive and the unanesthetized, genetically hypertensive rat. In studies with normotensive rats, propranolol impaired renin release and tachycardia resulting from hydralazine and minoxidil and potentiated their hypotensive action. Two additional interventions against the renin-angiotensin system were used in evaluating the mechanism of this potentiation. One was removal of the renin source by nephrectomy, and the second was blockade of angiotensin's vasoconstrictor action using a selective angiotensin antagonist, saralasin (1-Sar-8-Ala-angiotensin II [previously known as P-113]). Both interventions potentiated vasodilatory drug hypotension, as did propranolol, but did not prevent reflex tachycardia. When combined with saralasin propranolol did not add to protentiation by this peptide. A similar pattern of blood pressure decrement and potentiation was seen in genetically hypertensive rats when propranolol or saralasin treatment preceded hydralazine. Propranolol was demonstrated to block hydralazineinduced increases in serum renin activity in genetically hypertensive rats. We conclude that hypotensive potentiation of vasodilating drugs by propranolol in these animal models is mediated to a large extent by impair-

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A radioimmunoassay for the new angiotensin antagonist, saralasin , was developed and applied to pharmacologic studies in rats and hypertensive man. Specificity of the assay was established using naturally occurring angiotensins, potential saralasin metabolites, and other synthetic angiotensin analogues. Saralasin pharmacologic half-life of 3.9 min after intravenous administration to rats was similar to the biochemical half-life of 4.2 min. The pharmacologic half-life in high-renin hypertensive patients averaged 8.2 with a biochemical half-life of 3.2 min. These observations suggest that metabolites of saralasin do not accumulate in sufficient quantity in man or rat to interfere with the assay. The biochemical half-life of 3.2 min is consistent with infusion time of less than 20 min required to achieve a stable plasma concentration and pharmacologic activity of saralasin during constant saralasin infusion into hypertensive man. These studies provide a rational basis of future experimental design for saralasin and possibly other peptide analogues.Recent reports have indicated that substituted angiotensin II analogues can specifically antagonize the vascular, 2, 3, 10, 11,17,20,22,24,25,27,35,39 endocrine,s, 18 adrenergic potentiating,40 and central nervous system 27 , 35 effects of angiotensin II in animal systems. The advent of these compounds, in particular saralasin (l-Sar-8-Ala-angiotensin II), has provided a useful tool in the elucidation of the role of renin-angiotensin in blood pressure maintenance in acute and chronic unilateral renal hypertension in rats 24 , 27 Supported by grants from the Norwich Pharmacal co .• The Texas Heart Association, and the Merck Foundation.