Urocortin (Ucn) is a recently isolated peptide related to the corticotropin-releasing factor (CRF) family, which can produce hemodynamic and hormonal actions in conscious rats. This study examined in detail the cardiovascular actions of Ucn and CRF after intravenous injection in chronically instrumented, conscious sheep. Injection of Ucn produced dose-dependent changes in cardiac contractility [rate of increase of aortic flow (dF/dt)], maximum aortic flow (Fmax), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and coronary blood flow (CF). Ucn injected at 100 micrograms produced a potent increase in dF/dt, from 909 +/- 44 to a maximum of 1,849 +/- 901.min-1.s-1, and in Fmax, from 25.5 +/- 0.8 to 36.6 +/- 1.4 l/min. Cardiac contractility increased within 30 min of injection and remained significantly elevated for up to 24 h. MAP increased from 78 +/- 2 to 90 +/- 3 mmHg, and HR increased from 73 +/- 4 to 103 +/- 9 beats/min. CO rose from 5.0 +/- 0.1 to 5.8 +/- 0.2 l/min, whereas central venous pressure, total peripheral conductance, and stroke volume were unchanged. All Ucn-induced cardiovascular effects were inhibited by prior treatment with the CRF antagonist alpha-helical CRF-(9-41). Equimolar doses of CRF produced little change in any hemodynamic parameter. Both peptides increased plasma levels of adrenocorticotropin and cortisol, with Ucn having a more potent effect than CRF. We have shown for the first time that Ucn can produce potent and long-lasting actions to elevate cardiac contractility in conscious animals.

Beta-adrenergic blockers are increasingly used in the treatment of angina pectoris (Hamer et al., 1964Srivastava, Dewar, and Newell, 1964; Gillam andPrichard, 1965, 1966;Keelan, 1965;Rabkin et al., 1966;Wolfson et al., 1966), cardiac arrhythmias (Stock and Dale, 1963;Ginn, Irons, and Orgain, 1965;Harrison, Griffin, and Fiene, 1965;Bath, 1966;Harris, 1966;Rowlands, Howitt, and Markman, 1965;Schamroth, 1966;Szekely et al., 1966), and some other less common conditions (Harrison et al., 1964). The danger of inducing or aggravating heart failure by beta-blockade remains a matter of controversy (Stephen, 1966). Whereas this risk has been considered as relatively small and acceptable by Snow (1965Snow ( , 1966, undesirable side-effects and sometimes severe complications related to the depressant action of propranolol on myocardial contractility have been reported, in isolated instances with fatal outcome (Fleckenstein et al., 1964;Vogel, 1965;Scheu, 1966;Luthy and Hegglin, 1966). This risk undoubtedly represents an important drawback to this kind of therapy.In the present study, propranolol was given intravenously to patients with organic disease of the left heart, and its circulatory effects were assessed during the course of standard pre-operative catheterization of the heart. In a second stage of this study, these effects were compared with those of CIBA 39,089-Ba, a new specific beta-adrenergic blocking agent. Fig. 1 shows the chemical structures of isoprenaline, propranolol, and CIBA 39,089-Ba. Fig. 2 shows that the two drugs are apparently equipotent beta-blockers in terms of their negative chronotropic effect. This study Received March 30, 1967. suggests that propranolol depresses myocardial contractility, and this effect correlates well with the severity of the heart disease. CIBA 39,089-Ba has a negative chronotropic effect fairly similar to that of propranolol, but produces a significantly less marked depression of myocardial contractility. RESULTSThe results are shown in Tables III and IV and in Fig. 3-7. Both drugs slowed the heart rate to much the same extent. At rest, the heart rate was reduced from 77 to 64 beats/min. (-16%) after BLE I

suMMARY The role of the renin angiotensin system was evaluated in 18 normotensive patients with chronic congestive heart failure and in 5 controls. No correlation was observed between plasma renin activity and cardiac index. There was a significant inverse correlation between renin and pulmonary capillary wedge pressure (r = -0-61, P < 0.01). Renin values of the patients appeared to be increased when compared with controls with similar left ventricular filling pressure. Specific angiotensin II inhibition by saralasin decreased arterial pressure in 8 out of 14 patients: their renin was significantly higher than that of the remaining 6 patients (P < 0.01). The 2 patients with the lowest renin levels responded to saralasin with a blood pressure increase. Left ventricular filling pressure decreased in all but these latter 2 patients with either little change or an increase in stroke volume. Thus, renin levels appear to be increased in normotensive patients with congestive heart failure when related to left ventricular filling pressure. Renin via angiotensin II plays a role in the blood pressure control of many patients with congestive heart failure. In some patients angiotensin II blockade appears to improve cardiac function by unloading the left ventricle.

Guillemin and Forsham 1974). However, the potential therapeutic value of somatostatin is limited by the fact that it is relatively ineffective when injected subcutaneously and must be given by continuous intravenous infusion. The present study was designed to identify analogs that might be more effective than somatostatin upon subcu taneous administration.