The synthesis of a series of N2-[4-[(arylmethyl)amino]-2, 6-dichlorophenyl]-N1,N1-dimethylformamidines that caused marked blood pressure lowering and/or diuresis in spontaneously hypertensive rats (SHR) is reported. Diuretic activity was not always associated with acute antihypertensive activity. Central nervous system effects, most notably sedation, were observed. Compound 9d, which lowered arterial blood pressure 37 mmHg in SHR when dosed at 100 mg/kg, was further evaluated in chronic hypertensive dogs because of apparent minimal CNS effects. A reduction in arterial blood pressure of 32 mmHg at 1.0 mg/kg during a 6-h postdosing interval was observed. This response was unrelated to alpha- or beta-adrenergic blockade, angiotensin I antagonism, or neuronal or ganglionic blockade. CNS effects were also observed.

Renin released from rat renal cortical slices was measured under conditions designed to elevate intracellular Ca2+. Rats were sacrificed by cervical dislocation and the kidneys flushed retrograde with 0.9% saline. The kidneys were then removed, slices (-1 mm thick, 10-30 mg) prepared, placed in sealed 1-ml wells and superfused (250 pl/minute/well) using two bottles of Krebs-Ringers phosphate (KRP) buffer containing 5.9 mM KCI. One bottle was gassed with 0 2 / C 0 2 (19 : l), the other served as the vehicle for test agents. After one hour of superfusion, three consecutive superfusion periods of 30 minutes each (CI, CII, CIII) commenced, the superfusates collected on ice and assayed for renin activity.' Norepinephrine-depleted slices were prepared by dosing rats with 6-hydroxydopamine (6-HD), 100 mg/kg i.p. seven and four days before slice preparation (6-HD slices). Renin release rates were calculated as ng AI/ml superfusate/ 1-hour incubation, normalized to ng AI/hour/mg cortex/30minute superfusion and expressed as percent changes in release relative to CI. Antagonists superfused were verapamil, trifiuoperazine, indomethacin, and timolol. All were dissolved in KRP and superfused in accordance with TABLE 1.Supraphysiological KCl concentrations have been demonstrated to inhibit renin release by enhancing Ca2+ influx through voltage-dependent channels." As predicted from the results of earlier experiments,24 when the KCl concentration of the KRP was increased from 5.9 mM to 60 mM at the start of CII and continued to the end of CIII, an inhibition of renin release occurred (TABLE 1). However, the inhibitory response occurred late (CIII) and, was, in fact, preceded by a stimulatory response (CII). This biphasic response was specifically associated with elevated KCl concentration as slices superfused with 5.9 mM KCI-KRP exhibited only minor changes in release (TABLE 1). Hence, the superfusion technique unmasked a stimulatory response to a supraphysiological concentration of KCl. This effect has been undetected when, using supraphysiological KCl, renal cortical slices were maintained in a static bathing medium.24KCl-evoked release in CII was antagonized (TABLE 1) by blocking Ca2+ influx through voltage-dependent channels (verapamilO.05-5 pM), inhibiting Ca'+-calmodulin association (trifluoperazine), inhibiting prostaglandin synthesis (indomethacin), and 8-adrenergic antagonism (timolol). 6-HD slices also failed to release renin when superfused with 60 mM KCl-KRP (FIG. 1). Accordingly, the stimulatory response in aAddress correspondence to:

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Preservation of human cadaver kidneys for transplantation has been achieved primarily by two methods, hypothermic pulsatile perfusion with cryoprecipitated plasma and cold storage with an electrolyte solution. It has been suggested that pulsatile perfusion results in an increased antigenicity of the transplanted kidney. To investigate the possibility that pulsatile perfusion causes changes which may accelerate allograft rejection, machine preservation was compared with simple cold storage. The kidneys were preserved by either one of the two methods for 6 or 24 hours followed by allotransplantation in nephrectomised dogs. No immunosuppressive drugs were given. Kidneys which were allografted without undergoing any preservation (0 hrs) had a mean survival time of 10.4 +/- 1.7 days (n =5). Kidneys preserved by machine perfusion for 6 and 24 hours survival for 9.6 +/- 1.4 (n = 5) and 10.9 +/- 1.3 (n =9) days respectively. The mean survival time for simple cold storage for 6 and 24 hours was 9.3 +/- 1.3 (n =7) and 12.0 +/- 1.9 (n =6) days. Our findings suggest that in kidneys exposed to minimal warm ischaemia there is no significant difference between the two methods of preservation on renal allograft survival for the time intervals tested.

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