Effect of chronic treatment of spontaneously hypertensive rats with D 600

The effects of chronic treatment of spontaneously hypertensive rats (SHR) with methoxyverapamil (D 600) on blood pressure (BP) and on the in vitro contractile response of aortic and portal vein strips of rats were examined. D 600, prepared as the free base and dissolved in sesame oil, was injected subcutaneously daily into SHR to maintain the systolic blood pressure (SBP) at less than 130 mm Hg for 24 hours after injections. The dose required increased progressively from 4 to 8.5 mg/day/rat. As controls, normotensive rats (WKY) and untreated SHR received daily injections of the vehicle. After 2 weeks, aortic and portal vein strips were prepared from each rat for studies of cumulative dose-response curves to norepinephrine (NE) in Krebs' solution containing normal (2.5 mM) and low (0.2 and 0.4 mM) calcium (Ca). Chronic treatment with D 600 restored to control values the ordinarily depressed contractile response to NE and increased the ED50 values for NE (i.e., the NE dose that produces 50% of the maximum response) of aortic strips from SHR in nord-mal and low Ca. Portal veins from SHR showed increased spontaneous activity, supernormal responses to NE, and decreased ED50 values for NE that were all exaggerated by chronic D 600 treatment. These results imply that SHR developed a tolerance to D 600 associated with enhanced contractility of vascular smooth muscles.