Studies on the anti-vasoconstrictor activity of BRL 34915 in spontaneously hypertensive rats; a comparison with nifedipine

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Abstract
1 The blood pressure lowering and anti-vasoconstrictor effects of BRL 34915 and nifedipine were compared in female spontaneously hypertensive rats (SHR). 2 In conscious SHR, intravenous injection of BRL 34915 (0.1, 0.3 mg kg-1) produced rapid, dose-related falls in mean arterial pressure of greater than 3 h duration. Nifedipine, at the same intravenous dose levels, also evoked rapid anti-hypertensive effects, though these responses were of lesser magnitude and duration than those observed for BRL 34915. 3 In anaesthetized, ganglion-blocked SHR, BRL 34915 (0.1, 0.3 mg kg-1 i.v.) dose-dependently antagonized the pressor responses to incremental intravenous infusions of noradrenaline (3.8-28.5 ng min-1) or phenylephrine (120-907 ng min-1) but did not inhibit pressor responses to incremental infusions of methoxamine (0.47-3.63 .mu.g min-1), angiotensin II (7.0-52.9 ng min-1) or vasopressin (0.27-2.0 mu min-1). 4 In anaesthetized, ganglion-blocked SHR, nifedipine (0.1, 0.3 mg kg-1 i.v.) antagonized the pressor responses to each of the infused vasoconstrictor agents, being most effective against responses to noradrenaline or angiotensin II. 5 In pithed SHR, both BRL 34915 and nifedipine (each at 0.3 mg kg-1 i.v.) reduced the basal blood pressure level and produced marked inhibition of frequency-dependent pressor responses evoked by electrical stimulation of the spinal cord sympathetic outflow (0.25-4.0 Hz). Restoration of the basal diastolic blood pressure to within the control range, using a continuous intravenous infusion of vasopressin (0.98 mu min-1), prevented the inhibitory effect of BRL 34915. In the case of nifedipine, however, even raising the basal blood pressure to a level exceeding that recorded in control rats (with vasopressin, 2.0 mu min-1), did not reverse the inhibitory effect of the drug on frequency-dependent pressor responses. 6 It is concluded that the anti-hypertensive properties of BRL 34915 in SHR are probably unrelated to an anti-vasoconstrictor action. In contrast, it is suggested that the broadly-based antivasoconstrictor properties of nifedipine may contribute substantially to the anti-hypertensive properties of this drug.

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