Studies on the anti-vasoconstrictor activity of BRL 34915 in spontaneously hypertensive rats; a comparison with nifedipine.
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 micrograms 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 mgkg-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 anti-vasoconstrictor properties of nifedipine may contribute substantially to the anti-hypertensive properties of this drug.
Buckingham
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Beecham Pharmaceuticals Research Division, Medicinal Research Centre, Harlow, Essex.
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D005260:Female; D006973:Hypertension / Q000503:physiopathology*; D007262:Infusions, Intravenous; D009543:Nifedipine / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D014661:Vasoconstriction / Q000187:drug effects*; D014667:Vasopressins / Q000494:pharmacology
D001578:Benzopyrans; D011758:Pyrroles; D019806:Cromakalim; D014667:Vasopressins; D000804:Angiotensin II; D010656:Phenylephrine; D009543:Nifedipine; D009638:Norepinephrine