Analysis of the cardiovascular effects of co-derocrine (Hydergine)

Abstract

The antihypertensive effect of co-dergocrine (Hydergine) has previously been thought to be due to alpha-adrenoceptor blockade and/or an action exerted in the CNS. The present experiments do not support this view. The doses necessary to inhibit vasoconstrictor responses to phenylephrine and noradrenaline by 50% in anaesthetized cats and dogs are 10-50 times that which lowers blood pressure in these species by 30 mmHg. Despite the fact that co-dergocrine is a potent alpha-adrenoceptor antagonist in isolated tissues (pA2: 8.4-9.4), its activity in vivo is too weak to contribute significantly to its effect on blood pressure. Slow intravertebral artery infusion of 10 micrograms/kg co-dergocrine produces a smaller blood pressure fall in the dog than intravenous infusion of the same dose. The reverse is true for the centrally-acting alpha 2-adrenoceptor stimulant, guanfacine. In addition, efferent splanchnic nerve activity in the cat is not affected by doses up to 100 micrograms/kg i.v. The dose of co-dergocrine depressing nerve activity by 50% is approximately 900 micrograms/kg; the dose of clonidine producing comparable inhibition is 3.4 micrograms/kg i.v. Since falls in blood pressure and heart rate can be obtained with co-dergocrine at a dose of only 10 micrograms/kg i.v., a central action cannot be considered to play a role in the cardiovascular effects of the drug in response to acute administration. Heart rate increases evoked by stimulating the accelerans nerve of ganglion-blocked cats are inhibited dose-dependently by co-dergocrine from a dose of 1 microgram/kg i.v. The drug also depresses pressor responses to stimulation of the lumbar sympathetic outflow in pithed rats. Both effects are prevented by pretreatment with the dopamine receptor antagonist, sulpiride (300 micrograms/kg). Intravenous administration of 10 micrograms/kg co-dergocrine depresses pressor responses to a psychological stimulus or raising the forequarters in conscious dogs, and produces marked falls in blood pressure and heart rate in anaesthetized, baroreceptor-denervated dogs. These effects are also abolished by sulpiride. It is concluded that the cardiovascular responses to acute administration of low doses of co-dergocrine are due to stimulation of prejunctional dopamine receptors.