Read the information below that describes the cardiovascular effects of a newly developed drug, CV147. Use ALL of the evidence presented to assess whether the drug's cardiovascular effects are mediated via:
a) an effect on the central nervous system
b) an endothelium dependent vasodilator effect
c) an effect on adrenoceptors
d) an intracellular effect on cardiac and vascular muscle
CV147 produced a dose-dependent reduction in mean arterial blood pressure with no change in heart rate when injected into the cerebral ventricles of rats in doses of 1-10?g/kg. These small doses were ineffective when administered intravenously. The fall in mean arterial blood pressure, produced by intracerebral injection of CV147, was prevented by the ?-adrenoceptor antagonist, phentolamine (10?g by intra-cerebroventricular injection) but not by the ?-adrenoceptor antagonist, propanolol. This fall in mean arterial blood pressure was not observed in animals that had been pre-treated with reserpine which depletes the sympathetic nerve terminals of noradrenaline.
When CV147 was injected intravenously in higher doses of 0.1-5mg/kg, a dose-dependent fall in diastolic arterial blood pressure was observed, systolic arterial blood pressure was increased slightly but heart rate was not changed. Intravenous injection of isoprenaline also lowered diastolic but increased systolic arterial blood pressure in rats. The effects of isoprenaline on diastolic arterial blood pressure, but not those of CV147, were prevented by prior administration of propanolol. Likewise the effects of isoprenaline on systolic arterial blood pressure, but not that of CV147, were prevented by atenolol. When rats were pithed, CV147, given intravenously, still produced a fall in diastolic and a rise in systolic arterial blood pressure.
A set of experiments was carried out in isolated tissues in order to study further the mechanism of action of CV147. In isolated rat ventricular preparations, isoprenaline caused an increase in the force of contraction which was reversed on washout of the drug. In this preparation CV147 also increased the force of contraction but this increase was maintained on washout of the drug. CV 147 also markedly potentiated the isoprenaline-induced increase in cardiac force of contraction.
In rat aorta pre-contracted with phenylephrine or angiotensin II, both CV147 and isoprenaline caused a concentration dependent relaxation, as did acetylcholine. After removal of the endothelium, the relaxation caused by acetylcholine was abolished but that to CV147 and isoprenaline was unaffected. Atropine prevented the relaxation caused by acetylcholine but did not affect the relaxation caused by CV147 or isoprenaline. The relaxation caused by isoprenaline was prevented in the presence of propanolol but that due to CV147 was not affected.
The levels of cAMP were measured in both the ventricular muscle and aorta following administration of isoprenaline or CV147. In both tissues cAMP levels were increased in a concentration dependent manner by isoprenaline or CV147. When given in combination, CV147 markedly potentiated the increase in cAMP caused by isoprenaline.