Studies on the mode of action of hydrallazine and reserpine

Kirpekar, S. M (1960) Studies on the mode of action of hydrallazine and reserpine. PhD thesis, University of Glasgow.

Abstract

Hydrallazine and reserpine are used in the treatment of hypertension and reserpine is also employed in the treatment of certain forms of mental illness. Hypotheses regarding the mode of action of these drugs are numerous. Thus hydrallazine is believed to act on the vasometer centre and reserpine to depress central sympathetic tone. Reserpine is also believed to mediate its actions by liberating noradrenaline and 5-hydroxytryptamine from the brain and, in the case of noradrenaline, from the arteries. The work described in this thesis, undertaken to clarify some aspects of the mode: of action of these drugs at cellular level. Experimental evidence has indicated that hydrallazine, dihydrallazine and related compounds did not antagonise certain pressor reflexes - notably the pressor responses due to central vagal stimulation, bilateral carotid occlusion and anoxia. This speaks against their having a central site and mechanism of action, because if this were so, all pressure refluxes mediated via the central nervous system should, he antagonised or depressed. This does not, however rule out the possibility that hydrallazine acts specifically upon certain cell groups in the central nervous system. Hydrallazine antagonised the pressor effect of adrenaline more than those of noradrenaline, and the antagonism of this drug to some pressor reflexes only was explained by assuming that there are quantitative variations in the proportions of the two humoral agents secreted during the initiation of these reflexes. The fact that hypertension caused by constant infusion of a solution of adrenaline was promptly brought back to normal levels by hydrallazine, also favours a peripheral site of action for this drug. Many of the effects of hydrallazine and reserpine can be explained by assuming that both drugs interfere with the normal energy-yielding mechanisms of the smooth muscle cell. It has been shown that hydrallazine has an effect upon carbohydrate metabolism which underlies its actions upon isolated arterial smooth muscle. Intermediate a of carbohydrate metabolism antagonised hydrallazine depression of drug-induced contractions of arterial smooth muscle. The reserpine effect was so persistent that the tissue did not recover. Anoxia and cyanide also antagonised drug-induced contractions of arterial smooth muscle. Intermediates of carbohydrate metabolism gave protection against anoxia and not against cyanide. The use of hydrallazine was, in effect analogous to rendering the tissue anoxic. Reserpine did not have marked effects on tissue respiration while hydrallazine depressed it. Reserpine was found to cause in vivo inhibition of oxidative phosphorylation in rat brain and livery since the ATP/ADP ratio was significantly lowered. Hydrallazine had similar effects in rat brain and liver. Neither drug influenced the, adenosine nucleotide levels in rat skeletal muscle and heart. On the basis of this experimental evidence it has been suggested that hydrallazine may interfere with biological oxidation and reserpine with oxidative phosphorylation. It has been shown that reserpine depleted the adrenal medulla of catechol amines and ATP in roughly the same proportions. Since the characteristic breakdown products of ATP (ADP and AMP) were not found as they were: found in brain and liver it is suggested that ATP possesses a specialised function in the storage or release of catechol amines from this gland. 4. Inhibitors of metabolism, such as cyanide and have marked effects on the transport of sodium and potassium ions in tissues. Roserpine was found to have practically no effect either upon the release of potassium or on the uptake of potassium and sodium. Hydrallazine, however, increased the release of potassium. It decreased potassium retention but increased sodium retention. Cyanide and aside increased potassium release but anoxia and IMP had no effect. On the other hand, cyanide, aside, Die and anoxia had marked effects on sodium and potassium uptakes Which usually , varied inversely. Thus a reduction in the efficiency of the enzymes controlling metabolism may reduce the ability of muscle to retain potassium, resulting in the release of this ion. Hydrallazine formed chelates with different metals, and the iron-hydrallazine chelate was shown to be inert. Hydrallazine in high doses inhibited catalase, depressed the iron-catalysed oxidation of cysteine to cystine and was shown to cause haemolysis. Doses of reserpine and hydrallazine used in this study are (moldered by the author to be comparable to those used in man. Since the intact experimental animal or man is more sensitive than the isolated tissue or organ, the slightly higher doses used in some experiments on isolated tissues do in fact approximate to the therapeutic dose levels. It is finally suggested that interference by these drugs with tissue metabolism may result in a decreased availability of energy for muscular contraction. It is postulated that hydrallazine Produces an "anoxia-like" condition in smooth muscle, while in oxidative phosphorylation, reserpine acts as an "uncoupling agent". Such an effect may explain the reduction of inherent tone in vascular smooth muscle and is probably responsible for the lowering of blood pressure.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: J J Lewis
• Keywords: Pharmacology
• Date of Award: 1960
• Depositing User: Enlighten Team
• Unique ID: glathesis:1960-72915
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 11 Jun 2019 11:06
• Last Modified: 11 Jun 2019 11:06
• URI: https://theses.gla.ac.uk/id/eprint/72915