This thesis has investigated several aspects of the clinical pharmacology of calcium antagonists in man. The first study in normal volunteers was designed to compare the acute pharmacodynamics and pharmacokinetics of a new dihydropyridine analogue, nisoldipine, with those of the established drug, nifedipine. The results with both drugs showed only minor changes in blood pressure and heart rate, both drugs had similar terminal elimination half-lifes and there were no major adverse effects. The antihypertensive potential of nisoldipine was, therefore, next assessed in a group of patients with essential hypertension following both single and multiple dosing. The efficacy of the drug was demonstrated after acute dosing and was maintained during a one month period with nisoldipine as monotherapy. For many antihypertensive drugs it has proved difficult to describe correlations between plasma concentration and therapeutic effect and accordingly this was one of the specific aims of a subsequent study of the acute and chronic effects of the calcium antagonist verapamil in a further group of hypertensive patients. To investigate this relationship in detail in individual patients concentration effect analysis was applied and similar relationships between the fall in blood pressure and the plasma concentration of verapamil were found after both acute and chronic treatment. Verapamil and nisoldipine were then used in a comparative study to investigate the inter-relationship between alpha adrenergic receptors and calcium channels. The effects of each drug on the pressor responses to adrenergic and non adrenergic vasoconstriction were assessed in a group of normotensive subjects. Intravenous incremental infusions of phenylephrine and alpha-methylnoradrenaline were used to measure the effects on peripheral vascular responsiveness, mediated via alpha1 and alpha2 adrenoceptors respectively, and angiotensin II was similarly used to assess non adrenergic responsiveness. Despite the theoretical differences in the relative peripheral vascular actions of these two drugs a comparable attenuation of all pressor responses was observed after both acute and repeated administration. Additionally, there was no evidence from this study in man to substantiate the finding in some animal experiments that calcium antagonists preferentially antagonised responses mediated via alpha2 adrenoceptors. The inter-relationship between alpha adrenoceptors and calcium channels was also assessed in two further studies. With both verapamil and nisoldipine, during 4 days oral dosing, there was significant inhibition of platelet aggregation. This effect, however, was only in part due to an inhibition of alpha2 adrenoceptor mediated aggregation. The combined effects of calcium channel blockade and alpha adrenoceptor antagonism were then assessed in a study with verapamil and prazosin. The therapeutic potential of this combination was investigated in normotensive subjects to evaluate the possible dynamic and kinetic interactions between the two drugs. The combination showed an earlier, longer and greater hypotensive effect than either drug alone. In part this increased effect was due to changes in prazosin pharmacokinetics with increases in peak concentration and AUC indicating an enhancement of prazosin bioavailability. Changes in liver blood flow, as assessed- by indocyanine green clearance, were thought to have a role in the interaction between verapamil and prazosin. Both verapamil and nisoldipine were shown to cause acute increases in apparent liver blood flow, in normotensive subjects. Similar changes in renal function were observed. With verapamil there were transitory increases in effective renal plasma flow whereas nisoldipine significantly increased glomerular filtration rate and urinary sodium excretion in addition to effective renal plasma flow. The changes returned towards placebo values following repeated administration. In the final part of the thesis the effects of calcium antagonists on the release of various hormones were studied.(Abstract shortened by ProQuest.).
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