Calcium channel blockers are a group of drugs used for the treatment of hypertension. Carbonic anhydrase (CA) I detected in vascular smooth muscle and in other cells in the organism has a major role in the acid-base balance and in vascular processes. Our previous work has proven that verapamil inhibits CA activity by a direct mechanism of action. Starting from our results in this article we studied in vitro and in vivo the effect of calcium channel blockers (verapamil and amlodipine) on erythrocyte CA I, on vascular smooth muscles CA I, and on arterial blood pressure values in human and in animals. Our in vitro and in vivo results have proved that verapamil and amlodipine are strong CA I inhibitors both in human erythrocytes and also in vascular smooth muscles in animals. In humans, calcium channel blockers studied here progressively reduce arterial blood pressure in hypertensive subjects, in parallel with progressive lowering of erythrocyte CA I activity in the normal range in normotensive subjects. From our point of view verapamil and amlodipine possess a dual mechanism of action: the first well-known action consists of their action on calcium channels. The second mechanism, suggested by us, directly acts on the vascular smooth muscle CA I isozyme, so that its inhibition should ensure an adequate pH for calcium ions transport through the channels, having as result vasodilation. This double mechanism could explain the hypotensive effect of verapamil and amlodipine, with a mechanism that partially dependent on CA I inhibition.
We studied the relationship between alpha-and beta-adrenergic agonists and the activity of carbonic anhydrase I and II in erythrocyte, clinical and vessel studies. Kinetic studies were performed. Adrenergic agonists increased erythrocyte carbonic anhydrase as follows: adrenaline by 75%, noradrenaline by 68%, isoprenaline by 55%, and orciprenaline by 62%. The kinetic data indicated a non-competitive mechanism of action. In clinical studies carbonic anhydrase I from erythrocytes increased by 87% after noradrenaline administration, by 71% after orciprenaline and by 82% after isoprenaline. The increase in carbonic anhydrase I paralleled the increase in blood pressure. Similar results were obtained in vessel studies on piglet vascular smooth muscle. We believe that adrenergic agonists may have a dual mechanism of action: the first one consists of a catecholamine action on its receptor with the formation of a stimulus-receptor complex. The second mechanism proposed completes the first one. By this second component of the mechanism, the same stimulus directly acts on the carbonic anhydrase I isozyme (that might be functionally coupled with adrenergic receptors), so that its activation ensures an adequate pH for stimulus-receptor coupling for signal transduction into the cell, resulting in vasoconstriction. Correspondence
Our previous studies have shown that angiotensin II increases carbonic anhydrase activity both in vitro and in vivo. In this study we investigated in vitro the effect of angiotensin II on carbonic anhydrase I and II from erythrocytes and on arteriolar vascular smooth muscle carbonic anhydrase I. We also studied in vitro and in vivo the effect of angiotensin II receptor blockers (irbesartan and candesartan) on purified carbonic anhydrase I and II, on vascular smooth muscle carbonic anhydrase I and on arterial blood pressure in humans and in animals. In vitro results showed that angiotensin II is a direct and stronger activator of carbonic anhydrase I than II. Angiotensin II receptor blockers reduced mainly carbonic anhydrase I activity and completely antagonized the activating effect of angiotensin II both on purified and on vascular smooth muscle carbonic anhydrase I. Our in vivo experiments showed that irbesartan and candesartan are powerful inhibitors of carbonic anhydrase I both in erythrocytes (in humans) and in vascular smooth muscles (in animals). In humans, irbesartan and candesartan progressively reduce arterial blood pressure in hypertensive subjects, in parallel with progressive reduction of erythrocyte carbonic anhydrase I activity. We believe that angiotensin II could have a dual mechanism of action: (1) angiotensin interacting with its receptor to form a stimulus-receptor complex; (2) the same stimulus directly acts on the carbonic anhydrase I isozyme (which might be coupled with angiotensin II receptors), ensuring an adequate pH for stimulus-receptor coupling for signal transmission into the cell and hence vasoconstriction.
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