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Vasodilatation in hypertension: the relevance of ISA. Concluding paper.

What is the importance of vasodilatation in the treatment of hypertension? There appears to be no doubt that what really matters is blood pressure reduction. Two of the recent controlled trials, mentioned in Robertson's review (1987), the Medical Research Council Trial (1983) and the IPPPSH (1985), have suggested that different drug regimens are equally successful in reducing cardiovascular mortality and morbidity, provided they are equally successful in lowering blood pressure. The MRC Trial compared therapy based on diuretic with treatment based on adrenoceptor blockade, whereas the IPPPSH compared therapy, including a ,B-adrenoceptor blocker, with treatment excluding ,B-adrenoceptor blockers but including, on average, a larger dose of diuretics. Clinical trials, however, can answer only a few questions convincingly (Zanchetti, 1986) and the answers provided by the MRC Trial and the IPPPSH cover only a few facets of the much wider problem of antihypertensive therapy. Haemodynamically, essential hypertension is characterized by diffuse vasoconstriction, the cardiac output being either normal or slightly lower than normal and total peripheral resistance being higher bothat rest and during exercise (Lund-Johansen, 1983). Although the main target of antihypertensive therapy is the lowering of blood pressure by whatever tolerable means, a more rational approach would be to lower blood pressure by correcting the deranged haemodynamic pattern, i.e. by vasodilatation. However, some of the commonly used drugs in therapy, such as non-selective 1-adrenoceptor blockers, lower blood pressure with a reduction of cardiac output whereas total peripheral resistance, both at rest and during exercise, remains higher than before treatment, even years after the institution of therapy (Lund-Johansen, 1976). This change has also been observed with 13-adrenoceptor selective blockers, such as atenolol (LundJohansen, 1979). Despite the fact that vasodilatation appears to be a logical approach, the use of vasodilators in hypertension has been limited by the properties of available vasodilating agents, such as hydralazine and minoxidil. It is well known that, as a result of vasodilatation, drugs of this class usually induce a marked reflex sympathetic activation, which results in an annoying tachycardia and increased renin release. They also have renal effects which result in sodium and water retention: therefore, they are often co-prescribed with a 1-adrenoceptor blocker and a diuretic in so-called triple therapy (Koch-Weser, 1974). A few years ago our own experience (Leonetti et al., 1971) with another powerful vasodilator, guancydine, showed that it was quite effective in lowering blood pressure, but that this effect was accompanied by tachycardia and by a marked sodium and water retention which often resulted in a rapid increase in body weight and loss of blood pressure control. Administration with a diuretic in most cases prevented the renal effects but did not abolish the annoying tachycardia. It has been shown also (Tarazi et al., 1983), that hydralazine and minoxidil are unable to prevent or reverse left ventricular hypertrophy in hypertensive patients, probably because of the stimulant effect of reflex cardiac sympathetic activation. It is not surprising, therefore, that in the stepped care programme suggested by the WHO (1978), hydralazine was relegated to the third step and minoxidil to an even lower position. However, it is also not surprising that the attractions of vasodilatation have not waned. This continued interest has brought attempts to develop better tolerated vasodilating agents. One of these attempts focused on ,B-adrenoceptor blocking compounds with vasodilator properties. Examples are labetalol (combining 13and a-adrenoceptor blocking properties), prizidilol (combining a 13-adrenoceptor blocking moiety with a hydralazine moiety: but now withdrawn from clinical use) as well as celiprolol,