This Week ’ s

Many years ago, between 1963 and 1970, we found that Ca-dependent myocardial contractile energy expenditure (and oxygen requirement), as well as Ca-dependent vascular smooth-muscle activity, can be damped directly with the use of a new family of drugs that in 1966 we designated “calcium antagonists.” These agents inhibit transmembrane Ca supply to the contractile system so that the Ca-dependent transformation of phosphate-bond energy into mechanical work is restricted to any desired extent. Needless to say, these drugs also allow a neutralization of both hyperkinetic myocardial disorders and spastic smooth-muscle hyperactivity that mainly reflect an abnormal rise in transmembrane Ca inflow. In our search for drugs that embody the new pharmacodynamic principle in a most specific manner, we discovered the prototypical Ca antagonists, verapamil, methoxyverapamil (0 600, gallopamil), nifedipine, and other 1,4-dihydropyridine derivatives. Later on we enriched this group of highly selective Ca antagonists by inclusion ofa Ca antagonist that had originally been introduced in 1975 by Japanese researchers, i.e., diltiazem.’ Nowadays, medicine is facinga worldwide Ca antagonist boom: thus, the three top Ca antagonists, verapamil, nifedipine, and diltiazem, are used for a host of indications having a damping effect on excessive transmembrane Ca uptake as the common therapeutic denominator. The three compounds cover more than 80 percent of the Ca antagonist market, amounting annually to an equivalent of almost two billion US dollars. In fact, Ca antagonists turned out to be strong cardioprotective drugs against ischemic, anoxic, or catecholamine-induced myocardial fiber necroses. Hereditary cardiomyopathy of Syrian hamsters, bypertrophic cardiomyopathy in humans, and a variety of cardiac dysrhythmias can also be controlled with suitable Ca antagonists. Even more dramatic was the therapeutic success against all forms of arterial or arteriolar spasm in coronary, cerebral, mesenteric, or renal circulation as well as on systemic peripheral resistance vessels. With respect to the latter effect, the Ca antagonists havebecome the drugs of choice for the interruption ofacute hypertensive crises, but they are also increasingly used for long-term treatment of essential or renal hypertension. Peripheral circulatory impairment in patients with Raynaud’s disease is similarly responsive. Even spasms of visceral smooth muscle are not refractory to this medication. The appearance in 1977 of my review of the fundamental actions of Ca antagonists coincided precisely—after 10 years of dispute—with the international breakthrough of these drugs in practical therapy. This fortunate constellation may have brought the interest in this topic to a climax, since other comprehensive reports 24 that we published before or after 1977 did not attain comparably high citation frequencies. Since the mid-1980s, we have been in the calm, and academic distinctions are beginning to accumulate; for example, I have been awarded four honorary degrees in medicine, by the Universities of Munich, Heidelberg, LimbureJlhe Netherlands, and La Plata/Argentina. In addition, I received a series of 10 national and international prizes. The latest one was the ASPET-AWARD 1987 for Outstanding Basic Pharmacological Investigations of the American Society for Pharmacology and Experimental Therapeutics. — Cc:NuMISER 23 This Week’s Citation Classic IUNE 6,988