THE RADIOSENSITIZER NICOTINAMIDE INHIBITS ARTERIAL VASOCONSTRICTION

Nicotinamide (NA) is currently entering clinical trials as a radiosens itizer. A major component of its activity is the improvement of tumour oxygenation resulting from a reduction in microregional ischaemia. NA is known to reduce arterial blood pressure in rodents, suggesting a v ascular component in its mechanism of action. We have used an ex vivo system to study the direct action of NA on the contractile properties of vascular smooth muscle. Isolated pieces of rat tail artery were int ernally perfused with Krebs' solution at a constant flow rate so that constriction of the arterial smooth muscle could be measured as an inc rease in perfusion pressure. Transient vasoconstrictor responses lasti ng up to 10 min were induced with bolus injections (10 mu l) of phenyl ephrine, at concentrations ranging from 10(-5) to 10(-2) M, into the i nternal perfusate whereas a constant increase in vasoconstrictor tone, giving perfusion pressures of 43-84 mmHg, was induced by constantly p erfusing with PE (5 x 10(-6) M) or raising the K+ concentration of the Krebs' solution to 122 mM. The addition of NA to the perfusate signif icantly reduced the size of the transient vasoconstrictor responses in a dose-dependent manner and induced the precontracted vessels to rela x. This action of NA could not be blocked either by N omega-nitro-L-ar ginine methyl ester (L-NAME), indomethacin or propranolol. We conclude that direct effects on supplying blood vessels probably contribute to the oxygenating action of NA in tumours, though the precise mechanism remains obscure.