Modification of the 31P magnetic resonance spectra of a rat tumour using vasodilators and its relationship to hypotension

Abstract

Summary The effects of different doses of hydralazine and prostacyclin on the 31P magnetic resonance spectra of the LBDS, fibrosarcoma were investigated and related to their effects on mean arterial blood pressure (MABP) and heart rate. The effect of reducing MABP by bleeding the animals, via the tail artery, was also investigated. Tumour spectral changes following high dose drug treatment (an (Hahn, 1974;Overgaard & Bichel, 1977;Overgaard & Nielsen, 1980). Hydralazine has also been shown to potentiate the cytotoxicity in solid rodent tumours in vivo of the bioreductive drugs RSU-1069(Chaplin & Acker, 1987 and SR4233 (Brown, 1987). These drugs are cytotoxic to hypoxic cells and their potentiation by hydralazine is presumably brought about by induced hypoxia secondary to a decrease in tumour blood flow.Selective reduction of tumour blood flow also has potential in more conventional chemotherapy. Stratford et al. (1987) showed that a carefully timed administration of hydralazine could increase the cytotoxic action of melphalan in transplanted rodent tumours whilst normal tissue toxicity remained unaffected. This could be explained by a hydralazine-induced selective reduction in tumour blood flow leading to entrapment of melphalan in the tumour tissue.Hydralazine is used clinically to control hypertension. Its plasma half-life in man is less than 60 min (Shepherd et al., 1980), but its half-life in vascular smooth muscle may be as high as 30 h (Gross, 1977) which is a possible disadvantage for application in tumour therapy. Horsman et al. (1989) have shown that, in mice, the mean arterial blood pressure, which falls on administration of hydralazine, has not returned to normal 8 h after injection. Tumour blood flow was not measured directly but there was also some indication that it too had not returned to pre-drug levels by 8 h. Any longterm reduction in the tumour blood supply would be a disadvantage for radiotherapy. Therefore, in the present study, the effect of hydralazine on cardiovascular parameters and tumour energy metabolism was compared with that of prostacyclin, an endogenous vasodilator formed from arachidonic acid (Moncada et al., 1976). This compound is rapidly hydrolysed in whole blood and plasma with a half-life of around 6 min (Orchard & Robinson, 1981). In man, the onset and offset of the cardiovascular actions of prostacyclin are rapid, less than 5 min, which means that its effects can be easily reversed (O'Grady et al., 1980;Lewis & Dollery, 1983

Direct evidence that hydralazine can induce hypoxia in both transplanted and spontaneous murine tumours

“…However, this again is unlikely to be the explanation for the lack of effect with so many tumours in the 3"P-MRS studies; even in our experiments some 60% of the spontaneous tumours could be considered reasonably well oxygenated. Nor does it explain why hydralazine-induced changes in metabolic activity can be detected with 3'P-MRS in transplanted tumours (Okunieff et al, 1988;Bhujwalla et al, 1990;Tozer et al, 1990;Bremner et al, 1991). Clearly there is no easy explanation as to why our current study showed substantial effects of hydralazine in spontaneous tumours using measurements Of PO2 as the end point, and other studies using 3"P-MRS failed to find such effects.…”

“…This effect leads to changes in tumour oxygenation (Stratford et al, 1987;Horsman et al, 1989;Lin and Song, 1990;Fisker et al, 1991; Lemmon and Brown, 1991) and energy metabolism (Okunieff et al, 1988;Bhujwalla et al, 1990;Tozer et al, 1990;Bremner et al, 1991), and as a result this drug will enhance the anti-tumour activity of a range of agents. These include hypoxic cell cytotoxins such as bioreductive drugs Bremner et al, 1990) and hyperthermia (Horsman et al, 1989;Kalmus et al, 1990), as well as certain conventional chemotherapeutic agents such as melphalan (Stratford et al, 1987;Adams et al, 1989;Chaplin et al, 1989) and chlorambucil (Skarsgard et al, 1992).…”

Stable bioenergetic status despite substantial changes in blood flow and tissue oxygenation in a rat tumour

“…Any studies investigating changes in the energy status in tumours induced by physical, chemical or biological manoeuvres should thus be cognisant of alterations in blood flow. Changes in tumour blood flow following vasodilators Tozer et al, 1990), high-dose hyperthermia (Sijens et al, 1987;Kruger et al, 1991;Mayer et al, 1992), tumour necrosis factor a (TNF-a), lymphotoxin or interleukin 1 (Constantinidis et al, 1989;Kluge et al, 1992), X-irradiation (Tozer et al, 1989) or after i.p. mannitol administration are always followed by parallel alterations in tumour energy status.…”

Effects of the mycelial extract of cultured Cordyceps sinensis on in vivo hepatic energy metabolism and blood flow in dietary hypoferric anaemic mice

“…We established a technique appropriate for mice and estimated the mouse liver blood flow by in vivo 2 H NMR spectroscopy of D 2 O uptake after intravenous injection of D 2 O. Okunieff et al (1988) and Tozer et al (1990) reported that hepatic blood flow and energy metabolism are closely linked. In a recent study, Whalen & Shapiro (1991) measured liver blood flow using a D 2 O washout technique, using 2 H NMR and liver concentration of ATP and intracellular pH determined by 31 P NMR techniques in normal rats, and confirmed that liver blood flow rates are linked to liver ATP levels.…”

“…In vivo 31 P NMR analysis of the liver was performed on Fe-deficient anaemic mice administered Cs extract. As blood flow and energy metabolism are thought to be linked (Okunieff et al 1988;Tozer et al 1990), 2 H NMR spectroscopy of deuterated water (D 2 O) uptake after intravenous injection of D 2 O was used to measure hepatic blood flow in the anaemic mice treated with Cs extract (Mattiello & Evelhoch, 1991;Zhao et al 1995). The in vivo structurebiological assessment techniques for energy metabolism and blood flow are useful not only for pharmaceutical and toxicological sciences but also for nutritional sciences.…”