Hemodynamic effects of epidermal growth factor in conscious rats and monkeys.

Abstract

The therapeutic application of growth factors to human disease has become closer to reality with the advent of faster means of synthesizing these molecules and novel drug delivery strategies. Epidermal growth factor (EGF) belongs to a large family of molecules with the ability to modulate growth. Purified extracts of EGF have been used clinically to modulate gastrointestinal secretion of hormones and accelerate healing. EGF is also reported to have both vascular smooth muscle contractile and relaxing activity. Cardiovascular studies were performed with the bioactive 48-amino acid fragment of human EGF in rodents and primates to determine the effects of EGF on blood pressure and heart rate in conscious animals. Intravenous infusion of EGF induced an initial pressor response in rats followed by a prolonged decrease in blood pressure. In contrast, in monkeys, EGF had dose-related blood pressure-lowering effects only; significant hypotension was observed at doses ranging from 3 to 300 ,lg/kg i.v. Hypotension was associated with modest tachycardia.in both species. To our knowledge, this is the first report of hemodynamic effects of EGF in primates, and it clearly documents that the mitogenic role of growth factors such as EGF is but one aspect of their physiology.In addition to the well-recognized mitogenic activity of growth factors, there is an increasing understanding of their vasoactive effects. Epidermal growth factor (EGF) belongs to a large family of molecules with the ability to modulate growth (1, 2). EGF is also reported to have both vascular smooth muscle contractile and relaxing activity in vitro (3-6). Berk et al. (4) reported that EGF produced contractions in isolated rat aorta that were roughly 40% of the maximal response to angiotensin; time to peak tension was relatively short (2-3 min). In contrast, Namiki and Akatsuka (7) reported that EGF relaxed isolated rat aortic strips; Muramatsu et al. (6) reported similar findings in isolated canine mesenteric arteries. Divergent results have also been obtained from in vivo studies. Gan et al. (8) reported that EGF had no effect on regional hemodynamics in anesthetized rats; however, regional bed vasodilatation was observed in the anesthetized dog (5). Thus, there is remarkable species heterogeneity in the vasoactive properties of EGF.A number of growth factors are receiving increased attention as potential therapeutic agents. EGF, hepatocyte growth factor, and insulin-like growth factor are reported to protect against or ameliorate renal ischemic injury in a variety of models (9-13), although these effects show some species variation (14). EGF is also reported to accelerate gastric ulcer healing and inhibit gastric acid secretion (15-17). The potential therapeutic effects of EGF have been of interest for a number of years. Partially purified EGF preparations extracted from human urine (referred to as urogastrone) have been administered to humans as early as the mid-1970s to modulate gastric acid secretion (18)(19)(20)(21). Using gene transfer techni...

Angiogenic growth factors and hypertension

“…VEGF preferentially dilates arterioles and venules without an effect on medium-sized arteries and veins [18]. Subsequently, several studies in humans and animals have demonstrated a hypotensive effect of a variety of AGF (Table 1 [19][20][21][22][23][24][25][26][27]). In the VIVA (VEGF in Ischemia for Vascular Angiogenesis) trial, both intracoronary and intravenous infusions of recombinant human VEGF produced falls in systolic blood pressure of up to 22% at the highest doses [19].…”

Epidermal growth factor (EGF) increases the renal amino acid transport capacity in amino acid loaded rats

“…Beside these renal effects, a prolonged decrease in blood pressure found in conscious rats treated subchronically with EGF (Keiser and Ryan, 1996) could contribute to the fall in GFR. In contrast to the latter paper, reporting an increase in kidney weight after 4 weeks pretreatment with EGF, in our study the kidney weight was reduced, but only to a slight degree.…”

EGF Receptor as a Drug Target in Arterial Hypertension

“…In some studies vasodilating and/or blood pressure-lowering effects of EGF have been reported [46,47], whereas in others no effect or increase in blood pressure after EGF administration have been observed [48,49]. Moreover, ERK and PI3-K have also been implicated in vasoconstrictor response.…”