Synergistic hypotensive effect of vasoactive intestinal polypeptide and α-blockade with phentolamine: evidence for vasoactive intestinal peptide α-adrenoceptor coupling in the cardiovascular system of newborn dogs
Vasoactive intestinal polypeptide (VIP) is a neuropeptide with potent circulatory effects in the adult animal and human. Little is known about its effects or mechanism of action in the immature animal. These series of experiments evaluated the effects and possible mechanism of action of VIP on the developing canine cardiovascular system. In all three series, measurements of mean heart rate and blood pressure were taken in the control state, after parasympathetic denervation with bilateral cervical vagotomies, and after autonomic blockade with propranolol (1 mg/kg) and phentolamine (0.5 mg i.v.). In series 1, we characterized the role of α-adrenergic receptors in early newborn puppies by investigating the hemodynamic effects of phentolamine alone in five early newborn puppies. In series 2, the hemodynamic effects of intravenous VIP infusion (0.2 μg/kg/min) were recorded and compared in six early newborn puppies and in 10 late newborn puppies. In series 3, the hemodynamic effects of phentolamine in the presence of VIP receptor binding inhibitor were studied. In early newborn puppies, VIP had essentially no effect on heart rate or blood pressure until phentolamine was given; then, blood pressure decreased by 17% (p < 0.005). In late newborn puppies, VIP resulted in an increase in heart rate in the control state but not after parasympathetic or sympathetic denervation. In early newborn puppies, phentolamine alone resulted in a 24% decrease (p < 0.005) in blood pressure, compared with an 54% decrease (p < 0.005) in early newborn puppies preexposed to VIP infusion. VIP receptor binding inhibitor alone had no effect on heart rate or blood pressure but blocked the hypotensive effect of phentolamine even at a dose 10 times higher (5.0 mg phentolamine). It is concluded that 1) VIP has distinctly different effects on the developing canine cardiovascular system from those reported in the adult and 2) VIP and phentolamine have a synergistic hypotensive effect that is abolished by VIP receptor binding inhibitor, suggesting a unique interaction between VIP and α-adrenoceptors in the newborn cardiovascular system.