Interaction between the renin-angiotensin system and the sympathetic nervous system has been proposed to be like a physiological regulation mechanism. The present work was designed to study the cross talk between angiotensin II and adrenergic receptors on the smooth muscle contractile response and the endothelium influence in this phenomenon. Homologous and endothelium independent desensitization of angiotensin II-contractile response was observed. Treatment with noradrenaline between two cumulative doses response curves (CDRC) to angiotensin II caused a rightward shift of the second CDRC in unrubbed arteries and increased the maximal response in rubbed arteries. Prazosin blocked these effects. No homologous desensitization of noradrenaline contractile response was found. Treatment with angiotensin II between two CDRC to noradrenaline caused a loss of affinity in the second CDRC in unrubbed arteries. Losartan was able to avoid this phenomenon. Maximal response was enhanced both in arteries with and without endothelium treated or not with angiotensin II. Results demonstrate homologous and endothelium-independent desensitization of the contractile response to angiotensin II but not to noradrenaline. In addition, heterologous and endothelium-dependent desensitization induced by noradrenaline and angiotensin II on the contractile response to each other was found. Furthermore, results provided the first evidence that there is an endothelium-dependent cross talk between α1-adrenergic and angiotensin II receptors in smooth muscle of rabbit aorta.
Several experimental and clinical studies have clearly demonstrated physiologically important interactions between the renin-angiotensin system and the sympathetic nervous system. Experimental evidence suggests that these 2 systems have an effect on each other both at the level of the peripheral vasculature and at the central nervous system level. 1 Angiotensin II (Ang II) produces vasoconstriction not only through the interaction with AT1 receptors in the vascular smooth muscle but also through its ability to modulate sympathetic neural function. 2 It is known that Ang II facilitates neurotransmitter release from the presynaptic nerves terminals, which can cause vasoconstriction and myocardial damage. 3,4 Furthermore, important interactions between AT1 receptors and α1-adrenergic receptors (α1-ARs) also exist. It has been shown that released noradrenaline (NA) negatively regulates Ang II receptors in cultured brain neurons 5 and in vascular tissue through its interactions with α1-Ars. 6 In neonatal rat cardiac myocytes Ang II selectively down-regulates α1a-AR subtype mRNA and its corresponding receptors. 7 However, recently there has been increasing evidence that the cross talk between AT1 and α1-ARs is present only under physiologic conditions because it is lacking in neurons of spontaneously hypertensive rat brain 8 and aortic rings of cardiomyophatic hamsters. 9
Numerous reports have shown that the exposure to elevated catecholamines or Ang II results in homologous desensitization of both adrenergic or AT1-mediated vascular smooth muscle contraction in the rat or rabbit aorta. 10–12 This desensitization mediated by G-protein coupled receptors may result from changes in receptors, G proteins, carriers, or the interaction among these component systems. 13,14 Furthermore, it has been reported that desensitization of NA receptor function and homologous short-term desensitization to Ang II may be attributed to G protein uncoupling. 15,16
On the other hand, it has also been shown 17 that the control of vascular tone is the function of 2 regulatory systems: the sympathetic nervous system and the endothelium. NA can affect responses of the endothelium and endothelium-derived factors can alter responses of the NA. Moreover, Ang II stimulates endothelial synthesis of vasodilators such as NO 18–20 and prostaglandins 21 and vasoconstrictors such as endothelin 22 and lipoxygenase-derived eicosanoids. 23,24 However, the endothelium influence on the interaction between AT1 and α1-ARs has not been studied. In a previous work we have found that the endothelium was able to enhance the Ang II-desensitization in rabbit aortic rings. 25
The present study was designed to study (i) the cross talk between Ang II and adrenergic receptors in the smooth muscle contractile response and (ii) the influence of the endothelium in this phenomenon.