α1-Adrenoceptors in proximal segments of tail arteries from control and reserpinised rats

Abstract

It has been recently shown that the supersensitivity of distal segments of the rat tail artery to phenylephrine after chemical sympathectomy with reserpine results from the appearance of alpha(1D)-adrenoceptors. It is known that both alpha(1A)- and alpha(1D)-adrenoceptors are involved in the contractions of proximal portions of the rat tail artery. Therefore, this study investigated whether sympathectomy with reserpine would induce supersensitivity in proximal segments of the rat tail artery, a tissue in which alpha(1D)-adrenoceptors are already functional. Proximal segments of tail arteries from reserpinised rats were three- to sixfold more sensitive to phenylephrine and methoxamine than were arteries from control rats (n = 6-2; p < 0.05). The imidazolines N-[5-(4,5-Dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide hydrobromide (A-61603) and oxymetazoline, which activate selectively alpha(1A)-adrenoceptors, were equipotent in tail arteries from control and reserpinised rats (n = 4-2; p < 0.05), whereas buspirone, which activates selectively alpha(1D)-adrenoceptor, was approximately 4-fold more potent in tail arteries from reserpinised rats (n = 4-6; p < 0.05). Prazosin (nonselective) and 5-methylurapidil (alpha(1A)-selective), were competitive antagonists of contractions induced by phenylephrine and were equipotent in tail arteries from control and reserpinised rats (n = 4-6). The selective alpha(1D)-adrenoceptor antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (BMY-7378) presented similar complex antagonism in tail arteries from control and reserpinised rats, with Schild slopes much lower than 1.0 (p < 0.05, n = 4-6). Semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) revealed that mRNA encoding alpha(1A)-and alpha(1B)-adrenoceptors are similarly distributed in tail arteries from control and reserpinised rats, whereas mRNA for alpha(1D)-adrenoceptors is twice more abundant in the tail artery from reserpinised rats. In conclusion, the supersensitivity induced by reserpine is related only to alpha(1D)-adrenoceptors, even in tissues where this receptor subtype is already present and functional. Only the use of subtype-selective alpha(1)-adrenoceptor agonists detected the increased alpha(1D)-adrenoceptor component after reserpinisation, as the antagonists behaved similarly in tail arteries from control and reserpinised rats.

Transient supersensitivity to α‐adrenoceptor agonists, and distinct hyper‐reactivity to vasopressin and angiotensin II after denervation of rat tail artery

“…However, while displacement of [ 3 H]prazosin binding by the a1A-adrenoceptor selective antagonist KMD-3213 was unaffected, the a1D-adrenoceptor selective antagonist, BMY 8378, inhibited high affinity binding of [ 3 H]prazosin in reserpine-pretreated arteries. Increased expression of a1Dadrenoceptors was confirmed by a selective increase in their mRNA (Taki et al, 2004; see also Kamikihara et al, 2007). However, nerve-evoked contractions of the tail artery are almost completely blocked by a1A-adrenoceptor selective antagonists (Sulpizio and Hieble, 1991;Brock and Tripovic, unpublished observations).…”

“…Increased expression of α 1D ‐adrenoceptors was confirmed by a selective increase in their mRNA (Taki et al. , 2004; see also Kamikihara et al. , 2007).…”

Updates in the function and regulation of α1‐adrenoceptors

“…On the other hand, in the more densely innervated smaller resistance arteries, noradrenaline released from sympathetic terminals activates α 1Aadrenoceptors and causes less sustained vasoconstriction allowing rapid vascular tonus adjustment in response to autonomic activation. The positive relationship between the density of adrenergic fibres and dominance of α 1Aadrenoceptors is reversible, as sympathetic denervation increases the expression and participation of the other two subtypes in vasoconstriction (Kamikihara et al, 2005;Kamikihara et al, 2007;Stassen et al, 1998;Taki et al, 2004). In addition, the potencies of antipsychotics in producing orthostatic hypotension correlated with their affinities for α 1Aadrenoceptors but not for α 1Dadrenoceptors (Nourian et al, 2008), as most of the antipsychotics behave as competitive antagonists of α 1 -adrenoceptors, and this positive correlation further indicates that noradrenaline released from sympathetic terminals targets the α 1Aadrenoceptors to increase peripheral vascular resistance.…”

Long-term cardiovascular re-programming by short-term perinatal exposure to nicotine‘s main metabolite cotinine

“…Sustained overactivation by low dietary levels of natural plant toxins can "turn-off" (deplete) signalling-competent PKC (41) and blunt the contractile response to catecholamines (noradrenaline, adrenaline) and adrenergic agonists like nicotine (37,42). Loss of signal coupling to smooth muscle contractile proteins may initiate a compensatory upregulation of the membrane (adrenergic) receptors that mediate sympathetic vasoconstrictor / pressor reactivity to "re-balance" the system (43), but this may not fully reverse a hypo-contractile / hypo-adrenergic state or restore BP ( Figure 5D-E; Table 1). Of course, mRNA levels are only indicative of transcriptional gene regulation: with limited tissue available we did not show that cotinine down-regulates PKC (and upregulates ADR) proteins.…”