Hypertension in humans and experimental animals is known to be associated with an increase in left ventricular myocardial mass. The development of cardiac hypertrophy is not caused by increased blood pressure alone; the autonomic nervous system may also play an important role.The functional responses to the beta-adrenoceptor agonists isoprenaline, dobutamine, salbutamol and terbutaline, and the alpha 1-adrenoceptor agonists methoxamine, cirazoline and phenylephrine were studied in isolated (Langendorff) hearts from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) controls. The results were compared with data from radioligand binding experiments.There was no significant difference in the increase of left ventricular pressure induced by all beta-adrenoceptor agonists studied in SHR and WKY rat hearts. Although there was no significant difference in the response to phenylephrine, the inotropic responses to cirazoline and methoxamine proved to be significantly weaker in hearts from SHR than in those from WKY rats. Binding experiments with 3H-prazosin revealed no differences in density or affinity for cardiac tissues from SHR and WKY rats.Long-standing hypertension leads to an impaired response of the isolated heart to alpha 1-adrenoceptor stimulation, without changes in alpha 1-receptor density or affinity. It seems likely that changes in postreceptor events are responsible for the impaired inotropic response to alpha 1-adrenoceptor agonists in hearts from SHR.
Beenen OHM, Batink HD, Pfaffendorf M, van Zwieten PA. β-Andrenoceptors in the hearts of diabetic-hypertensive rats: Radioligand binding and functional experiments.Myocardial β-adrenoceptors and inotropic responses to β-adrenoceptor agonists were studied in isolated hearts obtained from diabetic and/or hypertensive rats. Streptozotocin diabetic Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), as well as normoglycaemic SHR-stroke prone rats were used. At the age of 18-20 weeks, β-adrenoceptor density was assessed in the left ventricle and isolated hearts were perfused according to Langendorff. Concentration response curves were made for dobutamine, salbutamol and the adenylyl cyclase activator forskolin. In both SHR and SHR-SP preparations a blunted inotropic response to β-adrenoceptor stimulation was observed, although responses to forskolin and β-adrenoceptor density and affinity were not different from those in normotensive hearts. In hearts taken from diabetic WKY and SHR, a decrease in β-adrenoceptor density was observed, but no parallel blunted response to β-adrenoceptor stimulation occurred. Moreover, the absolute (and percentual) inotropic responses to dobutamine and forskolin were increased in hearts from diabetic SHR when compared to their hypertensive norinoglycaemic controls. These results suggest an impaired activity of the stimulatory G-protein in hearts obtained from hypertensive rats, whereas the simultaneous occurrence of hypertension and diabetes may result in a compensatory increase in activity of the adenylyl cyclase activated pathway.
Some alpha-adrenoceptor-mediated cardiovascular activities and alpha-adrenoceptor binding affinities for (+)- and (-)-lofexidine (Dexlofexidine and Levlofexidine) have been studied in comparison with racemic lofexidine. In pithed normotensive rats, i.v. (-)-lofexidine elicited pressor effects at doses (0.1-30 micrograms/kg), which were approximately 20 times lower than those of the (+)-isomer. Both yohimbine and prazosin in selective amounts of 1.0 and 0.1 mg/kg (i.v., -15 min), respectively, attenuated the increase in diastolic pressure induced by (+/-)-, (+)- and (-)-lofexidine, showing the involvement of alpha 1- as well as alpha 2-adrenoceptors in the vasopressor responses. No differences were observed in the sensitivity of the pressor effects of the (+)- and (-)-enantiomers to blockade by either yohimbine or prazosin. Following i.v. administration to pentobarbitone-anaesthetized normotensive rats, (-)-lofexidine (0.5-5.0 micrograms/kg) was found about 20 times more effective than the dextrorotatory isomer in decreasing mean arterial pressure and heart rate. The increase in heart rate evoked by electrical stimulation in pithed rats was dose-dependently reduced by (+/-)-, (-)- and (+)-lofexidine, the (-)-isomer being about 30 times more potent than the (+)-isomer. Similarly, the electrical stimulation-induced increase in diastolic pressure was also most effectively impaired by the laevorotatory enantiomer of lofexidine. (-)-Lofexidine showed an approximately 9-fold higher affinity than (+)-lofexidine for the alpha 2-adrenoceptor-like binding sites in rat brain membranes identified by [3H]-clonidine and was 4 times more potent at displacing [3H]-prazosin from alpha 1-adrenoceptors. It is concluded that the alpha-adrenoceptor activity of lofexidine resides predominantly in the (-)-isomer. The isomeric activity ratio of the enantiomers of lofexidine (about 20-fold) is higher than normally found for other imidazolines.
1 The aim of the present investigation was to analyse whether three prototype allosteric modulators of ligand binding to muscarinic receptors, i.e. alcuronium, gallamine, and the alkane‐bis‐ammonium compound W84 (hexane‐1,6‐bis[dimethyl‐3′‐phthalimidopropyl‐ammonium bromide]), may have allosteric effects on radioligand‐binding characteristics at other G‐protein‐coupled receptors, such as cerebral A1 adenosine receptors (Gi‐coupled), cardiac left ventricular α1‐adrenoceptors (Gq), and β‐adrenoceptors (Gs). 2 The modulators were applied at concentrations known to be high with regard to the allosteric delay of the dissociation of the antagonist [ 3 H]‐ N ‐methylscopolamine (NMS) from muscarinic M2‐receptors: 30 μmol l−1 W84, 30 μmol l−1 alcuronium, 1000 μmol l−1 gallamine. As radioligands, we used the adenosine A1‐receptor ligand [ 3 H]‐cyclopentyl‐dipropylxanthine (CPX), the α1‐adrenoceptor ligand [ 3 H]‐prazosin (PRAZ), and the β‐adrenoceptor ligand (−)‐[ 125 I]‐iodocyanopindolol (ICYP). Allosteric actions on ligand dissociation and the equilibrium binding were measured in the membrane fractions of rat whole forebrain (CPX) and of rat cardiac left ventricle (PRAZ, ICYP, NMS), respectively. 3 CPX and PRAZ showed a monophasic dissociation with half‐lives of 5.88±0.15 and 12.27±0.46 min, respectively. In the case of CPX, neither the binding at equilibrium nor the dissociation characteristics were influenced by the allosteric agents. With PRAZ, the binding at equilibrium remained almost unaltered in the presence of W84, whereas it was reduced to 36±2% of the control value with alcuronium and to 42±2% with gallamine. The dissociation of PRAZ was not affected by W84, whereas it was moderately accelerated by alcuronium and gallamine. In the case of ICYP, the binding at equilibrium was not affected by the allosteric modulators. The dissociation of ICYP was slow, and after 3 h, more than 50% of the radioligand was still bound, so that a reliable half‐life could not be calculated. ICYP dissociation was not affected by W84. In the presence of alcuronium and gallamine, the dissociation curve of ICYP revealed an initial drop from the starting level, followed by the major phase of dissociation being parallel to the control curve. 4 In summary, the allosteric action of the applied agents is not a common feature of G‐protein‐coupled receptors and appears to be specific for muscarinic receptors.
