As interactions between the renin-angiotensin and sympathetic nervous systems have been suggested in the pathogenesis of hypertension, we wanted to investigate the effect of chronic renin-angiotensin blockade with losartan and enalaprilat on the sympathetic reactivity to hypotension and on the cardiac beta-adrenergic-coupled adenylyl cyclase pathway in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Both treatments, exerting equipotent shifts of angiotensin-pressure responses, lowered blood pressure and attenuated cardiac hypertrophy similarly in SHR. The nitroprusside-induced hypotension was similar in both strains, but the associated increases in plasma catecholamines and heart rate were higher in SHR. In SHR treated with losartan and enalaprilat, the nitroprusside-induced hypotension was greater and associated with markedly attenuated increases in norepinephrine and heart rate. The binding affinity of cardiac beta-adrenoceptors was significantly lower, and beta2-adrenoceptor subtype was dominant in untreated SHR in contrast to WKY, in which beta1-adrenoceptor subtype was dominant. Enalaprilat treatment increased total beta-adrenoceptor density, whereas both treatments restored the binding affinity and beta1- and beta2-adrenoceptor proportions to normal in SHR. Isoproterenol-, guanylylimidodiphosphate [Gpp(NH)p]-, and forskolin-stimulated adenylyl cyclase reactivity was increased in SHR. Enalaprilat restored adenylyl cyclase reactivity to normal in SHR and reduced the sensitivity (EC50) of Gpp(NH)p-induced cAMP formation in both strains. The present study supports the possibility that functional alterations of the renin-angiotensin and sympathetic systems are involved in hypertension in SHR. The antihypertensive action of losartan and enalaprilat in SHR may be partly mediated through the normalization of sympathetic hyperreactivity and the restoration of beta-adrenergic signaling pathway sensitivity.

Age-related changes in intracellular calcium ([Ca2+]i)-vasoreactivity coupling efficiency (i.e., perfusion pressure divided by [Ca2+]i) were studied in vitro in tail arteries of male, normotensive, WAG/Rij rats aged 6, 12, 24, or 30 mo; one-half of these were chronically treated with the angiotensin I-converting enzyme inhibitor (ACEI) perindopril (1 mg.kg-1.day-1 orally) from 6 mo onward. Arterial segments were perfused at a constant flow rate (perfusion pressure taken as an index of arterial tone) and loaded with the acetoxymethyl ester of fluorescent dye fura 2 (fura 2-AM). Increases in [Ca2+]i were measured simultaneously with vasoconstriction after stimulation with a depolarizing hyperkalemic solution or the agonists norepinephrine or serotonin. Age had no effect on increases in [Ca2+]i vasoconstrictor responses, or electromechanical coupling efficiency (hyperkalemic solution). Increases in [Ca2+]i after agonists were similar in all groups, but vasoconstrictor responses and pharmacomechanical coupling efficiency decreased with age. ACEI had no effect on vasoconstriction or [Ca2+]i signals. In conclusion, coupling efficiency after agonist stimulation decreased with age; ACEI had no effect on coupling efficiency.

To measure, simultaneously, intracellular free Ca2+ ([Ca2+]i) and vasoconstriction in a perfused vessel, we used the fluorescent Ca2+ indicator fura 2 with a dual-wavelength excitation method. One-centimeter-long segments of the caudal artery were dissected from 12-mo-old male Wistar rats. The endothelium was removed by gentle rubbing. The artery was mounted in a specially constructed spectrofluorometer cuvette, perfused with oxygenated physiological saline solution at 37 degrees C, and loaded by perfusion with fura 2 acetoxymethyl ester (5 microM) over a 90-min period. This paper is a description of the technique and the experiments that validate it as a useful method for examining Ca(2+)-related vascular reactivity in an intact perfused vessel.

This study examined the contribution of phosphatidylinositol metabolism and the efficacy of protein kinase C-mediated desensitization in the exaggerated a lb -adrenergic receptor-mediated inositol phosphate response in the aorta of the deoxycorticosterone acetate (DOCA)-salt rat model of hypertension. The basal accumulation of inositol phosphates and the basal incorporation of pHJ/nyo-inositol in the phosphatidylinositol lipid pool were significantly higher in the aorta of these hypertensive rats. A positive correlation (r=.88, f<.01) was demonstrated between basal inositol phosphate levels and the fHJmyo-inositol-labeled phosphatidylinositol lipid pool. In hypertensive rats, a ]b -adrenergic receptor-mediated inositol phosphate production in response to phenylephrine was significantly higher compared with normotensive rats. Despite the normalization of phenylephrine-mediated inositol phosphate production to the [ 3 H]myo-inositol-labeled phosphatidylinositol lipid pool, the a, b -adrenergic response remained significantly higher in the hypertensive rats. Phorbol ester activation of protein kinase C attenuated to a lesser extent phenylephrinemediated inositol phosphate production (40%) in the aorta of hypertensive rats compared with the 80% attenuation observed in the aorta of normotensive rats. This desensitization was inhibited in both groups by the protein kinase C inhibitor staurosporine. The blunted desensitization of the a lb -adrenergic I n both human and animal models of hypertension, an enhanced sympathoadrenal tone leading to a chronic state of elevated circulating plasma catecholamines has been reported.1 In this setting, numerous studies have demonstrated a diminished /3-adrenergic vasodilator response, reflected by a decrease in agonistmediated cyclic AMP production.2 -3 By contrast, vascular smooth muscle reactivity to aradrenergic stimulation was enhanced and associated with an increase in both inositol 1,4,5-trisphosphate levels and Ca 2+ influx. receptor by protein kinase C activation was not associated with a decrease in protein kinase C activity in the hypertensive rats, because aortic strips from these animals were more responsive to phorbol ester activation than aortic strips from normotensive animals. Moreover, the in vivo administration of staurosporine reduced mean arterial pressure to a greater extent in the hypertensive rats. In the same vascular tissue of these hypertensive rats, endothelin-1 receptor-mediated inositol phosphate production was significantly reduced, and in contrast to the nonnotensive rats, in which a 50% decrease was observed, the endothelin-1 receptor was unresponsive to protein kinase C-mediated desensitization. From these results one can conclude that during the development of DOCA-salt hypertension, an increase in both basal phosphatidylinositol turnover and a lb -adrenergic receptor reactivity could contribute to an enhanced vascular smooth muscle tone. These observations provide further evidence for an important role of the sympathetic nervous system an...

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