Reported clinical and experimental findings have shown that baroreflex control of heart rate is attenuated in women compared with men. This study investigated whether the sexual dimorphism in baroreflex function relates to the ability of the male hormone testosterone to facilitate baroreflex responsiveness. Relative contributions of the vagal and sympathetic autonomic components to testosterone modulation of baroreflex function were also investigated. Baroreflex curves relating changes in heart rate to increases or decreases in blood pressure evoked by phenylephrine and sodium nitroprusside, respectively, were constructed in sham-operated rats and castrated rats with and without testosterone replacement. Slope of the curves was taken as an index of baroreflex sensitivity (BRS PE and BRS NP ). Castration (for 10 days) significantly reduced plasma testosterone levels and attenuated reflex bradycardia, as indicated by significantly smaller BRS PE in castrated rats compared with values in sham-operated rats (-0.85 +/- 0.07 vs. -1.51 +/- 0.10 beats/min per mm Hg). Testosterone replacement in castrated rats restored plasma testosterone and BRS PE to levels similar to those of sham-operated rats. Muscarinic blockade by atropine caused 55% reduction in BRS PE in sham-operated rats, an effect that was significantly (p < 0.05) attenuated in castrated rats and restored to intact levels after testosterone supplementation. beta-Adrenergic blockade by propranolol caused slight and insignificant decreases in BRS PE. Castration and testosterone supplementation had no effect on BRS NP, ruling out a modulatory effect of testosterone on reflex tachycardia. These data provide the first experimental evidence of a favorable role for testosterone in baroreceptor control of reflex bradycardia. Further, baroreflex modulation by testosterone appears to be autonomically mediated and involves an enhancement of cardiomotor vagal activity.

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Previous studies have shown that the immunosuppressant drug cyclosporine A attenuates arterial baroreceptor function. This study investigated whether the modulatory effect of cyclosporine on baroreceptor function involves inhibition of the baroreflex-facilitatory effect of testosterone. The role of cardiac autonomic control in cyclosporine-testosterone baroreflex interaction was also investigated. Baroreflex curves relating bradycardic responses to increments in blood pressure evoked by phenylephrine were constructed in conscious, sham-operated, castrated rats and in testosterone-replaced castrated (CAS ϩ T) rats in the absence and presence of cyclosporine. The slopes of the curves were taken as an index of the baroreflex sensitivity (BRS). Short-term (11-13 days) cyclosporine treatment or castration reduced plasma testosterone levels and caused similar attenuation of the reflex bradycardia, as indicated by the significantly smaller BRS compared with sham-operated values (Ϫ0.97 Ϯ 0.07, Ϫ0.86 Ϯ 0.06, and Ϫ1.47 Ϯ 0.10 beats/min/mm Hg, respectively). The notion that androgens facilitate baroreflexes is further confirmed by the observation that testosterone replacement of castrated rats restored plasma testosterone and BRS to sham-operated levels. Cyclosporine had no effect on BRS in castrated rats but caused a significant reduction in CAS ϩ T rats. Muscarinic blockade by atropine caused approximately 60% reduction in the BRS in sham-operated rats, an effect that was significantly and similarly diminished by castration, cyclosporine, or their combination. ␤-Adrenergic blockade by propranolol caused no significant changes in BRS. These findings suggest that cyclosporine attenuates baroreflex responsiveness via, at least partly, inhibition of the testosteroneinduced facilitation of cardiomotor vagal control.

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The present study investigated the acute effects of the immunosuppressant drug cyclosporine A on vasorelaxations evoked via activation of adenosine receptors in the phenylephrine-preconstricted rat perfused kidney and isolated aorta. The roles of endothelial relaxing factors in this interaction were also evaluated. The adenosine analogue 5'-N-ethylcarboxamidoadenosine (NECA; kidney, 6 x 10(-9)-1 x 10(-7) mol; aorta, 1 x 10(-9)-1 x 10(-5) M) elicited dose-dependent vasorelaxations. In the perfused kidney, NECA responses were similarly and significantly attenuated by N-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor) or tetraethylammonium (K channel blocker) versus no effect for diclophenac (cyclooxygenase inhibitor). NECA relaxations in the aorta were reduced by the three inhibitors; the reduction in the response evoked by the highest dose of NECA (1 x 10(-5) M) amounted to 37.7 +/- 2.0% (L-NAME), 19.8 +/- 1.7% (tetraethylammonium), and 29.4 +/- 1.1% (diclophenac). A combination of the three inhibitors almost abolished NECA relaxations in the two preparations. Cyclosporine (2 microM) reduced NECA relaxations in the two preparations. In the aorta, cyclosporine attenuation of NECA responses was significantly reduced after exposure to L-NAME or diclophenac but not tetraethyl-ammonium, suggesting selective involvement of nitric oxide and vasodilator prostanoids in the interaction. In contrast, the cyclosporine attenuation of NECA responses in the kidney was reduced by L-NAME or tetraethylammonium. L-arginine, a nitric oxide substrate, partially restored NECA relaxations in cyclosporine-treated preparations. These findings demonstrate that cyclosporine attenuates endothelium-dependent vasorelaxations elicited via activation of adenosine receptors and highlight the interesting possibility that the relative contribution of the endothelial relaxing factors to cyclosporine-NECA interaction is largely region dependent.