Desensitization of vascular tissue to parathyroid hormone and parathyroid hormone-related protein.

Although PTH and PTH-related protein (PTHrP) are vasodilators, prolonged exposure to elevated levels of PTH is often associated with hypertension. We investigated the effects of prolonged incubation with PTH or PTHrP on arterial segments and cultured vascular smooth muscle cells (VSMC). PTH or PTHrP transiently relaxed precontracted arterial segments within 10 min. Additional PTH or PTHrP added after 40-min exposure to these peptides had little effect on vascular tone, whereas forskolin, isoproterenol, isobutylmethyl-xanthine, or acetylcholine were still potent. In fura 2-loaded VSMC, 5-min incubation with PTH or PTHrP attenuated angiotensin II (Ang II)-induced calcium mobilization, an effect that was reduced by preincubation of VSMC with PTH for 1.5 h. Similarly, 1.5-h preincubation with PTH or PTHrP decreased the cAMP response to these peptides but not to forskolin or NaF. Ang II potentiated the cAMP response to PTH and PTHrP but was also subject to desensitization. Nle8, 18Tyr34 bovine PTH(3-34) amide did not desensitize vascular tissue to PTH or PTHrP. Our results suggest that homologous desensitization to PTH or PTHrP in vascular tissue requires receptor stimulation, occurs proximal to G stimulatory protein, and impairs attenuation of calcium mobilization by PTH or PTHrP. This may be a mechanism by which vasodilator effects of these peptides are decreased with prolonged elevation of PTH levels.

Increased functional Na(+)-K+ pump activity in the vasculature of fructose-fed hyperinsulinemic and hypertensive rats.

We hypothesized that hyperinsulinemia may alter insulin's ability to stimulate vascular Na+/K(+)-ATPase pump activity and modulate changes in vascular responsiveness associated with hypertension. We measured potassium-induced relaxation as an indicator of Na+/K(+)-ATPase pump activity in isolated femoral arteries from fructose-fed (FF) hyperinsulinemic, Sprague-Dawley rats. FF rats had higher mean arterial blood pressures than did normal diet-fed (NF) rats (FF, 125 +/- 2.2, n = 20, vs. NF, 113.5 +/- 2.5 mmHg, n = 20, p < 0.05) and were hyperinsulinemic (FF, 64 +/- 4 vs. NF, 37 +/- 2, microU/ml insulin, p < 0.01). FF rats were more sensitive to KCl in the Na+/K+ pump bioassay (FF, 0.86 +/- 0.07, n = 21 vs. NF, 1.18 +/- 0.08, n = 17, p < 0.05, expressed as ED50 in mmol/l KCl). Exogenous insulin (100 mU/ml) increased Na+/K+ pump sensitivity in FF rats as compared with a boiled insulin control (insulin 45 +/- 6%, n = 11, vs. control, 11 +/- 7%, n = 13, p < 0.01, expressed as percent increase in sensitivity, i.e., ED50). There were no significant differences in Na+/K+ pump sensitivity between insulin and control responses in the NF animals (insulin 29 +/- 6%, n = 11, vs. control 46 +/- 5%, n = 10, NS). Dose-response curves were obtained in tail and femoral arteries from the same animals to norepinephrine and acetylcholine, basally and after exogenous insulin. FF vessels had reduced sensitivity to norepinephrine as compared with the NF group. Insulin increased sensitivity to acetylcholine-induced relaxations and increased AII-induced contractions in FF-rat vessels. These data suggest that in the FF rat insulin's influence on the vascular Na+/K+ pump is enhanced and may modulate the changes in vascular responsiveness seen in this model.