Endothelium-Independent Linkage of Parathyroid Hormone Receptors of Rat Vascular Tissue with Increased Adenosine 3′,5′-Monophosphate and Relaxation of Vascular Smooth Muscle*

Ga, Nickols; Ma, Metz; Wh, Cline

doi:10.1210/endo-119-1-349

Cited by 57 publications

(26 citation statements)

References 27 publications

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“…direct on VSMC tissue because it has been demonstrated in isolated vessel preparations and is endothelium independent. 9 Our results in VSMCs support the contention that the cellular mechanism of PTH-induced vasodilation is mediated by the adenylate cyclase signaling system. Compared with the well-recognized /3-AR vasodilating system, PTH appears more potent (Fig 1).…”

Section: Sustained Effectssupporting

confidence: 81%

“…9 -2327 The vasodilator effect of PTH is endothelium independent 2327 and mediated at least in part by increases in the cAMP content of VSMCs. Our data showing brisk PTH-mediated cAMP responses in VSMCs in culture are in agreement with other studies in VSMC cultures as well as vascular tissues such as rat aorta, rabbit aorta, bovine pulmonary artery, and rabbit renal microvessels.…”

Section: Acute Effectsmentioning

confidence: 99%

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Parathyroid hormone/adenylate cyclase coupling in vascular smooth muscle cells.

Hanson

Linas

1994

Hypertension

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Parathyroid hormone (PTH) has been implicated in hypertension, but PTH infusion results in vasodilation. PTH activates adenylate cyclase in vascular smooth muscle, but little is known about the factors that regulate PTH receptor/ adenylate cyclase coupling in vascular cells. To characterize hormone-receptor signaling, we measured cyclic AMP levels in rat arterial smooth muscle cells in culture exposed to PTH (bovine 1-34). PTH yielded time-and concentration-dependent increases in cyclic AMP levels. Compared with isoproterenol, PTH was more potent, with a threshold at 2x10"' versus 5 x 10~8 mol/L and half maximal responses at 10" 8 versus 2.4xlO" 7 mol/L. PTH-induced increases in cyclic AMP were independent of extracellular calcium, cyclooxygenase metabolites, phospholipase C, and protein kinase C because PTHinduced increases in cyclic AMP were not prevented by variations in extracellular calcium, indomethacin, angiotensin II, vasopressin, and protein kinase C activators or inhibitors. PTH/adenylate cyclase coupling was G protein-dependent because increases in cyclic AMP were prevented by preincubation with cholera toxin but not with pertussis toxin. Pro-P arathyroid hormone (PTH) is important in the regulation of calcium, phosphate, and bone metabolism. In addition, PTH has significant effects on vascular tone and has been implicated in the generation and maintenance of high blood pressure. Sustained increases in PTH have been implicated in hypertension, 1 and parathyroidectomy has been found to reverse hypertension in some animal models.2 -3 However, infusion of PTH results in a reduction in blood pressure and vasodilation in several animal models. 46These apparent discrepancies are difficult to resolve in vivo because the primary effects of PTH may be offset by counterregulatory responses that mask hormone action.The cellular effects of PTH are mediated by receptors coupled to adenylate cyclase in nonvascular tissue such as bone. 7 In vascular smooth muscle cells (VSMCs), adenylate cyclase is an important signaling system mediating vasodilation. /3-Adrenergic agonists are major circulating vasodilators in vivo, and /3-adrenergic receptor (/3-AR)/adenylate cyclase coupling has been extensively studied. In addition to /3-AR, PTH is coupled to adenylate cyclase in vascular smooth muscle tissue. Because the in vivo hemodynamic effects of PTH are not clear and PTH appears to be an important regulator of vasodilator adenylate cyclase signaling in vascular smooth muscle tissue, our purpose was to determine factors that regulate PTH receptor/adenylate cyclase coupling in vitro. To accomplish this goal, we compared PTH with isoproterenol, a well-recognized vasodilator and activator of /3-AR and adenylate cyclase. In addition, we used VSMCs in culture to overcome problems inherent in vivo. Methods Cell CultureMesenteric arterial and aortic VSMCs from 8-to 11-weekold male Sprague-Dawley rats (140 to 245 g) were grown in culture using minimum essential medium (MEM) with Earle's salts supplemented with 10% fetal b...

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Section: Sustained Effectssupporting

confidence: 81%

Section: Acute Effectsmentioning

confidence: 99%

Parathyroid hormone/adenylate cyclase coupling in vascular smooth muscle cells.

Hanson

Linas

1994

Hypertension

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“…This result could be in correlation with PTH-mediated endothelium-independent vasorelaxing effects on vascular smooth muscle cells. 8,44 Interestingly, we observed in some patients a reduced CFR caused by abnormal flow velocity increase during adenosine. Although CFR assessment by adenosine does not allow us to distinguish between endothelium-dependent and -independent abnormalities, 45 this functional alteration can be recognized as the earliest detectable impairment in the process leading to the coronary microvasculopathy.…”

Section: Discussionmentioning

confidence: 74%

“…In PHPT, an involvement of both endotheliumdependent 9,43 and -independent 44 pathways has been reported. Baseline coronary flow was higher in patients with CFR Յ2.5 compared with patients with CFR Ͼ2.5, which is consistent with a resting microvascular vasorelaxation and could alone account for the lower CFR.…”

Section: Discussionmentioning

confidence: 99%

Coronary Microvascular Dysfunction Induced by Primary Hyperparathyroidism is Restored After Parathyroidectomy

et al. 2012

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Background-Symptomatic primary hyperparathyroidism (PHPT) is associated with increased cardiovascular mortality.However, data on the association between asymptomatic PHPT and cardiovascular risk are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic PHPT of recent onset. Methods and Results-We studied 100 PHPT patients (80 women; age, 58Ϯ12 years) without cardiovascular disease and 50 control subjects matched for age and sex. CFR in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperemic to resting diastolic flow velocity. CFR was lower in PHPT patients than in control subjects (3.0Ϯ0. 2).In multivariable linear regression analysis, PTH, age, and heart rate were the only factors associated with CFR (Pϭ0.04, Pϭ0.01, and Pϭ0.006, respectively). In multiple logistic regression analysis, only PTH increased the probability of CFR Յ2.5 (Pϭ0.03). In all PHPT patients with CFR Յ2.5, parathyroidectomy normalized CFR (3.3Ϯ0.7 versus 2.1Ϯ0.5; PϽ0.0001). Conclusions-PHPT patients have coronary microvascular dysfunction that is completely restored after parathyroidectomy. PTH independently correlates with the coronary microvascular impairment, suggesting a crucial role of the hormone in explaining the increased cardiovascular risk in PHPT.

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“…PTH-related peptide (PTHrP) was first identified as a factor that mimics the action of PTH when overexpressed by a number of tumors (9)(10)(11)(12). PTHrP is important for normal skeletal development (13)(14)(15)(16)(17) and stimulates differentiation of a number of cell types (18)(19)(20)(21)(22)(23), in addition to other physiological functions (24)(25)(26)(27)(28). In contrast to PTH, PTHrP is widely expressed both in the fetus and the adult and acts in a paracrine or autocrine manner under physiological conditions (29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%