P338	Desensitisation of the cardiac PTH-receptor contributes to the paradoxical vasoconstriction mediated by bioactive PTH-peptides.
G.Ross, A.Dolf, E.Bahner, K-D.Schlüter
Physilogisches Institut, Gießen, DE.

Peptides from the PTH-family reduce the vascular resistance. However, patients with primary hyperparathyroidism develop a hypertension. The aim of this study was to investigate how far a desensitisation of the PTH-receptor is contributed on this paradoxical behaviour. Methods: Rat hearts were perfused in the Langendorff mode. Changes in coronary resistance were investigated by analysing changes in perfusion pressures and flow rates. Contraction of intestine musculature as a model for other smooth musculature outside the cardiovascular system was examined in an organ bath. Results: Coronary vessels were pre-constricted by L-nitro-arginine (L-NA, 100 µmol/l). Addition of parathyroid hormone-related peptide (PTHrP (1-34), 100 nmol/l) attenuated perfusion pressure within 5 min on basal levels (from 97±3 mmHg to 50±2 mmHg). This dilating effect was reversible within 20 min. A following renewed exposition with PTHrP (100 nmol/l) increased perfusion pressure from 99±2 mmHg to 118±13 mmHg. If PTHrP was substituted in the first treating period by PTHrP (7-34, 100 nmol/l, high affinity to the PTH-receptor but lacking the cAMP/PKA-activating domain), a renewed treatment by PTHrP (100 nmol/l) resulted in vasodilation. If the first or alternatively the second PTHrP treatment was substituted by isoprenaline, which mediated vasodilation via activation of the cAMP/PKA-pathway, (β-adrenoreceptor agonist, 10 nmol/l) a following application of PTHrP or isoprenaline led to vasodilation again. Repeating the initial experiment with PTH (100 nmol/l) instead of PTHrP, the first as well as the renewed application of PTH decreased perfusion pressure (first: from 103±10 mmHg to 80±12 mmHg; renewed: from 111±11 mmHg to 76±13 mmHg. The intestine musculature was pre-constricted by acetylcholine (100 µmol/l). Treatment with PTHrP (100 nmol/l) led to relaxation, an additional application of PTHrP (100 nmol/l) resulted in relaxation again. Conclusion: Contrary to the intestine musculature the PTH-receptor of coronary vessels desensitises fast. As a result a paradoxical vasoconstrictor effect was mediated by a tissue-specific PTH-receptor-isoform. As PTH does not desensitise the receptor a contribution of PTH1-receptor-desensitisation to hypertension in patients with primary hyperparathyroidism is unlikely.

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