Aberrant Adenylyl Cyclase/cAMP Signal Transduction and G Protein Levels in Platelets From Hypertensive Patients Improve With Antihypertensive Drug Therapy

Abstract

We have previously demonstrated a decreased expression of Gi alpha 2 protein in platelets from spontaneously hypertensive rats that was associated with an altered responsiveness of adenylyl cyclase to hormone stimulation and inhibition. In the present studies, we have used platelets from hypertensive patients and examined the hormonal regulation of adenylyl cyclase as well as the levels of G proteins and their modulation by antihypertensive drug therapy. We performed these studies in platelets from four groups of subjects: normotensive subjects (group 1), untreated mildly essential hypertensive patients (group 2), and treated moderately to severely hypertensive patients whose blood pressure was uncontrolled (group 3) or controlled with drug treatment (group 4). GTP gamma S, 5'-(N-ethylcarboxamido)adenosine (NECA), and prostaglandin E1 stimulated adenylyl cyclase activity to a greater extent in hypertensive patients (group 2). This effect was partially corrected (by approximately 50% to 80%) in the patients under antihypertensive drug therapy (groups 3 and 4). In addition, inhibition of adenylyl cyclase mediated by a ring-deleted analogue of atrial natriuretic factor (C-ANF4.23) observed in control normotensive subjects was blunted in hypertensive patients (group 2) and was not corrected in treated patients. Gi alpha levels determined by immunoblotting were in the same range for the four groups, whereas Gi alpha 2 and Gi alpha 3 levels were decreased by 70% and 60%, respectively, in hypertensive patients (group 2) compared with normotensive subjects. Antihypertensive drug therapy (groups 3 and 4) partially restored Gi alpha 2 levels toward normal (group 1) by about 60% and 70%, respectively; however, the reduced Gi alpha 3 levels in group 2 hypertensive patients were not improved in group 3 but were raised toward normal levels in group 4 by about 55%. These results suggest that the altered responsiveness of platelet adenylyl cyclase to hormones in hypertension and the normalization of the response with antihypertensive drug therapy could partly be due to the ability of the latter to modulate Gi alpha protein expression. These effects on platelet function may underlie the beneficial effects of antihypertensive agents on some of the complications of hypertension.

Downregulation of Atrial Natriuretic Peptide ANP-C Receptor Is Associated with Alterations in G-Protein Expression in A10 Smooth Muscle Cells†

“…In this regard, a relationship between the levels of Gi proteins and functions has been reported by several investigators (28,(41)(42)(43). In the present studies, we have shown that the treatment of A-10 cells with C-ANP 4-23 for 24 h decreased the levels of GiR proteins by about 40%, which may partially contribute to the attenuation of C-ANP 4-23 -mediated inhibition of adenylyl cyclase.…”

Angiotensin II-evoked enhanced expression of RGS2 attenuates Gi-mediated adenylyl cyclase signaling in A10 cells

“…The inactivation of Gia-proteins by pertussis toxin [29] or the decreased expression of Gia-protein in platelets from SHR and hypertensive subjects has been shown to augment FSK-stimulated adenylyl cyclase activity [33,34]. In addition, the decreased expression of Gia-protein by C-ANP 4-23 has also been reported to augment FSK-stimulated adenylyl cyclase activity in A10 VSMC [35].…”

Effects of 2-hydroxyoleic acid on the structural properties of biological and model plasma membranes

“…Gaq/11 proteins are involved in the regulation of the phospholipase C (PLC)/inositol phosphate (IP) signalling pathway. Accordingly, several abnormalities in receptormediated vasodilation, G-protein expression, and PLC activity, have been reported in hypertensive subjects [7,37] and in animal models of hypertension [38,39]. Recent studies have demonstrated that lipids rafts isolated from basolateral plasma membranes of rat hepatocytes were also enriched for Na ' /K ' ATPase activity [40].…”