Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objectives of the present study were to determine whether angiotensin II (Ang II) modifies beta-adrenoceptor-induced cAMP production in preglomerular microvascular smooth muscle cells (PMVSMCs), to determine whether the Ang II/beta-adrenoceptor interaction on cAMP production differs in PMVSMCs from normotensive Wistar-Kyoto (WKY) rats vs. PMVSMCs from spontaneously hypertensive rats (SHR), and to elucidate the mechanism of Ang II/beta-adrenoceptor interactions on cAMP production in PMVSMCs. In cultured PMVSMCs, isoproterenol increased cAMP levels and this effect was markedly enhanced by Ang II. The Ang II enhancement of isoproterenol-induced cAMP was significantly greater in SHR PMVSMCs compared with WKY PMVSMCs. Neither inhibition of calcineurin with FK506, inhibition of calcium-calmodulin with W-7 and calmidazolium, nor inhibition of Gi proteins with pertussis toxin attenuated Ang II enhancement of isoproterenol-induced cAMP in PMVSMCs from either SHR or WKY rats. Moreover, the effect of Ang II on isoproterenol-induced cAMP was not mimicked by alpha-2 adrenoceptor stimulation. In contrast, chelation of intracellular calcium with BAPTA-AM attenuated, increasing intracellular calcium with A23187 augmented, and inhibition of protein kinase C with either calphostin C or chelerythrine chloride abolished Ang II enhancement of isoproterenol-induced cAMP. We conclude that in cultured PMVSMCs Ang II enhances the cAMP response to beta-adrenoceptor agonists via a mechanism that involves coincident activation of adenylyl cyclase by stimulatory G proteins and protein kinase C. Thus, protein kinase C-mediated activation of adenylyl cyclase may attenuate Ang II-induced vasoconstriction in the renal microcirculation by raising the intracellular levels of cAMP, and this mechanism may be augmented in genetic hypertension.
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PMID:Modulation by angiotensin II of isoproterenol-induced cAMP production in preglomerular microvascular smooth muscle cells from normotensive and genetically hypertensive rats. 976 41

The Gi pathway augments renal vasoconstriction induced by angiotensin II in spontaneously hypertensive but not normotensive Wistar-Kyoto rats. Because the Gi-coupled pancreatic polypeptide (PP)-fold peptide receptors Y1 and Y2 are expressed in kidneys and are activated by endogenous PP-fold peptides, we tested the hypothesis that these receptors regulate angiotensin II-induced renal vasoconstriction in kidneys from hypertensive but not normotensive rats. A selective Y1-receptor agonist [(Leu31,Pro34)-neuropeptide Y; 6 to 10 nmol/L] greatly potentiated angiotensin II-induced changes in perfusion pressure in isolated, perfused kidneys from hypertensive but not normotensive rats. A selective Y2-receptor agonist (peptide YY(3-36); 6 nM) only slightly potentiated angiotensin II-induced renal vasoconstriction and only in kidneys from hypertensive rats. Neither the Y1-receptor nor the Y2-receptor agonist increased basal perfusion pressure. BIBP3226 (1 micromol/L, highly selective Y1-receptor antagonist) and BIIE0246 (1 micromol/L, highly selective Y2-receptor antagonist) completely abolished potentiation by (Leu31,Pro34)-neuropeptide Y and peptide YY(3-36), respectively. Y1-receptor and Y2-receptor mRNA and protein levels were expressed in renal microvessels and whole kidneys, but the abundance was similar in kidneys from hypertensive and normotensive rats. Both Y1-receptor-induced and Y2-receptor-induced potentiation of angiotensin II-mediated renal vasoconstriction was completely abolished by pretreatment with pertussis toxin (30 microg/kg IV, blocks Gi proteins). These data indicate that, in kidneys from genetically hypertensive but not normotensive rats, Y1-receptor activation markedly enhances angiotensin II-mediated renal vasoconstriction by a mechanism involving Gi. Although Y2 receptors can also potentiate angiotensin II-mediated renal vasoconstriction via Gi, the effect is modest compared with Y1 receptors. These findings may have important implications for the etiology of genetic hypertension.
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PMID:Pancreatic polypeptide-fold peptide receptors and angiotensin II-induced renal vasoconstriction. 1636 88

Treatment with pertussis toxin (PTX) which eliminates the activity of G(i) proteins effectively reduces blood pressure (BP) and vascular resistance in spontaneously hypertensive rats (SHR). In this study we have compared the functional characteristics of isolated arteries from SHR with and without PTX-treatment (10 microg/kg i.v., 48 h before the experiment). Rings of thoracic aorta, superior mesenteric artery and main pulmonary artery were studied under isometric conditions to measure the reactivity of these vessels to receptor agonists and to transmural electrical stimuli. We have found that the treatment of SHR with PTX had no effect on endothelium-dependent relaxation of thoracic aorta induced by acetylcholine. In PTX-treated SHR, the maximum contraction of mesenteric artery to exogenous noradrenaline was reduced and the dose-response curve to cumulative concentration of noradrenaline was shifted to the right. Similarly, a reduction in the magnitude of neurogenic contractions elicited by electrical stimulation of perivascular nerves was observed in the mesenteric artery from PTX-treated SHR. PTX treatment of SHR also abolished the potentiating effect of angiotensin II on neurogenic contractions of the main pulmonary artery. These results indicate that PTX treatment markedly diminishes the effectiveness of adrenergic stimuli in vasculature of SHR. This could importantly affect BP regulation in genetic hypertension.
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PMID:Inactivation of G(i) proteins by pertussis toxin diminishes the effectiveness of adrenergic stimuli in conduit arteries from spontaneously hypertensive rats. 1857 May 36

High blood pressure (BP) of spontaneously hypertensive rats (SHR) is maintained by enhanced activity of sympathetic nervous system (SNS), whereas that of Ren-2 transgenic rats (Ren-2 TGR) by increased activity of renin-angiotensin system (RAS). However, both types of hypertension are effectively attenuated by chronic blockade of L-type voltage-dependent calcium channel (L-VDCC). The aim of our study was to evaluate whether the magnitude of BP response elicited by acute nifedipine administration is proportional to the alterations of particular vasoactive systems (SNS, RAS, NO) known to modulate L-VDCC activity. We therefore studied these relationships not only in SHR, in which mean arterial pressure was modified in a wide range of 100-210 mm Hg by chronic antihypertensive treatment (captopril or hydralazine) or its withdrawal, but also in rats with augmented RAS activity such as homozygous Ren-2 TGR, pertussis toxin-treated SHR or L-NAME-treated SHR. In all studied groups the magnitude of BP response to nifedipine was proportional to actual BP level and it closely correlated with BP changes induced by acute combined blockade of RAS and SNS. BP response to nifedipine is also closely related to the degree of relative NO deficiency. This was true for both SNS- and RAS-dependent forms of genetic hypertension, suggesting common mechanisms responsible for enhanced L-VDCC opening and/or their upregulation in hypertensive animals. In conclusions, BP response to nifedipine is proportional to the vasoconstrictor activity exerted by both SNS and RAS, indicating a key importance of these two pressor systems for actual L-VDCC opening necessary for BP maintenance.
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PMID:Nifedipine-sensitive blood pressure component in hypertensive models characterized by high activity of either sympathetic nervous system or renin-angiotensin system. 2439 13

Cardiac sympathetic nerves release neuropeptide Y (NPY)1-36, and peptide YY (PYY)1-36 is a circulating peptide; therefore, these PP-fold peptides could affect cardiac fibroblasts (CFs). We examined the effects of NPY1-36 and PYY1-36 on the proliferation of and collagen production ([(3)H]proline incorporation) by CFs isolated from Wistar-Kyoto (WKY) normotensive rats and spontaneously hypertensive rats (SHRs). Experiments were performed with and without sitagliptin, an inhibitor of dipeptidyl peptidase 4 [DPP4; an ectoenzyme that metabolizes NPY1-36 and PYY1-36 (Y1 receptor agonists) to NPY3-36 and PYY3-36 (inactive at Y1 receptors), respectively]. NPY1-36 and PYY1-36, but not NPY3-36 or PYY3-36, stimulated proliferation of CFs, and these effects were more potent than ANG II, enhanced by sitagliptin, blocked by BIBP3226 (Y1 receptor antagonist), and greater in SHR CFs. SHR CF membranes expressed more receptor for activated C kinase (RACK)1 [which scaffolds the Gi/phospholipase C (PLC)/PKC pathway] compared with WKY CF membranes. RACK1 knockdown (short hairpin RNA) and inhibition of Gi (pertussis toxin), PLC (U73122), and PKC (GF109203X) blocked the proliferative effects of NPY1-36. NPY1-36 and PYY1-36 stimulated collagen production more potently than did ANG II, and this was enhanced by sitagliptin and greater in SHR CFs. In conclusion, 1) NPY1-36 and PYY1-36, via the Y1 receptor/Gi/PLC/PKC pathway, activate CFs, and this pathway is enhanced in SHR CFs due to increased localization of RACK1 in membranes; and 2) DPP4 inhibition enhances the effects of NPY1-36 and PYY1-36 on CFs, likely by inhibiting the metabolism of NPY1-36 and PYY1-36. The implications are that endogenous NPY1-36 and PYY1-36 could adversely affect cardiac structure/function by activating CFs, and this may be exacerbated in genetic hypertension and by DPP4 inhibitors.
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PMID:NPY1-36 and PYY1-36 activate cardiac fibroblasts: an effect enhanced by genetic hypertension and inhibition of dipeptidyl peptidase 4. 2637 Nov 60