Spontaneously hypertensive rats (SHR) are characterized by enhanced sympathetic vasoconstriction, whereas their vasodilator mechanisms are relatively attenuated compared to their high BP. The objective of our in vivo study was to evaluate whether the impaired function of BKCa and/or KV channels is responsible for abnormal cAMP-induced vasodilatation in genetic hypertension. Using conscious SHR and normotensive WKY rats we have shown that under the basal conditions cAMP overproduction elicited by the infusion of beta-adrenoceptor agonist (isoprenaline) caused a more pronounced decrease of baseline blood pressure (BP) in SHR compared to WKY rats. Isoprenaline infusion prevented BP rises induced by acute NO synthase blockade in both strains and it also completely abolished the fully developed BP response to NO synthase blockade. These cAMP-induced vasodilator effects were diminished by the inhibition of either BKCa or KV channels in SHR but simultaneous blockade of both K(+) channel types was necessary in WKY rats. Under basal conditions, the vasodilator action of both K(+) channels was enhanced in SHR compared to WKY rats. However, the overall contribution of K(+) channels to cAMP-induced vasodilator mechanisms is insufficient in genetic hypertension since a concurrent activation of both K(+) channels by cAMP overproduction is necessary for the prevention of BP rise elicited by acute NO/cGMP deficiency in SHR. This might be caused by less effective activation of these K(+) channels by cAMP in SHR. In conclusion, K(+) channels seem to have higher activity in SHR, but their vasodilator action cannot match sufficiently the augmented vasoconstriction in this hypertensive strain.
- MeSH
- agonisté adrenergních beta-receptorů MeSH
- AMP cyklický metabolismus MeSH
- cévní rezistence MeSH
- draslíkové kanály řízené napětím metabolismus MeSH
- hypertenze genetika metabolismus patofyziologie MeSH
- isoprenalin MeSH
- krevní tlak MeSH
- NG-nitroargininmethylester MeSH
- potkani inbrední SHR MeSH
- potkani inbrední WKY MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory MeSH
- vápníkem aktivované draslíkové kanály s vysokou vodivostí - alfa-podjednotky metabolismus MeSH
- vazodilatace * MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Essential hypertension is a multifactorial disorder which belongs to the main risk factors responsible for renal and cardiovascular complications. This review is focused on the experimental research of neural and vascular mechanisms involved in the high blood pressure control. The attention is paid to the abnormalities in the regulation of sympathetic nervous system activity and adrenoceptor alterations as well as the changes of membrane and intracellular processes in the vascular smooth muscle cells of spontaneously hypertensive rats. These abnormalities lead to increased vascular tone arising from altered regulation of calcium influx through L-VDCC channels, which has a crucial role for excitation-contraction coupling, as well as for so-called "calcium sensitization" mediated by the RhoA/Rho-kinase pathway. Regulation of both pathways is dependent on the complex interplay of various vasodilator and vasoconstrictor stimuli. Two major antagonistic players in the regulation of blood pressure, i.e. sympathetic nervous system (by stimulation of adrenoceptors coupled to stimulatory and inhibitory G proteins) and nitric oxide (by cGMP signaling pathway), elicit their actions via the control of calcium influx through L-VDCC. However, L-type calcium current can also be regulated by the changes in membrane potential elicited by the activation of potassium channels, the impaired function of which was detected in hypertensive animals. The dominant role of enhanced calcium influx in the pathogenesis of high blood pressure of genetically hypertensive animals is confirmed not only by therapeutic efficacy of calcium antagonists but especially by the absence of hypertension in animals in which L-type calcium current was diminished by pertussis toxin-induced inactivation of inhibitory G proteins. Although there is considerable information on the complex neural and vascular alterations in rats with established hypertension, the detailed description of their appearance during the induction of hypertension is still missing.
- MeSH
- adrenergní receptory fyziologie MeSH
- cévní endotel patofyziologie MeSH
- guanosinmonofosfát cyklický metabolismus MeSH
- hypertenze metabolismus patofyziologie MeSH
- krevní tlak fyziologie MeSH
- lidé MeSH
- membránové potenciály MeSH
- svaly hladké cévní fyziologie MeSH
- sympatický nervový systém patofyziologie MeSH
- vápník metabolismus MeSH
- vápníkové kanály - typ L metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: High blood pressure (BP) in spontaneously hypertensive rats (SHRs) is attributed to excessive activity of sympathetic nervous system (SNS) and relative nitric oxide deficiency. An important part of SNS hypertensive action is exerted by calcium influx through L-type of voltage-dependent calcium channels (L-VDCC). The overexpression of pertussis toxin (PTX)-sensitive inhibitory G-proteins (Gi) participating in the development and maintenance of high BP in SHRs suggested us to study Gi-protein involvement in the pathway through which noradrenergic vasoconstriction and calcium influx can be coupled. METHOD: The participation of main vasoactive systems (angiotensin II, norepinephrine, nitric oxide) in BP maintenance was investigated in conscious SHR and WKY rats (half of them being pretreated with PTX, 10 microg/kg i.v., 48 h before the experiment). To evaluate the contribution of Gi-proteins and L-VDCC to vasoconstriction induced by exogenous norepinephrine, dose-response curves were determined before and after acute nifedipine administration. RESULTS: PTX pretreatment of SHRs significantly decreased BP and reduced sympathetic vasoconstriction, which was partially substituted by enhanced angiotensin II-dependent vasoconstriction. PTX pretreatment also reduced nitric oxide-dependent vasodilation in both rat strains. PTX pretreatment of SHRs decreased BP component sensitive to acute blockade of calcium entry by nifedipine. In both strains, PTX pretreatment as well as acute nifedipine administration caused substantial rightward shift of norepinephrine dose-response curves (without additive effects of both treatments). CONCLUSION: The enhanced contribution of SNS to hypertension maintenance in SHRs is mediated by Gi-protein-coupled pathway controlling calcium influx through L-VDCC.
- MeSH
- hypertenze patofyziologie MeSH
- krevní tlak účinky léků fyziologie MeSH
- krysa rodu rattus MeSH
- nifedipin farmakologie MeSH
- noradrenalin farmakologie MeSH
- pertusový toxin farmakologie MeSH
- potkani inbrední SHR MeSH
- potkani inbrední WKY MeSH
- proteiny vázající GTP - alfa-podjednotky Gi-Go antagonisté a inhibitory fyziologie MeSH
- sympatický nervový systém účinky léků patofyziologie MeSH
- vápníková signalizace účinky léků MeSH
- vápníkové kanály - typ L fyziologie MeSH
- vazokonstrikce účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
