On Pharmacological Education: Integrative Pharmaco-Physiology on Example of Idiopathic Hypertension incl. Cerebral Apoplexy

[Speaker] Michael Ch. Michailov:1
[Co-author] Eva Neu:1, Ursula Welscher:1, Gerald Werner:2, Michael Bornhausen:1, Walter Kilchenstein:1, Horst Meissner:1, Alfons Hofstetter:1,3, Ernst R. Weissenbacher:1,4, Dieter G. Weiss:1,5
1:Inst. Umweltmedizin c/o ICSD/IAS e. V. POB 340316, 80100 Muenchen (Int. Council Sci. Develop./Int. Acad. Sci. Berlin-Innsbruck-Muenchen-NewDelhi-Paris-Sofia-Vienna), Germany, 2:Clinic Internal Med. I, Kl. Darmstadt, Germany, 3:Klinikum Grosshadern (Dir. a. D.), Univ. Muenchen, Germany, 4:Practice Premium Med., former Dept. Gynecology (Dir. a. D.), Univ. Muenchen, Germany, 5:Inst. Cell Physiol., Univ. Rostock, Germany

INTRODUCTION: Since discovery of blood-circulation (William HARVEY 1628) about cellular (Claude BERNARD), blood-pressure (Walter CANNON) & blood-volume (Otto H. GAUER) homeostasis exists enormous information, but till today genuine hypertension pathogenesis incl. apoplexy cerebri (HIPPOCRATES) as fundamental for pharmaco-therapy is not clarified. Future pharmacological education&research needs holistic and multidimensional considerations counteracting ultra-specialization.
METHODS: Motor/electrical activities-preparations, EEG/blood pressure=BP/electrostimulation, pharmaco-physiological tests (ref.)
RESULTS (recent/earlier): Relation of spontaneous phasic (SPC: 0.5-2/min) and periodic slow-tonic contractions (STC: 0.1-0.2/min) induced by hormones (angiotensin-II/5-HT/PGs/vasopressin=VP) in rat-aorta, human renal & ovarian-uterine arteries, also motor oscillations in cerebral basilar-artery (rat) to SPC-STC in urogenital-tract (vesical&myometrial), also to low-frequency blood-pressure fluctuations (Mayer-waves) & pericytes, is to be investigated.
Importance of SPC-STC for BP-reactions (normal/spinal rats: decapitation&artificial respiration&thermoregulation) is not clear. Nicotine/1-10mg/kg & mercptoethylguanidine/MEG: NO-synthase-inhibitor/200-300mg/kg induce transformation of acetylcholine depressor-response=dR, also of electrical central-vagal-stimulation (CVS:55Hz,2ms,5s,5V), into biphasic depressor-pressor=dR/pR, potentiate pR of non-AHR-600/McN-A-343 & nicotine-like/DMPP: 0.1µg-100mg/kg ganglion-stimulating agents, invert serotoninergic dR into pR, potentiate VP-pR/5-100mIU, also bradykinin-dR/1-20µg/kg (antagonization by propranolol).
On bronchodilators & tocolytic β-sympathomimetic therapy: Adrenaline-contractions (rat-aorta/portal-vein), also frequency of electrical spike/burst activities (intracellular rec., vesical-myocytes) are decreased after buphenin=B&Fenoterol=F/10nmol-1µM.
After B/1mg/kg&F/0.05-0.20mg/kg cardiac&respiratory frequency in rats&cats are increased, blood-pressure decreased, correlated with EEG-patterns-synchronization in cats (stereotaxically-implanted electrodes: hippocampus/ hypothalamus posterior/nucleus tractus solitarii).
Open questions. What is the kind of interaction between MEG-Nicotine and chemical structure of:
1. CNS-types from nicotinic cholinergic-receptors (=nACHRs, esp. types alpha-4-2-beta2-3)?
2. 5-HT1-7 receptors (G-protein coupled), esp. 5-HT1a-f, 5-HT2a-c, 5-HT7?
3. Neuronal VPR1b and vascular VPR1a receptors? Why VP-octapeptide has different action mechanisms than nonapeptide bradykinin?
4. What kind of neuronal β-receptors are responsible for electrical-effects of B&F?
CONCLUSION: Results support hypothesis of 3 pathogenetic mechanisms of idiopathic hypertension (independent from renal): Sensitization of neuroeffector regulatory-structures by endogenic/exogenic factors:
a. Central adrenergic/cholinergic neurons (CNS:formatio-reticularis/hypothalamus),
b. Preganglionic sympathetic-neurons (nicotinic-cholinergic receptors: nACHRs),
c. Vascular effector-cells (myocytes, endothelial),
d. dR/pR cause probably cardiac/cerebral angiospasms.
An integrative pharmaco-physiology could open new dimension for antihypertonic-therapy.
References Michailov-Neu-Welscher-et-al.: IUPHAR-2014-Cape-Town, Basic&Clin.Pharm.&Tox.(BCPT), Vol.115/s1, p.77-78/312-313; 2010-Copenhagen Basic&ClinPharm&Tox 17/S1,454-5/488-9; 2006-Beijing ActaPharmSinica S1,178/411; 1981-Tokyo 1530/1880; 1978-Paris 36/2175&2680. IUPS (IntUnPhysiolSci) 2017-Rio-de-Janeiro, Congr-Proc-no.977/999/1001/1003; 2009 Kyoto 22:JPhysiolSci 59/S1:168&214&447-8. FEPS-2017-Vienna, Acta-Physiol./Suppl.B12-7; 2003-Nice Abs-Book 121/123. Strahlenther.Onkol.151/6, 549-554, 1976. Indian-J.Physiol.Pharmac. 23/4, 254-260, 1979.

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