Blood pressure activity

Figure 20. Influence of substitution with different halogens and halogen with methyl in the phenyl ring on blood pressure activity...

Ginsengoside Rbi (60) is a representative of the saponins derived from 20(5)-protopanaxadiol. It exhibits central nervous system-depressant and antipsychotic activity, protection against stress ulcer, increase of gastrointestinal motility and weak anti-inflammatory action. Rgi (61) -the major saponin of 20(5)-protopanaxatriol - shows weak CNS-stimulant action, antrfatigue activity and blood pressure activity [108,109] (O Scheme 25). 

Platelet-activating factor (structure) is a glycerol ether with potent physiological properties. At concentrations as low as 1 picomolar, it stimulates of blood platelet aggregation, reduction of blood pressure, activation of several white blood cell classes, decreased cardiac output, glycogenolysis, uterine contraction. 

The posterior lobe of the pituitary, ie, the neurohypophysis, is under direct nervous control (1), unlike most other endocrine organs. The hormones stored in this gland are formed in hypothalamic nerve cells but pass through nerve stalks into the posterior pituitary. As early as 1895 it was found that pituitrin [50-57-7] an extract of the posterior lobe, raises blood pressure when injected (2), and that Pitocin [50-56-6] (Parke-Davis) causes contractions of smooth muscle, especially in the utems (3). Isolation of the active materials involved in these extracts is the result of work from several laboratories. Several highly active posterior pituitary extracts have been discovered (4), and it has been deterrnined that their biological activities result from peptide hormones, ie, low molecular weight substances not covalendy linked to proteins (qv) (5). 

Two AT-II receptors, AT and AT2 are known and show wide distribution (27). The AT receptor has been cloned and predominates ia regions iavolved ia the regulation of blood pressure and water and sodium retention, eg, the aorta, Hver, adrenal cortex, and ia the CNS ia the paraventricular nucleus, area postrema, and nucleus of the soHtary tract. AT2 receptors are found primarily ia the adrenal medulla, utems, and ia the brain ia the locus coeruleus and the medial geniculate nucleus. AT receptors are GCPRs inhibiting adenylate cyclase activity and stimulating phosphoHpases C, A2, and D. AT2 receptors use phosphotyrosiae phosphatase as a transduction system. 

Nitrous oxide produces respiratory depression (38,39). It has been shown to produce a direct myocardial depressant effect in dogs (40) and in humans breathing a 40% N2O/60% oxygen mixture (41) however, this may be offset by the activation of the sympathetic nervous system (42). The combination of nitrous oxide and opioids can produce decreases in myocardial contractiHty, heart rate, and blood pressure (43). 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

P-Adrenoceptor Blockers. There is no satisfactory mechanism to explain the antihypertensive activity of P-adrenoceptor blockers (see Table 1) in humans particularly after chronic treatment (228,231—233). Reductions in heart rate correlate well with decreases in blood pressure and this may be an important mechanism. Other proposed mechanisms include reduction in PRA, reduction in cardiac output, and a central action. However, pindolol produces an antihypertensive effect without lowering PRA. In long-term treatment, the cardiac output is restored despite the decrease in arterial blood pressure and total peripheral resistance. Atenolol (Table 1), which does not penetrate into the brain is an efficacious antihypertensive agent. In short-term treatment, the blood flow to most organs (except the brain) is reduced and the total peripheral resistance may increase. 

Glonidine. Clonidine decreases blood pressure, heart rate, cardiac output, stroke volume, and total peripheral resistance. It activates central a2 adrenoceptors ia the brainstem vasomotor center and produces a prolonged hypotensive response. Clonidine, most efficaciously used concomitantly with a diuretic in long-term treatment, decreases renin and aldosterone secretion. 

The resting membrane potential of most excitable cells is around —60 to —80 mV. This gradient is maintained by the activity of various ion channels. When the potassium channels of the cell open, potassium efflux occurs and hyperpolari2ation results. This decreases calcium channel openings, which ia turn preveats the influx of calcium iato the cell lea ding to a decrease ia iatraceUular calcium ia the smooth muscles of the vasculature. The vascular smooth muscles thea relax and the systemic blood pressure faUs. 

Piaacidil has a short half-life and most human studies were carried out ia slow-release formulatioas. The reductioa ia blood pressure produced by piaacidil is accompanied by tachycardia and fluid retention. Plasma catecholamines and renin activity are iacreased. Other side effects are headache, di22iaess, and asthenia. 

Cromakalim. Cromakalim has along half-life (254). Cromakalim at an oral dose of 1.5 mg ia humans significantly lowers blood pressure 19/12 mm Hg (systohc/diastoHc pressure). It iacreases reaal blood flow, PRA, and heart rate. Cromakalim has bronchodilating activity that is beneficial for hypertensive asthmatic patients. Because of some undesirable effects seen ia cardiac papillary muscles of animals oa long-term treatmeat, future clinical trials are to be carried out usiag the active enantiomer, lemakalim (BRL 38227). 

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