PRESSOR RESPONSES TO SEROTONIN INJECTED INTO THE NUCLEUS TRACTUS SOLITARIUS OF SPRAGUE-DAWLEY RATS AND SPONTANEOUSLY HYPERTENSIVE RATS

Previous studies in rats have shown that injection of nanomoles of serotonin (5-hydroxytryptamine; 5HT) into the nucleus tractus solitarius (NTS) acts on 5HT3 receptors to increase arterial pressure (AP). We investigated the effect of 5HT in Sprague-Dawley (SD) rats and in spontaneously hypertensive rats (SHR). Injection of nanomoles of 5HT into the NTS of chloralose-anesthetized SD rats increased AP. This effect was inhibited by prior injection of 5HT3 receptor antagonist ondansetron. The GABA_A receptor antagonist bicuculline did not inhibit the effect of 5HT. Bilateral injection of 5HT or ondansetron did not affect the baroreflex sensitivity. Bilateral injection of ondansetron did not alter AP. The pressor effect of 5HT was exaggerated in SHR. These results suggest that stimulation of 5HT3 receptors in the NTS increases AP independently of activation of GABAA receptors and the baroreflex sensitivity. Furthermore, this serotonergic system is supersensitive in the NTS of SHR.     

Observations on Pain Perception and Hypertension in Spontaneously Hypertensive Rats

Pain sensitivity in Spontaneously Hypertensive Rats (SHR) and normotensive Wistar-Kyoto controls (WKY) as well as in experimentally hypertensive Wistar rats has been studied. Results indicate a diminished responsiveness to noxious stimuli in SHR when compared with WKY. This hypoalgesia is altered neither by chronic treatment with the antihypertensive drugs hydralazine and captopril nor by the peripherally acting opiate antagonist N-methyl-naloxone. Induction of renal and DOCA-salt hypertension in Wistar rats and Wistar-Kyoto rats did not affect nociceptive responsiveness. It is concluded that opiate receptors within the central nervous system are involved in the hypoalgesia in SHR and that pain perception appears to be dissociated from blood pressure regulation in the rat strains used     

Brain Monoamines and Metabolites in Hypertensive and Hyperactive Rat Strains

ABSTRACT

Monoamines and metabolites were measured by HPLC-EC in brain regions of four Wistar-Kyoto derived rat strains, in whom the traits of genetic hypertension or hyperactive behavior were expressed together (SHR), separately (WK-HT and WK-HA strains, respectively), or not at all (WKY). These genetically related inbred strains were used to allow more discrete correlations between neurochemical changes and the hypertensive and/or hyperactive state, than was hitherto possible using SHR and WKY alone. Numerous age and/or strain differences in monoamine and metabolite levels were present in the six brain regions examined, however, no correlations with hypertension were observed. Limited correlations were seen between hyperactivity and forebrain serotonergic systems. These findings demonstrate that neurochemical differences between SHR and WKY may be erroneously attributed to the hypertension and/or hyperactivity of the SHR, unless additional genetic control strains, such as WK-HT and WK-HA rats are utilized.     

Immediate Hemodynamic Changes Produced by Urapidil in Normotensive and Spontaneously Hypertensive Rats

The immediate effects on regional and systemic hemodynamics of urapidil (1 mg/kg IV), a recently synthesized vasodilator with a possible combined central and peripheral action, were studied in spontaneously hypertensive (SHR) and normotensive (WKY) rats. Maximal decrease in mean arterial pressure was achieved within the first minute after injection (154 ± 4 vs 113 ± 6 mm Hg in SHR and 111 ± 4 vs 82 ± 4 mm Hg in WKY, p < 0.01). This effect was accompanied by a transient (10 min) significant increase in heart rate in both strains. There was a significant fall in total peripheral resistance (0.43 ± 0.02 vs 0.30 ± 0.02 U/kg in WKY and 0.62 ± 0.03 vs 0.43 ± 0.03 U/kg in SHR, p < 0.01) and rise in cardiac index 15 min after drug injection (371 ± 9 vs 425 ± 12 m1/min/kg in WKY and 395 ± 8 vs 432 ± 12 ml/min/kg in SHR, p < 0.01). Organ vascular resistance decreased significantly in all the organs of WKY and most of the organs of SHR rats. However, a significant increase in blood flow was observed only in skeletal muscle. The data indicate that urapidil is a potent hypotensive agent. The pressure fall is mediated through a decreased total peripheral resistance that is distributed through all circulations. The increased cardiac output and heart rate are most likely reflexly induced.     

Effect of Meta-Chlorophenylpiperazine (mCPP), A Central Serotonin Agonist and Vascular Serotonin Receptor Antagonist,on Blood Pressure in SHR

mCPP (meta-chlorophenylpiperazine) has agonist activity at some central serotonin receptors and antagonist activity at peripheral vascular 5HT₂ receptors, both effects that have been postulated to lower blood pressure. mCPP (10 and 30 mg/kg, i.p. 1 hr after administration) increased serotonin and decreased 5-hydroxy-indolacetic acid (5-HIAA) brain concentrations and elevated serum corticosterone and prolactin, indications of central serotonergic agonist activities. The same doses of mCPP also antagonized vascular 5HT₂ receptors as measured by blockade of pressor responses to serotonin in pithed rats. Although mCPP could be demonstrated to activate central serotonergic receptors and block peripheral vascular 5HT₂ receptors, mCPP (10 and 30 mg/kg, i.p.) produced little effect on blood pressure in either the anesthetized or conscious spontaneously hypertensive rat (SHR) up to 1 hr after intraperitoneal administration. The findings are consistent with initial studies in normotensive humans that have not demonstrated a reduction in blood pressure clinically after mCPP in doses that produce elevations in serum cortisol and prolactin levels.     

Beta-2 Adrenoceptor Mediated Vasodilation: Role in Cardiovascular Responses to Acute Stressors in Spontaneously Hypertensive Rats

The present paper summarizes our studies on the role of beta-2 adrenoceptor mediated vasodilatory mechanisms in the cardiovascular defense response of spontaneously hypertensive rats (SHR) and presents new data on the contribution of altered vascular responsiveness to vasodilators. SHR had similar blood pressure but exaggerated plasma norepinephrine (NE) and epinephrine (EPI) responses compared to their normotensive control strain, the Wistar-Kyoto (WKY), while the plasma catecholamine response of the first generation (F1) cross was intermediate. An examination of regional blood flow changes to footshock stress indicated that SHR compared to WKY had greater increases in mesenteric vascular resistance that appeared to be offset by more pronounced decreases in hindquarter vascular resistance. Blockade of beta-2 adrenoceptors, which are densely located in the skeletal muscle vasculature, led to greatly increased pressor responses to stress in SHR but was without effect in WKY. Results of our current work indicate that this response is due to increased stimulation of the beta-2 adrenoceptors during stress rather than to increased vascular reactivity. These results indicate that in SHR relative to WKY, the exaggerated sympatho-adrenal response to stress does not produce greater blood pressure responses because of the offsetting influences upon vasodilation and vasoconstriction.     

Enhanced Natriuretic and Hypotensive Responsiveness to α-Human Atrial Natriuretic Polypeptide (α-hANP) in Shr

Natriuretic and hypotensive effects of synthetic α-human atrial natriuretic polypeptide (α-hANP) were investigated in anesthetized spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The renal excretory and hypotensive effects of α-hANP were strengthened in a dosedependent manner in both strains of rat. The natriuretic response to three doses of α-hANP (0.3, 1.0 and 3.0 μg/kg) were significantly greater in SHR than in WKY. These results suggest that atrial natriuretic polypeptide may play some role in waterelectrolyte balance and control of blood pressure in SHR.     

Brainstem PNMT Neurons and Experimental Hypertension in the Rat

The number of phenylethanolamine-N-methyl transferase (PNMT) cells visualised with immunohistochemical techniques in the medulla oblongata is increased by 20% in 4 week old spontaneously hypertensive rats (SHR) and stroke prone spontaneously hypertensive rats (SHR-SP). This is associated with a 50% increase in the activity of PNMT and a significant rise in the amount of PNMT enzyme protein present in the medulla and spinal cord of both 4 weeks old and 4 months old SHR and SHR-SP.

Since previous experiments had demonstrated that sinoaortic denervation also increased spinal cord PNMT activity we subjected normotensive Wistar Kyoto control rats (WKY) and hypertensive SHR and SHR-SP to denervation and measured the changes in blood pressure and in PNMT activity. Mean arterial pressure rose immediately after denervation in all 3 strains of rats, with much greater rises in the SHR and SHR-SP than in WKY, but the increase in pressure was only sustained in the normotensive WKY, in which it remained elevated throughout the one week observation period. In a similar way, denervation of the arterial baro-receptors increased the activity of PNMT in the medulla and spinal cord of normotensive WKY controls, confirming the results of previous studies but was not able to increase the already elevated PNMT levels in the SHR and SHR-SP any further in these two tissues. We suggest that there is good evidence that PNMT neurons contribute t o the maintenance and elevation of arterial pressure in both the neurogenic and genetic models of hypertension. It also seems likely that the activity of descending spinal PNMT neurons is more important in the maintenance of a sustained increase in pressure than in the induction of a transient rise.     

Age Related Changes of Noradrenaline Content in Brain Regions of Spontaneously Hypertensive (SHR) and Normotensive Wistar-Kyoto (WK) Rats

Noradrenaline (NA) was assayed in brain regions of male and female WK and SHR of 6 to 40 weeks of age, using high performance liquid chromatography with electrochemical detection (HPLC-ECD). The change of levels with age was similar in brain regions of both strains except in brainstem and thoracic spinal cord where levels fell progressively with age in SHR but not in WK rats. The fall in NA content in these two regions is associated with a rise in blood pressure with age in the SHR and suggests a relationship between NA levels and hypertension. The demonstration of different patterns of change in NA levels with age between WK and SHR represents a new approach to resolving the problem of the lack of appropriate control animals for genetic models of disease. However, the data also emphasise that differences in catecholamine metabolism may occur between in-bred strains of rat such as the WK and SHR, and between male and female rats, unrelated to differences in blood pressure.     

The Effect of Diet on Simvastatin and Losartan Enhancement of Endothelial Function

Patients with hypertension take antihypertensive agents and cholesterol-lowering drugs; however, few studies describe the effects of the interaction of antihypertensive agents with statins. Therefore, the purpose of this study was to characterize the effects of losartan, simvastatin, and their combination on the progression of hypertension in the spontaneously hypertensive rats (SHRs). Also, we determined whether diet influenced the drug responses. Rats were fed three different diets—low-salt (LS), high-salt (HS), and lipid-rich (LR)—and treated with either no drug (control), losartan (LOS, 10 mg/kg/day), simvastatin (SIM, 2 mg/kg/day) or LOS combined with SIM for four weeks. After four weeks on the diets, systolic blood pressure rose in all groups and remained elevated. Treatment with LOS alone or in combination with SIM reduced BP in the rats fed the LS and HS diet, respectively. Furthermore, LOS alone increased NO in the LS and LR groups; however, LOS combined with SIM completely abolished this rise in NO in LS group. Plasma PGI₂ and TXA₂ levels were increased in the presence of SIM alone; however LOS combined with SIM completely blocked SIM-induced increases in PGI₂ and TXA₂. Kidney levels of angiotensin II were higher in the LS group and significantly increased in the HS group following treatment with LOS alone. However, kidney aldosterone levels were significantly reduced in the presence of LOS in the HS group. Total cholesterol, LDL cholesterol, and triglycerides were significantly higher in the LR group. Together, these data suggest a contribution of endogenous NO and PGs in the antihypertensive effect of LOS and SIM that may be affected by the type of diet.