Central Pressor Research Articles

Central pressor effects induced by muscarinic receptor agonists: Evidence for a predominant role of the M 2 receptor subtype

The cardiovascular effects induced in the rat several muscarinic receptor agonists were studied. All the agonists produced a clear decrease in heart rate. This decrease appeared to be peripherally mediated, because it was antagonized by methylscopolamine. The effects on blood pressure varied depending on the presence of anaesthesia, previous treatments and the type of agonists tested. When peripheral muscarinic activity was blocked by administration of methylscopolamine, a dose-dependent hypertension was obtained following the injection of oxotremorine, arecoline and aceclidine, by both intraperitoneal and intracerebroventricular routes. The muscarinic receptor agonist RS 86 produced a slight increase in blood pressure but the increase was weaker than those observed with the agonists cited above. On the other hand, the muscarinic receptor agonists pilocarpine, AF-30 and McN-A-343, considered as partially M 1-selective compounds, did not produce any effect on blood pressure. Moreover, the hypertension induced by oxotremorine was completely blocked by intracerebroventricular administration of the non-subtype-selective muscarinic receptor antagonist scopolamine but was unaffected by the M 1-selective antagonist pirenzepine. We propose that the central hypertensive response induced by muscarinic receptor agonists in the unanaesthetized rat is, at least partially, mediated through the stimulation of the so-called M 2 muscarinic receptor subtype.

Differential Actions of Neuronal and Hormonal Vasopressin on Blood Pressure and Baroreceptor Reflex Sensitivity in Rats

The central cardiovascular actions of arginine vasopressin (AVP) and the role of this peptide in the modulation of baroreceptor reflex (BRR) sensitivity were investigated in conscious, chronically instrumented rats. Intracerebroventricular (i.c.v.) injections of AVP (1-100 ng) produced dose-dependent pressor effects together with increases in heart rate, splanchnic, and renal sympathetic nerve activity and a reduction of mesenteric blood flow. These responses were prevented by i.c.v. pretreatment with a V1-AVP receptor antagonist. Furthermore, the central pressor effects of AVP were abolished by peripheral alpha-adrenoceptor blockade with phentolamine. In contrast to the i.c.v. injections, intravenous (i.v.) or intracarotid injections of AVP produced pressor responses accompanied by bradycardia and a decrease in sympathetic nerve activity. Intracerebroventricular pretreatment with a V1-AVP receptor antagonist shifted the slope of the BRR curve (increases in pulse interval plotted against increases in systolic blood pressure in response to i.v. methoxamine) toward higher sensitivity, whereas i.v. pretreatment with a V2-AVP receptor antagonist shifted the slope of the BRR curve toward lower sensitivity of the reflex. These findings suggest that central (neuronal) AVP, by acting on V1-AVP receptors in the brain, participates in central pressor mechanisms, activates the sympathetic nervous system, and desensitizes the BRR. Conversely, circulating (hormonal) AVP can sensitize the BRR by acting on V2-AVP receptors accessible from the blood. Our data provide evidence pointing to a direct interaction between the neuronal and the hormonal axis of the AVP system within cardiovascular control.

Neurohumoral contributions to chronic angiotensin-induced hypertension.

A central pressor effect of angiotensin II (ANG II) has been implicated in the pathogenesis of several forms of experimental hypertension. Therefore, the present studies were designed to investigate mechanisms that contribute to hypertension resulting from selective stimulation of brain ANG II receptors by chronic intracerebroventricular (ICV) infusion of ANG II. Specifically, the role of the sympathetic nervous system, the pressor actions of vasopressin, and the direct vasoconstrictor effect of blood-borne ANG II were investigated in rats made hypertensive by 5- to 7-day ICV ANG II infusions (6 micrograms/h). Rats were chronically instrumented with indwelling arterial and venous catheters and a lateral cerebral ventricular cannula. Acute intravenous infusion of the competitive ANG II receptor antagonist [Sar1-Ala8]ANG II during the period of ICV ANG II infusion resulted in a moderate decrease in arterial pressure, indicating that an increase in blood-borne ANG II may account for a small component of the hypertensive response to ICV ANG II. Activation of the sympathetic nervous system appeared to be the major contributor to the elevated arterial pressure, since acute ganglionic blockade and combined alpha- and beta-adrenergic blockade produced greater depressor responses in rats made hypertensive with chronic ICV ANG II infusion than in normotensive rats. Furthermore, peripheral sympathectomy delayed hypertension development. Intravenous administration of a specific antagonist of the vascular vasopressin receptor did not cause a depressor response in rats made hypertensive with chronic ICV ANG II infusions. These studies demonstrate that a major mechanism involved in the pressor response to acute ICV ANG II injections, namely vasopressin release, does not appear to contribute to hypertension produced by chronic ICV infusions of ANG II. Rather, this form of hypertension is characterized predominantly by an increase in sympathetic vasoconstrictor tone and possibly by a mechanism activated by a small increase in circulating levels of ANG II.

Centrally-induced vasodepressor responses to diltiazem, a calcium channel blocker, in rats.

The effects of a calcium channel blocker, diltiazem, on central cardiovascular regulation were investigated by injecting it intracerebroventricularly (i.c.v.) in urethane-anaesthetized rats. The blood pressure decreased immediately after the injection returning to baseline level 20-30 min later. Both heart rate and abdominal sympathetic nerve activity decreased correspondingly. Diltiazem injected intravenously (i.v.) decreased both blood pressure and heart rate without affecting sympathetic nerve firing. Although the central pressor responses to carbachol and prostaglandin E2 were not affected by i.c.v. pretreatment with diltiazem, diltiazem attenuated the pressor responses to angiotensin II. Furthermore, electrical lesioning of the anteroventral third ventricle (AV3V) area significantly attenuated the depressor responses to diltiazem injected i.c.v. These results suggest that diltiazem injected i.c.v. affects the central nervous system to decrease sympathetic outflow, and thereby to attenuate the central vasopressor effects of angiotensin II in the brain AV3V area.

Role of prostaglandins and the areas postrema in the central pressor action of bradykinin

Vertebral and carotid artery infusions of bradykinin increased blood pressure and heart rate in anaesthetised greyhounds. Indomethacin pretreatment abolished the pressor response to vertebral infusion and reduced that to carotid infusion. Areas postrema ablation abolished the pressor response to bradykinin with both routes of administration. The tachycardia responses to cranial artery infusions and the entire cardiovascular response to intravenous infusion were unaffected by either treatment. It is concluded that intact areas postrema and normal prostaglandin synthesis are essential for the full expression of the central pressor action of bradykinin.

Differential effects of central angiotensin II and substance P on sympathetic nerve activity in conscious rats. Implications for cardiovascular adaptation to behavioral responses.

The centrally induced effects of angiotensin II and substance P on the cardiovascular system and on neuronal efferent activity of the splanchnic, renal, and adrenal nerves were investigated in chronically instrumented conscious rats. The pressor responses to substance P injected into the lateral brain ventricle were accompanied by marked and short latency increases in heart rate, cardiac output, splanchnic, renal, and adrenal nerve activity, and a rise in plasma noradrenaline and adrenaline. Behaviorally, an arousal-type reaction was observed. In contrast, the pressor responses to intracerebroventricular angiotensin II were associated with initial decreases in heart rate, cardiac output, splanchnic, renal, and adrenal nerve activity, and a fall in plasma noradrenaline at the time of the maximal blood pressure increase. In some but not all animals, a second blood pressure peak associated with increases in heart rate and splanchnic nerve activity was observed after several minutes. Incomplete chronic sinoaortic baroreceptor deafferentiation prevented the angiotensin II-induced fall in heart rate but not the initial fall in splanchnic nerve activity. The decreases in splanchnic nerve activity also occurred in diabetes insipidus rats and persisted in Long Evans rats after vascular vasopressin receptor blockade with d(CH2)5AVP, despite marked reductions of the pressor responses in both groups. Peripheral alpha-adrenoceptor blockade with prazosin or ganglion blockade with hexamethonium inhibited the central angiotensin II pressor responses only in combination with vasopressin receptor blockade. On the other hand, either sympatholytic drug, alone, abolished the pressor responses in the diabetes insipidus rats. This indicates that in intact conscious rats the central pressor effects of angiotensin II are initiated by vasopressin release but become dependent on the sympathetic nervous system when vasopressin is absent or not effective. When rats were allowed to drink in response to angiotensin II, a further sharp rise in blood pressure occurred, together with increases in heart rate and splanchnic nerve activity. The results demonstrate fundamental differences in the mechanisms by which central pressor peptides can influence cardiovascular and autonomic function. It is conceivable that the distinct sympathetic response patterns to central angiotensin II and substance P receptor stimulation form part of a specific cardiovascular adjustment to the individual behavioral reactions, such as drinking, as in the case of angiotensin II, or arousal within the central processing of pain, as in the case of substance P.

Studies on the role of intracellular sodium and calcium in the centrally mediated pressor effects of CSF [Na+], ouabain and angiotensin II in anesthetized dogs.

Cerebroventricular infusions of hyperosmotic Na+ solutions, ouabain and/or Angiotensin-II produced significant increases in the arterial blood pressure in chloralose anesthetized, vagotomized dogs. A lower concentration of ouabain (10(-6) M) which did not alter blood pressure, significantly potentiated the centrally mediated pressor effects of hyperosmotic Na+ and angiotensin-II. Hence, the data suggested that the magnitude of the central pressor effects of Angiotensin-II or hyperosmotic Na+ may depend upon net accumulation of sodium in the neuronal cells. Prior cerebroventricular infusions of felodipine, a "calcium antagonist," significantly inhibited the pressor actions of higher concentrations of ouabain as well as that of hyperosmotic Na+-solutions, indicating that cellular calcium may be essential for triggering these central effects. These studies collectively indicate that disturbances in the Na+-transport in the neuronal cells may account for the involvement of the central nervous system in various types of hypertension.

GABA agonists inhibit central sodium-induced vasopressin-dependent increases in arterial pressure

Previous studies have demonstrated that intraventricular (i.v.t.) administration of low doses of GABA agonists reduced the central pressor effects of cerebrospinal fluid (CSF) made hypertonic with sodium (Na). The following studies were designed to determine if GABA agonists acted to decrease the pressor response of Na through inhibition of the vasopressin-dependent pressor component. Following pretreatment with vascular vasopressin antagonist, the pressor response of i.v.t. administered Na was reduced approximately 60%. Hypophysectomy produced a similar reduction in the pressor eesponse elicited by hypertonic CSF. These results indicate that vasopressin contributed to approximately 60% of the pressor response of Na. In order to generate a vasopressin-dependent pressor response, the sympathetic nervous system was eliminated with ganglionic blockade by chlorisondamine. The increase in arterial pressure produced by i.v.t. injection of hypertonic CSF was augmented after ganglionic blockade compared to untreated rats. The augmented pressor effect of i.v.t. administered Na was markedly reduced by the vascular vasopressin antagonist or by hypophysectomy. Therefore, the pressor effect of Na after ganglionic blockade was caused almost entirely by the pressor actions of arginine-vasopressin (AVP). This AVP-dependent pressor effect of i.v.t. injected Na in rats subjected to ganglionic blockade was reduced by pretreatment with 100 μg of GABA or 50 ng of the GABA agonist muscimol. These doses of GABA and muscimol have previously been shown to reduce the pressor response of i.v.t. administered Na in untreated rats. Thus, pretreatment with low doses of GABA agonists reduced the pressor effect of Na in part through inhibition of the vasopressin component of the pressor response. GABA pretreatment also antagonized the increase in plasma AVP levels produced by i.v.t. administered hypertonic CSF.

Localization of the central pressor action of bradykinin to the cerebral third ventricle.

Bradykinin injected into the lateral ventricle produces a rise in blood pressure. Cream plugs selectively localized to discrete regions of the ventricular system were used to block drug access to periventricular sites. Third ventricular plugs blocked the pressor response to lateral ventricular injections of 5 micrograms bradykinin (27 +/- 5 before vs. 5 +/- 5 mmHg after plug, n = 7) and 100 ng angiotensin II (22 +/- 3 before vs. 4 +/- 2 mmHg after plug, n = 5). Third ventricular plugs also suppressed the drinking response to angiotensin II (3.7 +/- 0.6 before vs. 0.9 +/- 0.6 ml after plug, n = 5). However, plugs that occluded the fourth ventricle failed to suppress the central bradykinin pressor response (27 +/- 8 before vs. 35 +/- 9 mmHg after plug, n = 5). The data suggest that the central bradykinin pressor response has a site of action similar to that of angiotensin II in the ventral third ventricle.

Anteroventral hypothalamus and hemorrhagic shock: cardiovascular and neuroendocrine responses

The anteroventral third ventricle (AV3V) region was shown to be a site of central integration of sympathetic pressor pathways and central pressor and vasopressin (VP) release by angiotensin II (ANG II). Since the AV3V area seems to have an important role in the regulation of the three major pressor systems, we investigated the role of the AV3V in cardiovascular recovery after hemorrhage, a known stimulus for sympathetic, ANG II, and VP release. Conscious AV3V-lesioned (n = 19) and sham-operated rats (n = 14) underwent bleeding (40% of blood volume) through an arterial line. Mean blood pressure, heart rate, and plasma ANG II, VP, and catecholamines were monitored over 24 h. The exact site of lesion was determined by microscopic examination. The mean blood pressure and heart rate of both groups of rats were not different before or after hemorrhage. Plasma catecholamines, ANG II, and VP responses were also the same as were hematocrit and water consumption 24 h after the bleeding. Despite the lack of difference between control and lesioned animals with regard to cardiovascular, humoral, and neuroendocrine responses to hypovolemia, the AV3V-lesioned rats had a significantly higher early mortality rate. These data indicate that the AV3V may be an important region in recuperation and survival after hemorrhagic shock, but through mechanisms unrelated to activation of VP, renin-ANG II, or the sympathetic nervous system.

The angiotensin II pressor system of the rat forebrain.

An anterior hypothalamic knife cut that leaves intact two central sites of action of angiotension II produces the same deficits in the pressor responses to angiotensin II that have been attributed to destruction of two circumventricular organs (the subfornical organ and the organum vasculosum of the lamina terminalis). The central pressor actions of angiotensin II are necessary for the full expression of renin-dependent renal hypertension. The anterior hypothalamic knife cut attenuates renin-dependent aortic ligation hypertension. It has been shown that electrolytic destruction more anterior to this knife cut, in the anteroventral 3rd ventricle region, also attenuates two forms of renin-dependent hypertension, aortic ligation hypertension and two-kidney Goldblatt hypertension in the rat. Electrolytic lesions in the subfornical organ also reduce renin-dependent, two-kidney Goldblatt hypertension. These data are consistent with the hypothesis that a common efferent system from the organum vasculosum of the lamina terminalis and subfornical organ mediates the central pressor response to angiotensin II and is involved in the development of renin-dependent hypertension. A model is proposed for the circuitry in the rat forebrain that is involved in the pressor response to angiotensin II.

Pressor responses to intracisternal injection of hypertonic NaCl in rats.

Hypertonic NaCl solution injected into the cisterna magna of anesthetized rats produced dose-dependent pressor responses accompanied by slight tachycardia. Similar injections of hypertonic urea solution were ineffective. Because the early phase of the pressor response to hypertonic NaCl was always accompanied by increased sympathetic nerve firing and was inhibited following alpha-adrenergic blockade with phentolamine, initial pressor response was attributed to sympathetic hyperactivity. On the other hand, because the later phase of the pressor response was unaffected either by adrenalectomy or by alpha-adrenergic blockade, but was significantly inhibited by hypophysectomy or by pretreatment with a vasopressin antagonist, the later pressor response was ascribed to an increased release of endogenous vasopressin. Thus, our findings indicate that central pressor responses to hypertonic NaCl solution involve two different mechanisms: sympathetic hyperactivity in the early phase and vasopressin release during the later phase. In spontaneously hypertensive rats (SHR), both pressor and sympathetic responses to intracisternally injected NaCl were greater than in Wistar-Kyoto rats (WKY). Our results further indicate hypersensitivity to NaCl around the brain stem in SHR, which could account for the increased sympathetic activity and cause SHR to develop hypertension.

Modification of the cardiovascular response to enkephalin by preoptic-hypothalamic periventricular lesions

The cardiovascular effects of central and peripheral injection of [D-Ala2]-methionine-enkephalin were examined in rats with electrolytic lesions of anteroventral third ventricle periventricular tissue (AV3V). Sham-operated rats demonstrated a biphasic increase in blood pressure and a tachycardia after intracerebroventricular injection and an increase in blood pressure following intravenous injection. AV3V-lesions blunted the initial component of the central pressor response but did not affect the peripheral response. The AV3V region appears to mediate a portion of the blood pressure response to central enkephalin. The cardiovascular effects of enkephalin are complex and are probably mediated by more than one locus in the central nervous system. Intracerebroventricular (icv) and intravenous (iv) injections of the methionine-enkephalin analogue [D-Ala2]-met-enkephalin (DAME) increase blood pressure in conscious rats (Rockhold, Crofton and Share, 1981). However, the central nervous system sites upon which enkephalins act to cause cardiovascular changes are not yet defined. A circumventricular organ, the organum vasculosum of the lamina terminalis (OVLT), is of particular interest in this regard. The OVLT contains neuronal elements which demonstrate enkephalin-like immunoreactivity (Finley, Maderdrut and Petrusz, 1980) and electrolytic lesions of periventricular tissue of the antero-ventral third ventricle (AV3V) region (which includes the OVLT) abolish the pressor response to icv administration of another peptide hormone, angiotensin II (Bealer, Phillips, Johnson and Schmid, 1979). Such data suggest that the AV3V region may play a role in enkephalin-induced cardiovascular changes. The present investigation examines cardiovascular effects following icv and iv administration of DAME in sham-operated and AV3V-lesioned rats.

Effects of calcium antagonists on central pressor and dipsogenic activities of angiotensin II in rats.

Effects of calcium antagonists on central pressor and dipsogenic activities of angiotensin II in rats.

Hemodynamic effects of angiotensin II and bradykinin infused intraventricularly in conscious dogs.

A1 though angiotensin I1 (A-11) is a potent direct vasoconstrictor and bradykinin (BK) a potent direct vasodilator, both peptides elicit pressor responses when administered intraventricular ly (IVT) (1). The cardiac and regional changes associated with this rise in pressure in conscious animals remain undocumented. In addition, it is difficult to evaluate t he relative potency of these neuropeptides, since the data reported have been obtained using different doses, species, and anesthetics. The differences between the hemod namic roperties of A-I1 administered IVT or intravenously {IV~ are afso unclear for similar reasons. such a comparison might be of interest to discuss the potential role of these peptides in the central r egulation of blood pressure, especially since the AV3V, a paraventricular region, has been demonstrated to be implicated in the central pressor effect of A-11 in dogs (2). This study was desi ned to investigate and compare the hemodynamic properties of ?/ IVT infusions of A-I1 and BK and 2/ IVT vs IV A-I1 infusions in awake chronically instrumented dogs.

Centrally-induced vasopressor responses to sodium-potassium adenosine triphosphatase inhibitor, ouabain, may be mediated via angiotensin II in the anteroventral third ventricle in the brain.

Central cardiovascular effects of the sodium-potassium adenosine triphosphatase (Na+, K+-ATPase) inhibitor, ouabain, were investigated by injecting it intracerebroventricularly (ICV) using conscious Wistar rats. Ouabain, 0.1-10 micrograms injected ICV, produced dose-related pressor responses attaining peak elevations after about 5 min. To investigate the underlying mechanisms of these central pressor responses, angiotensin II blockers were injected ICV before the injections of ouabain. 1-Sar, 8-Ile angiotensin II (ang IIa), 50 micrograms, given 3 min before the ouabain, abolished the pressor responses to ouabain, 5 micrograms. Angiotensin I converting enzyme inhibitor (CEI, captopril), 100 micrograms, also significantly attenuated the pressor responses to ouabain. Since previous results with ICV injections of ouabain suggested that the pressor responses are mediated via a release of brain angiotension II, and the site of action of brain angiotensin II is believed to be the anteroventral third ventricle (AV3V) area of the brain, ICV injections of ouabain were repeated using rats whose AV3V areas had been destroyed electrically. The pressor responses were smaller in the AV3V lesioned rats than in sham-operated rats. The abdominal sympathetic nerve activity was recorded using three conscious, normotensive Wistar rats. ICV injections of ouabain, 5 micrograms, elicited pressor responses as described above and these were accompanied by a corresponding increase in the nerve firing, lasting for 5-7 min. These responses were again abolished by pretreatment with an angiotensin II antagonist. These results suggest that centrally administered ouabain elicits vasopressor responses which increase peripheral sympathetic nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of the central pressor action of angiotensin II in conscious rats.

Previous studies have demonstrated that, due to a central action, angiotensin II (ANG II) infused via the carotid artery of the rat elicited a greater pressor response than ANG II infused via the abdominal aorta. In the present study, regional vascular resistance responses to carotid and abdominal aortic infusions of ANG II and angiotensin I (ANG I) were compared in conscious unrestrained rats. Miniaturized pulsed Doppler flow probes were used to record regional blood flows. Carotid and aortic infusions caused vasoconstriction in the hindquarters, renal, and mesenteric vascular beds; the carotid route resulted in greater increases in arterial pressure and regional vascular resistances. The enhanced vasoconstrictor responses to carotid infusions of ANG II were significantly attenuated by systemic hexamethonium or central saralasin. Unlike ANG II, carotid and aortic infusions of ANG I produced equivalent regional vasoconstrictor responses not affected by central saralasin. It is concluded that in addition to its peripheral effects, central actions of ANG II induce neurally mediated vasoconstriction of the hindquarters, renal, and mesenteric vascular beds. Central effects of ANG II do not appear to result from conversion in the brain of blood-borne ANG I.

Inhibition of pressor responses induced by electrical stimulation of the mesencephalon by vasopressin and oxytocin.

Receptors for vasopressin are present in blood vessels, kidney and the brain. Earlier studies indicated that the memory and learning effects of vasopressin are exerted via receptor sites in the brain and that the classical hormonal effects in the periphery can be dissociated in the molecule from the central action. Vasopressin also affects blood pressure regulation. Arg8-vasopressin (AVP) and oxytocin upon intracerebroventricular administration reduced the pressor response elicited by electrical stimulation of the rat mesencephalic reticular formation. Desglycinamide-AVP also exerted this effect. Lesion and microinjection studies revealed that the dentate gyrus of the hippocampus may be a site of action of AVP or its active fragments, inhibiting central pressor responses. Oxytocin appeared to act on structures in the vicinity of the fourth cerebral ventricle.

Transection of subfornical organ neural connections diminishes the pressor response to intravenously infused angiotensin II

Knife-cut lesions were used to assess the participation of the subfornical organ (SFO) in the central pressor action of intravenously administered angiotensin. Knife-cuts of the ventral stalk of the SFO significantly attenuated pressor responses during infusion of 3 doses of angiotensin, although responses to bolus injections were unaffected. These results are consistent with previous work in implicating the SFO as an important mediator of the central pressor action of circulating angiotensin.

Central cardiovascular effects of mammalian neurohypophyseal peptides in conscious rats

To confirm and extend the results of previous studies which demonstrated central cardiovascular effects of vasopressin in anesthetized rats, we determined blood pressure and heart rate changes for 30 minutes after intracerebroventricular injections of arginine vasopressin, arginine vasotocin and oxytocin in conscious rats. As compared to sham injections, significantly greater increases in either systolic or diastolic blood pressure were noted over the 30 minutes which followed the injection of 0.15, 1.0 or 10.0 nM of either vasopressin or vasotocin. In animals given vasopressin, plasma levels of the peptide were determined. There was a substantial increase in plasma vasopressin only after the highest dose. Overall blood pressure responses to doses of oxytocin as high as 100 nM were not significantly different than sham injections. Heart rate following both vasopressin and vasotocin was increased at 0.15 nM, was initially decreased then increased at 1.0 nM and was substantially decreased after the 10.0 nM dose. There was a significant increase in heart rate at the 10.0 nM and 100 nM doses of oxytocin. Dose response curves for systolic blood pressure and heart rate 20 minutes after injection were similar for vasopressin and vasotocin. We conclude that arginine vasopressin has significant central pressor and tachycardic effects in conscious rats, and it is related, at least in part, to the tail structure of the peptide, which is shared with arginine vasotocin.