Imidazoline receptors, novel agents and therapeutic potential.

The initial realization that agents containing an imidazoline structure may interact with a distinct class of receptors, has led to a major class of cardiovascular agents, which now has the potential to enter a third generation. There is now general acceptance that there are three main imidazoline receptor classes, the I(1) imidazoline receptor which mediates the sympatho-inhibitory actions to lower blood pressure, the I(2) receptor which is an important allosteric binding site of monoamine oxidase and the I(3) receptor which regulates insulin secretion from pancreatic beta cells. Thus all three represent important targets for cardiovascular research. Interestingly, an I(1)- receptor candidate has been cloned (IRAS, imidazoline receptor antisera selected) which is a homologue of the mouse cell adhesion integrin binding protein Nischarin. There has been range of new agonists and antagonists with very high selectivity for I(1), I(2) and I(3) receptors developed. Three different endogenous ligands have been characterized including agmatine (decarboxylated arginine), a range of beta-carbolines including harman and harmane, and more recently imidazoleacetic acid-ribotide. The imidazoline field has recently seen an enormous diversification with discoveries that I(1) and I(2) receptors also play a role in cell proliferation, regulation of body fat, neuroprotection, inflammation and some psychiatric disorders such as depression. This diversification has continued with the addition of effective agents with imidazoline affinity in the fields of cancer, pain and opioid addiction, stress, cell adhesion, epilepsy and appetite. The imidazoline field has maturated considerably with a range of highly selective leader molecules, candidate receptors and endogenous ligands. We are therefore only at the threshold of an exciting new era as we begin to understand the diverse and complex nature of their function.

Angiotensin and baroreflex control of the circulation.

There is a close association between the location of angiotensin (Ang) receptors and many important brain nuclei involved in the regulation of the cardiovascular system. The present review encompasses the physiological role of Ang II in the brainstem, particularly in relation to its influence on baroreflex control of the heart and kidney. Activation of AT1 receptors in the brainstem by fourth ventricle (4V) administration to conscious rabbits or local administration of Ang II into the rostral ventrolateral medulla (RVLM) of anesthetized rabbits acutely increases renal sympathetic nerve activity (RSNA) and RSNA baroreflex responses. Administration of the Ang antagonist Sarile into the RVLM of anesthetized rabbits blocked the effects of Ang II on the RSNA baroreflex, indicating that the RVLM is the major site of sympathoexcitatory action of Ang II given into the cerebrospinal fluid surrounding the brainstem. However, in conscious animals, blockade of endogenous Ang receptors in the brainstem by the 4V AT1 receptor antagonist losartan resulted in sympathoexcitation, suggesting an overall greater activity of endogenous Ang II within the sympathoinhibitory pathways. However, the RSNA response to airjet stress in conscious rabbits was markedly attenuated. While we found no effect of acute central Ang on heart rate baroreflexes, chronic 4V infusion inhibited the baroreflex and chronic losartan increased baroreflex gain. Thus, brainstem Ang II acutely alters sympathetic responses to specific afferent inputs thus forming part of a potentially important mechanism for the integration of autonomic response patterns. The sympathoexcitatory AT1 receptors appear to be activated during stress, surgery and anesthesia.

Angiotensin and baroreflex control of the circulation

There is a close association between the location of angiotensin (Ang) receptors and many important brain nuclei involved in the regulation of the cardiovascular system. The present review encompasses the physiological role of Ang II in the brainstem, particularly in relation to its influence on baroreflex control of the heart and kidney. Activation of AT1 receptors in the brainstem by fourth ventricle (4V) administration to conscious rabbits or local administration of Ang II into the rostral ventrolateral medulla (RVLM) of anesthetized rabbits acutely increases renal sympathetic nerve activity (RSNA) and RSNA baroreflex responses. Administration of the Ang antagonist Sarile into the RVLM of anesthetized rabbits blocked the effects of Ang II on the RSNA baroreflex, indicating that the RVLM is the major site of sympathoexcitatory action of Ang II given into the cerebrospinal fluid surrounding the brainstem. However, in conscious animals, blockade of endogenous Ang receptors in the brainstem by the 4V AT1 receptor antagonist losartan resulted in sympathoexcitation, suggesting an overall greater activity of endogenous Ang II within the sympathoinhibitory pathways. However, the RSNA response to airjet stress in conscious rabbits was markedly attenuated. While we found no effect of acute central Ang on heart rate baroreflexes, chronic 4V infusion inhibited the baroreflex and chronic losartan increased baroreflex gain. Thus, brainstem Ang II acutely alters sympathetic responses to specific afferent inputs thus forming part of a potentially important mechanism for the integration of autonomic response patterns. The sympathoexcitatory AT1 receptors appear to be activated during stress, surgery and anesthesia

Telemetric blood pressure monitoring in conscious rats before and after compression injury of spinal cord.

Abnormal cardiovascular control after spinal cord injury (SCI) results in hypotension soon after injury. Later, paroxysmal hypertension and bradycardia in response to sensory stimulation below the level of injury develop in most people with SCI. In this study, we used a radiotelemetry system, in rats (n = 7), to investigate the effect of a clinically relevant compression model of SCI at T5 spinal segment on mean arterial pressure (MAP) and heart rate (HR) at rest and in response to colorectal distension. The transducers were implanted 1 month before clip compression (50-g) injury and continuous recording of MAP and HR was established for a period of 2.5 months. SCI was associated with hypotension (86+/-3 mm Hg) at 1 day after injury. In the following 2 days, MAP gradually returned to preinjury levels. By contrast, HR increased at 1 day after SCI and remained unchanged thereafter. Three days after SCI, colorectal distension caused an increase in MAP of 8+/-2 mm Hg accompanied by bradycardia (-18 bpm). One week after SCI, colorectal distension induced an increase in MAP of 9+/-2 mm Hg and bradycardia (-41 bpm). In the following days, the magnitude of reflex hypertension gradually increased, reaching 21+/-4 mm Hg at 1.5 months after SCI. In summary, our data show that resting MAP rapidly returns to control values after SCI. Episodic hypertension associated with autonomic dysreflexia can develop in rats within 1 month after incomplete SCI.

Central angiotensin and baroreceptor control of circulation.

Angiotensin (Ang) receptors are located in many important central nuclei involved in the regulation of the cardiovascular system. While most interest has focused on forebrain circumventricular actions, areas of the brainstem such as the nucleus of the solitary tract and the ventrolateral medulla contain high concentrations of AT1 receptors. The present review encompasses the physiological role of Ang II in the hindbrain, particularly in relation to its influence on baroreflex control mechanisms. In rabbits there are sympatho-excitatory AT1 receptors in the rostral ventrolateral medulla (RVLM), accessible to Ang II from the cerebrospinal fluid. Activation of these receptors acutely increases renal sympathetic nerve activity (RSNA) and RSNA baroreflex responses. However, blockade of endogenous Ang receptors in the brainstem also shows sympathoexcitation, suggesting there is greater endogenous activity of a sympathoinhibitory Ang II action. Microinjections of angiotensin antagonists into the RVLM showed relatively little tonic activity of endogenous Ang II influencing sympathetic activity in conscious rabbits. However, Ang II receptors in the RVLM mediate sympathetic responses to airjet stress in conscious rabbits. Similarly with respect to heart rate baroreflexes, there appears to be little tonic effect of angiotensin in the brainstem in normal conscious animals. Chronic infusion of Ang II for two weeks into the fourth ventricle of conscious rabbits inhibits the cardiac baroreflex while infusion of losartan increases the gain of the reflex. These actions suggest that Ang II in the brainstem modulates sympathetic responses depending on specific afferent and synaptic inputs in both the short term but importantly also in the long term, thus forming an important mechanism for increasing the range of adaptive response patterns.

Relative importance of rostral ventrolateral medulla in sympathoinhibitory action of rilmenidine in conscious and anesthetized rabbits.

The pressor region of the rostral ventrolateral medulla (RVLM) is a critical site in the sympathoinhibitory action of imidazoline receptor agonists as shown by studies in anesthetized animals. The aim of this study was to compare the importance of the RVLM in mediating the inhibitory action of rilmenidine on renal sympathetic nerve activity (RSNA) and arterial pressure in urethane-anesthetized rabbits (n = 11) and in conscious, chronically instrumented rabbits (n = 6). Bilateral microinjection of rilmenidine (4 nmol in 100 nl) into the RVLM caused a greater decrease in resting arterial pressure in anesthetized animals (-19 mm Hg) than in conscious animals (-8 mm Hg). By contrast, the decrease in resting RSNA evoked by rilmenidine was similar in conscious (-27%) and anesthetized (-36%) rabbits. Furthermore, rilmenidine microinjection into the RVLM was equally effective in inhibiting the RSNA baroreflex in both groups of animals. The upper plateau of the RSNA baroreflex decreased by 37% and 42%, and gain decreased by 41% and 44% after rilmenidine treatments in conscious and anesthetized rabbits, respectively. We conclude that the RVLM plays an equally important role in the inhibitory action of rilmenidine on RSNA in conscious and anesthetized rabbits either at rest or during baroreflex responses. A relatively moderate effect of rilmenidine on arterial pressure in conscious, chronically instrumented rabbits may relate to a lower level of sympathetic drive compared with anesthetized animals.

Influence of rostral ventrolateral medulla on renal sympathetic baroreflex in conscious rabbits.

Previous studies with anesthetized animals have shown that the pressor region of the rostral ventrolateral medulla (RVLM) is a critical site in vasomotor control. The aim of this study was to develop, in conscious rabbits, a technique for microinjecting into the RVLM and to determine the influence of this area on renal sympathetic nerve activity (RSNA) and arterial pressure (AP) using local injections of glutamate, rilmenidine, ANG II and sarile. Rabbits were implanted with guide cannulas for bilateral microinjections into the RVLM (n = 7) or into the intermediate ventrolateral medulla (IVLM, n = 6) and an electrode for measuring RSNA. After 7 days of recovery, injections of glutamate (10 and 20 nmol) into the RVLM increased RSNA by 81 and 88% and AP by 17 and 25 mmHg, respectively. Infusion of glutamate (2 nmol/min) into the RVLM increased AP by 15 mmHg and the RSNA baroreflex range by 38%. By contrast, injection of the imidazoline receptor agonist rilmenidine (4 nmol) into the RVLM decreased AP by 8 mmHg and the RSNA baroreflex range by 37%. Injections of rilmenidine into the IVLM did not alter AP or RSNA. Surprisingly, treatments with ANG II (4 pmol/min) or the ANG II receptor antagonist sarile (500 pmol) into the RVLM did not affect the resting or baroreflex parameters. Infusion of ANG II (4 pmol/min) into the fourth ventricle increased AP and facilitated the RSNA baroreflex. Our results show that agents administered via a novel microinjecting system for conscious rabbits can selectively modulate neuronal activity in circumscribed regions of the ventrolateral medulla. We conclude that the RVLM plays a key role in circulatory control in conscious rabbits. However, we find no evidence for the role of ANG II receptors in the RVLM in the moment-to-moment regulation of AP and RSNA.